It seems anachronistic that we still debate how best to fix the plumbing of clogged arteries. Our understanding of the pathogenesis of acute coronary syndromes has evolved in leaps and bounds since the first attempts at coronary revascularization. And yet, as Aggarwal et al discuss in their analysis of the FREEDOM trial,¹ practical and technical questions about how best to open coronary blockages remain clinically relevant, even as we develop strategies to reverse the atherosclerotic processes that created those blockages.

Many acute coronary events arise not from coronary stenoses but from unstable, vulnerable plaques, which may be a distance away from the stable stenoses and thus undetectable. These unstable plaques, embedded within the remodeled arterial wall and without a protective fibrous cap, may rupture and cause an acute thrombotic occlusion. Statins, aspirin, and perhaps anti-inflammatory drugs (now including colchicine) decrease acute coronary events, likely by interfering with the chain of events initiated by plaque rupture.

So why should coronary artery bypass grafting (CABG) be superior to drug-eluting stents (with antiplatelet therapy) in some diabetic patients, as the FREEDOM trial¹ found?

Stenting and balloon dilation repair discrete areas of critical narrowing presumed to be contributing to downstream myocardial ischemia. But areas of vulnerable, non-calcified plaque (with outward remodeling of the vessel wall but generally preserved lumen integrity) may be geographically separated from the identified stenosis and thus be left untreated by stenting. On the other hand, CABG may circumvent “silent” areas of nascent vulnerable plaque that, if left in place, might later rupture and cause acute syndromes or death.

This explanation is clearly hypothetical and one of many possibilities. But paying attention to the new biology of the atherosclerotic process should lead us all to be more aggressive in using treatments shown to reduce the progression of coronary artery disease and the occurrence of acute coronary syndromes. This is especially true in patients with diabetes who are known to have diffuse coronary involvement. So even as we more fully recognize the value of CABG in these patients, perhaps if we intervene earlier—with statins, hypertension control, improved diet, smoking cessation, prevention of chronic kidney disease, antiplatelet therapy, and anti-inflammatory therapy—we will not need it.

It seems anachronistic that we still debate how best to fix the plumbing of clogged arteries. Our understanding of the pathogenesis of acute coronary syndromes has evolved in leaps and bounds since the first attempts at coronary revascularization. And yet, as Aggarwal et al discuss in their analysis of the FREEDOM trial,¹ practical and technical questions about how best to open coronary blockages remain clinically relevant, even as we develop strategies to reverse the atherosclerotic processes that created those blockages.

Many acute coronary events arise not from coronary stenoses but from unstable, vulnerable plaques, which may be a distance away from the stable stenoses and thus undetectable. These unstable plaques, embedded within the remodeled arterial wall and without a protective fibrous cap, may rupture and cause an acute thrombotic occlusion. Statins, aspirin, and perhaps anti-inflammatory drugs (now including colchicine) decrease acute coronary events, likely by interfering with the chain of events initiated by plaque rupture.

So why should coronary artery bypass grafting (CABG) be superior to drug-eluting stents (with antiplatelet therapy) in some diabetic patients, as the FREEDOM trial¹ found?

Stenting and balloon dilation repair discrete areas of critical narrowing presumed to be contributing to downstream myocardial ischemia. But areas of vulnerable, non-calcified plaque (with outward remodeling of the vessel wall but generally preserved lumen integrity) may be geographically separated from the identified stenosis and thus be left untreated by stenting. On the other hand, CABG may circumvent “silent” areas of nascent vulnerable plaque that, if left in place, might later rupture and cause acute syndromes or death.

This explanation is clearly hypothetical and one of many possibilities. But paying attention to the new biology of the atherosclerotic process should lead us all to be more aggressive in using treatments shown to reduce the progression of coronary artery disease and the occurrence of acute coronary syndromes. This is especially true in patients with diabetes who are known to have diffuse coronary involvement. So even as we more fully recognize the value of CABG in these patients, perhaps if we intervene earlier—with statins, hypertension control, improved diet, smoking cessation, prevention of chronic kidney disease, antiplatelet therapy, and anti-inflammatory therapy—we will not need it.

It seems anachronistic that we still debate how best to fix the plumbing of clogged arteries. Our understanding of the pathogenesis of acute coronary syndromes has evolved in leaps and bounds since the first attempts at coronary revascularization. And yet, as Aggarwal et al discuss in their analysis of the FREEDOM trial,¹ practical and technical questions about how best to open coronary blockages remain clinically relevant, even as we develop strategies to reverse the atherosclerotic processes that created those blockages.

Many acute coronary events arise not from coronary stenoses but from unstable, vulnerable plaques, which may be a distance away from the stable stenoses and thus undetectable. These unstable plaques, embedded within the remodeled arterial wall and without a protective fibrous cap, may rupture and cause an acute thrombotic occlusion. Statins, aspirin, and perhaps anti-inflammatory drugs (now including colchicine) decrease acute coronary events, likely by interfering with the chain of events initiated by plaque rupture.

So why should coronary artery bypass grafting (CABG) be superior to drug-eluting stents (with antiplatelet therapy) in some diabetic patients, as the FREEDOM trial¹ found?

Stenting and balloon dilation repair discrete areas of critical narrowing presumed to be contributing to downstream myocardial ischemia. But areas of vulnerable, non-calcified plaque (with outward remodeling of the vessel wall but generally preserved lumen integrity) may be geographically separated from the identified stenosis and thus be left untreated by stenting. On the other hand, CABG may circumvent “silent” areas of nascent vulnerable plaque that, if left in place, might later rupture and cause acute syndromes or death.

This explanation is clearly hypothetical and one of many possibilities. But paying attention to the new biology of the atherosclerotic process should lead us all to be more aggressive in using treatments shown to reduce the progression of coronary artery disease and the occurrence of acute coronary syndromes. This is especially true in patients with diabetes who are known to have diffuse coronary involvement. So even as we more fully recognize the value of CABG in these patients, perhaps if we intervene earlier—with statins, hypertension control, improved diet, smoking cessation, prevention of chronic kidney disease, antiplatelet therapy, and anti-inflammatory therapy—we will not need it.

Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.^1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.^3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.⁶

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.⁷

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial⁸ was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.

WHY ARE DIABETIC PATIENTS DIFFERENT?

Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.^9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.¹¹

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.¹² Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.^13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.¹⁵ Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.^16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.^18,19

BEFORE THE FREEDOM TRIAL

The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),^5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 1^20–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.⁵

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)²¹ and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) ²² were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

The ARTS trial (Arterial Revascularization Therapy Study) compared PCI (with bare-metal stents) and CABG in 1,205 patients with multivessel coronary artery disease.²³ The mortality rate did not differ significantly between two treatment groups overall or in the diabetic subgroup. However, the repeat revascularization rate was higher with PCI than with CABG.

The SoS trial (Stenting or Surgery)²⁴ had similar results.

The ERACI II trial (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-Vessel Disease)²⁵ found no difference in mortality rates at 5 years with CABG vs PCI.

These trials were criticized, as none of them routinely used glycoprotein IIb/IIIa inhibitors with PCI, which by then had been shown to reduce mortality rates.³⁰ However, these trials made it clear that restenosis requiring repeat revascularization was a major disadvantage of PCI with bare-metal stents compared with CABG in patients with diabetes. Drug-eluting stents, which significantly reduced the rates of in-stent restenosis and target-lesion revascularization, were expected to overcome this major disadvantage.

Studies of PCI with drug-eluting stents vs CABG

ARTS II was the first trial to compare PCI with drug-eluting stents vs CABG. This was a nonrandomized single-arm study of 607 patients (including 159 with diabetes) who were treated with drug-eluting stents; the outcomes were compared with the CABG group from the earlier ARTS trial.³¹

At 3 years, in the diabetic subgroup, the rates of death, myocardial infarction, and stroke were not significantly different between treatments, although a trend favored PCI. However, this comparison was limited by selection bias, as ARTS II was a nonrandomized trial in which operators chose patients for drug-eluting stents in an attempt to match already known outcomes from the CABG cohort of ARTS.

SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) was the first randomized trial comparing PCI with drug-eluting stents (in this trial, paclitaxel-eluting) vs CABG in patients with three-vessel or left main coronary artery disease.^26,27 Subgroup analysis in patients with diabetes mellitus revealed a higher rate of major adverse cardiac and cerebrovascular events (death, myocardial infarction, stroke, or repeat revascularization) in the PCI group than in the CABG patients, largely driven by higher rates of repeat revascularization after PCI.^32,33 SYNTAX was not designed to assess significant differences in rates of death.

The CARDIa trial (Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and multivessel coronary artery disease to PCI (about one-third with bare-metal stents and two-thirds with drug-eluting stents) or CABG. Rates of major adverse cardiac and cerebrovascular events were higher in the PCI group, again largely driven by higher rates of repeat revascularization.⁴ CARDIa was stopped early because of a lack of enrollment and could not provide sufficient evidence to endorse one strategy over the other.

VA-CARDS (Veteran Affairs Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and proximal left anterior descending artery or multivessel coronary artery disease to receive PCI with drug-eluting stents or CABG.²⁸ Although the rate of death was lower with CABG than with PCI at 2 years, the trial was underpowered and was terminated at 25% of the initial intended patient enrollment. In addition, only 9% of diabetic patients screened were angiographically eligible for the study.²⁹

Registry data. Analysis of a large data set from the National Cardiovascular Disease Registry and the Society of Thoracic Surgeons revealed a survival advantage of CABG over PCI for a follow-up period of 5 years.³⁴ However, this was a nonrandomized study, so its conclusions were not definitive.

THE FREEDOM TRIAL

Given the limitations of the trials described above, the National Heart, Lung, and Blood Institute sponsored the FREEDOM trial—an appropriately powered, randomized comparison of PCI (with drug-eluting stents) and CABG (using arterial grafting) in patients with diabetes and multivessel coronary artery disease using contemporary techniques and concomitant optimal medical therapy.⁸

FREEDOM study design

The FREEDOM trial enrolled 1,900 patients with diabetes and angiographically confirmed multivessel coronary artery disease (83% with three-vessel disease) with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary-artery territories. The main exclusion criteria were severe left main coronary artery stenosis (≥ 50% stenosis), class III or IV congestive heart failure, and previous CABG or valve surgery. For CABG surgery, arterial revascularization was encouraged.

Dual antiplatelet therapy was recommended for at least 12 months in patients receiving a drug-eluting stent, and optimal medical management for diabetes, hypertension, and hyperlipidemia was strongly advocated.

Between April 2005 and April 2010, 32,966 patients were screened, of whom 3,309 were eligible for the trial and 1,900 consented and were randomized (953 to the PCI group and 947 to the CABG group). The patients were followed for a minimum of 2 years and had a median follow-up time of 3.8 years. Outcomes were measured with an intention-to-treat analysis.

Study results

Patients. The groups were comparable with regard to baseline demographics and cardiac risk factors.

The mean age was 63; 29% of the patients were women, and 83% had three-vessel coronary artery disease. The mean hemoglobin A_1c was 7.8%, and the mean ejection fraction was 66%. The mean SYNTAX score, which defines the anatomic complexity of lesions, was 26 (≤ 22 is mild, 23–32 is intermediate, and ≥ 33 is high). The mean EURO score, which defines surgical risk, was 2.7 (a score ≥ 5 being associated with a lower rate of survival).

The primary composite outcome (death, nonfatal myocardial infarction, or nonfatal stroke) occurred less frequently in the CABG group than in the PCI group (Table 2). CABG was also associated with significantly lower rates of death from any cause and of myocardial infarction. Importantly, survival curves comparing the two groups diverged at 2-year follow-up. In contrast to other outcomes assessed, stroke occurred more often in the CABG group. The 5-year rates in the CABG group vs the PCI group were:

• Primary outcome—18.7% vs 26.6%, P = .005
• Death from any cause—10.9% vs 16.3%, P = .049
• Myocardial infarction—6% vs 13.9%, P < .0001
• Stroke—5.2% vs 2.4%, P = .03.

The secondary outcome (death, nonfatal myocardial infarction, nonfatal stroke, or repeat revascularization at 30 days or 12 months) had occurred significantly more often in the PCI group than in the CABG group at 1 year (16.8% vs 11.8%, P = .004), with most of the difference attributable to a higher repeat revascularization rate in the PCI group (12.6% vs 4.8%, P < .001).

Subgroup analysis. CABG was superior to PCI across all prespecified subgroups, covering the complexity of the coronary artery disease. Event rates with CABG vs PCI, by tertiles of the SYNTAX score:

• SYNTAX scores ≤ 22: 17.2% vs 23.2%
• SYNTAX scores 23–32: 17.7% vs 27.2%
• SYNTAX scores ≥ 33: 22.8% vs 30.6%.

Cost-effectiveness. Although up-front costs were higher with CABG, at $34,467 for the index hospitalization vs $25,845 for PCI (P < .001), when the in-trial results were extended to a lifetime horizon, CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI.³⁵ Traditionally, therapies are considered costeffective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.

WHY MAY CABG BE SUPERIOR IN DIABETIC PATIENTS?

The major advantage of CABG over PCI is the ability to achieve complete revascularization. Diabetic patients with coronary artery disease tend to have diffuse, multifocal disease with several stenotic lesions in multiple coronary arteries. While stents only treat the focal area of most significant occlusion, CABG may bypass all proximal vulnerable plaques that could potentially develop into culprit lesions over time, truly bypassing the diseased segments (Figure 1).

In addition, heavy calcification may not allow optimal stenting in these patients.

Use of multiple stents increases the risk of restenosis, which could lead to a higher incidence of myocardial infarction and need for repeat revascularization. This was evident in the FREEDOM trial, in which the mean number of stents per patient was 4.2. Also, some lesions need to be left untreated because of the complexity involved.

The major improvement in outcomes after CABG has resulted from using arterial conduits such as the internal mammary artery rather than the saphenous vein.³⁶ The patency rates of internal mammary artery grafts exceed 80% over 10 years.³⁷ Internal mammary artery grafting was done in 94% of patients receiving CABG in the FREEDOM trial.

WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis^38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.⁴⁰

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.^1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.^3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.⁶

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.⁷

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial⁸ was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.

WHY ARE DIABETIC PATIENTS DIFFERENT?

Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.^9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.¹¹

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.¹² Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.^13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.¹⁵ Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.^16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.^18,19

BEFORE THE FREEDOM TRIAL

The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),^5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 1^20–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.⁵

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)²¹ and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) ²² were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

The ARTS trial (Arterial Revascularization Therapy Study) compared PCI (with bare-metal stents) and CABG in 1,205 patients with multivessel coronary artery disease.²³ The mortality rate did not differ significantly between two treatment groups overall or in the diabetic subgroup. However, the repeat revascularization rate was higher with PCI than with CABG.

The SoS trial (Stenting or Surgery)²⁴ had similar results.

The ERACI II trial (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-Vessel Disease)²⁵ found no difference in mortality rates at 5 years with CABG vs PCI.

These trials were criticized, as none of them routinely used glycoprotein IIb/IIIa inhibitors with PCI, which by then had been shown to reduce mortality rates.³⁰ However, these trials made it clear that restenosis requiring repeat revascularization was a major disadvantage of PCI with bare-metal stents compared with CABG in patients with diabetes. Drug-eluting stents, which significantly reduced the rates of in-stent restenosis and target-lesion revascularization, were expected to overcome this major disadvantage.

Studies of PCI with drug-eluting stents vs CABG

ARTS II was the first trial to compare PCI with drug-eluting stents vs CABG. This was a nonrandomized single-arm study of 607 patients (including 159 with diabetes) who were treated with drug-eluting stents; the outcomes were compared with the CABG group from the earlier ARTS trial.³¹

At 3 years, in the diabetic subgroup, the rates of death, myocardial infarction, and stroke were not significantly different between treatments, although a trend favored PCI. However, this comparison was limited by selection bias, as ARTS II was a nonrandomized trial in which operators chose patients for drug-eluting stents in an attempt to match already known outcomes from the CABG cohort of ARTS.

SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) was the first randomized trial comparing PCI with drug-eluting stents (in this trial, paclitaxel-eluting) vs CABG in patients with three-vessel or left main coronary artery disease.^26,27 Subgroup analysis in patients with diabetes mellitus revealed a higher rate of major adverse cardiac and cerebrovascular events (death, myocardial infarction, stroke, or repeat revascularization) in the PCI group than in the CABG patients, largely driven by higher rates of repeat revascularization after PCI.^32,33 SYNTAX was not designed to assess significant differences in rates of death.

The CARDIa trial (Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and multivessel coronary artery disease to PCI (about one-third with bare-metal stents and two-thirds with drug-eluting stents) or CABG. Rates of major adverse cardiac and cerebrovascular events were higher in the PCI group, again largely driven by higher rates of repeat revascularization.⁴ CARDIa was stopped early because of a lack of enrollment and could not provide sufficient evidence to endorse one strategy over the other.

VA-CARDS (Veteran Affairs Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and proximal left anterior descending artery or multivessel coronary artery disease to receive PCI with drug-eluting stents or CABG.²⁸ Although the rate of death was lower with CABG than with PCI at 2 years, the trial was underpowered and was terminated at 25% of the initial intended patient enrollment. In addition, only 9% of diabetic patients screened were angiographically eligible for the study.²⁹

Registry data. Analysis of a large data set from the National Cardiovascular Disease Registry and the Society of Thoracic Surgeons revealed a survival advantage of CABG over PCI for a follow-up period of 5 years.³⁴ However, this was a nonrandomized study, so its conclusions were not definitive.

THE FREEDOM TRIAL

Given the limitations of the trials described above, the National Heart, Lung, and Blood Institute sponsored the FREEDOM trial—an appropriately powered, randomized comparison of PCI (with drug-eluting stents) and CABG (using arterial grafting) in patients with diabetes and multivessel coronary artery disease using contemporary techniques and concomitant optimal medical therapy.⁸

FREEDOM study design

The FREEDOM trial enrolled 1,900 patients with diabetes and angiographically confirmed multivessel coronary artery disease (83% with three-vessel disease) with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary-artery territories. The main exclusion criteria were severe left main coronary artery stenosis (≥ 50% stenosis), class III or IV congestive heart failure, and previous CABG or valve surgery. For CABG surgery, arterial revascularization was encouraged.

Dual antiplatelet therapy was recommended for at least 12 months in patients receiving a drug-eluting stent, and optimal medical management for diabetes, hypertension, and hyperlipidemia was strongly advocated.

Between April 2005 and April 2010, 32,966 patients were screened, of whom 3,309 were eligible for the trial and 1,900 consented and were randomized (953 to the PCI group and 947 to the CABG group). The patients were followed for a minimum of 2 years and had a median follow-up time of 3.8 years. Outcomes were measured with an intention-to-treat analysis.

Study results

Patients. The groups were comparable with regard to baseline demographics and cardiac risk factors.

The mean age was 63; 29% of the patients were women, and 83% had three-vessel coronary artery disease. The mean hemoglobin A_1c was 7.8%, and the mean ejection fraction was 66%. The mean SYNTAX score, which defines the anatomic complexity of lesions, was 26 (≤ 22 is mild, 23–32 is intermediate, and ≥ 33 is high). The mean EURO score, which defines surgical risk, was 2.7 (a score ≥ 5 being associated with a lower rate of survival).

The primary composite outcome (death, nonfatal myocardial infarction, or nonfatal stroke) occurred less frequently in the CABG group than in the PCI group (Table 2). CABG was also associated with significantly lower rates of death from any cause and of myocardial infarction. Importantly, survival curves comparing the two groups diverged at 2-year follow-up. In contrast to other outcomes assessed, stroke occurred more often in the CABG group. The 5-year rates in the CABG group vs the PCI group were:

• Primary outcome—18.7% vs 26.6%, P = .005
• Death from any cause—10.9% vs 16.3%, P = .049
• Myocardial infarction—6% vs 13.9%, P < .0001
• Stroke—5.2% vs 2.4%, P = .03.

The secondary outcome (death, nonfatal myocardial infarction, nonfatal stroke, or repeat revascularization at 30 days or 12 months) had occurred significantly more often in the PCI group than in the CABG group at 1 year (16.8% vs 11.8%, P = .004), with most of the difference attributable to a higher repeat revascularization rate in the PCI group (12.6% vs 4.8%, P < .001).

Subgroup analysis. CABG was superior to PCI across all prespecified subgroups, covering the complexity of the coronary artery disease. Event rates with CABG vs PCI, by tertiles of the SYNTAX score:

• SYNTAX scores ≤ 22: 17.2% vs 23.2%
• SYNTAX scores 23–32: 17.7% vs 27.2%
• SYNTAX scores ≥ 33: 22.8% vs 30.6%.

Cost-effectiveness. Although up-front costs were higher with CABG, at $34,467 for the index hospitalization vs $25,845 for PCI (P < .001), when the in-trial results were extended to a lifetime horizon, CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI.³⁵ Traditionally, therapies are considered costeffective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.

WHY MAY CABG BE SUPERIOR IN DIABETIC PATIENTS?

The major advantage of CABG over PCI is the ability to achieve complete revascularization. Diabetic patients with coronary artery disease tend to have diffuse, multifocal disease with several stenotic lesions in multiple coronary arteries. While stents only treat the focal area of most significant occlusion, CABG may bypass all proximal vulnerable plaques that could potentially develop into culprit lesions over time, truly bypassing the diseased segments (Figure 1).

In addition, heavy calcification may not allow optimal stenting in these patients.

Use of multiple stents increases the risk of restenosis, which could lead to a higher incidence of myocardial infarction and need for repeat revascularization. This was evident in the FREEDOM trial, in which the mean number of stents per patient was 4.2. Also, some lesions need to be left untreated because of the complexity involved.

The major improvement in outcomes after CABG has resulted from using arterial conduits such as the internal mammary artery rather than the saphenous vein.³⁶ The patency rates of internal mammary artery grafts exceed 80% over 10 years.³⁷ Internal mammary artery grafting was done in 94% of patients receiving CABG in the FREEDOM trial.

WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis^38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.⁴⁰

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.^1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.^3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.⁶

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.⁷

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial⁸ was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.

WHY ARE DIABETIC PATIENTS DIFFERENT?

Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.^9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.¹¹

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.¹² Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.^13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.¹⁵ Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.^16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.^18,19

BEFORE THE FREEDOM TRIAL

The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),^5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 1^20–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.⁵

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)²¹ and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) ²² were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

The ARTS trial (Arterial Revascularization Therapy Study) compared PCI (with bare-metal stents) and CABG in 1,205 patients with multivessel coronary artery disease.²³ The mortality rate did not differ significantly between two treatment groups overall or in the diabetic subgroup. However, the repeat revascularization rate was higher with PCI than with CABG.

The SoS trial (Stenting or Surgery)²⁴ had similar results.

The ERACI II trial (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-Vessel Disease)²⁵ found no difference in mortality rates at 5 years with CABG vs PCI.

These trials were criticized, as none of them routinely used glycoprotein IIb/IIIa inhibitors with PCI, which by then had been shown to reduce mortality rates.³⁰ However, these trials made it clear that restenosis requiring repeat revascularization was a major disadvantage of PCI with bare-metal stents compared with CABG in patients with diabetes. Drug-eluting stents, which significantly reduced the rates of in-stent restenosis and target-lesion revascularization, were expected to overcome this major disadvantage.

Studies of PCI with drug-eluting stents vs CABG

ARTS II was the first trial to compare PCI with drug-eluting stents vs CABG. This was a nonrandomized single-arm study of 607 patients (including 159 with diabetes) who were treated with drug-eluting stents; the outcomes were compared with the CABG group from the earlier ARTS trial.³¹

At 3 years, in the diabetic subgroup, the rates of death, myocardial infarction, and stroke were not significantly different between treatments, although a trend favored PCI. However, this comparison was limited by selection bias, as ARTS II was a nonrandomized trial in which operators chose patients for drug-eluting stents in an attempt to match already known outcomes from the CABG cohort of ARTS.

SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) was the first randomized trial comparing PCI with drug-eluting stents (in this trial, paclitaxel-eluting) vs CABG in patients with three-vessel or left main coronary artery disease.^26,27 Subgroup analysis in patients with diabetes mellitus revealed a higher rate of major adverse cardiac and cerebrovascular events (death, myocardial infarction, stroke, or repeat revascularization) in the PCI group than in the CABG patients, largely driven by higher rates of repeat revascularization after PCI.^32,33 SYNTAX was not designed to assess significant differences in rates of death.

The CARDIa trial (Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and multivessel coronary artery disease to PCI (about one-third with bare-metal stents and two-thirds with drug-eluting stents) or CABG. Rates of major adverse cardiac and cerebrovascular events were higher in the PCI group, again largely driven by higher rates of repeat revascularization.⁴ CARDIa was stopped early because of a lack of enrollment and could not provide sufficient evidence to endorse one strategy over the other.

VA-CARDS (Veteran Affairs Coronary Artery Revascularization in Diabetes) randomized patients with diabetes and proximal left anterior descending artery or multivessel coronary artery disease to receive PCI with drug-eluting stents or CABG.²⁸ Although the rate of death was lower with CABG than with PCI at 2 years, the trial was underpowered and was terminated at 25% of the initial intended patient enrollment. In addition, only 9% of diabetic patients screened were angiographically eligible for the study.²⁹

Registry data. Analysis of a large data set from the National Cardiovascular Disease Registry and the Society of Thoracic Surgeons revealed a survival advantage of CABG over PCI for a follow-up period of 5 years.³⁴ However, this was a nonrandomized study, so its conclusions were not definitive.

THE FREEDOM TRIAL

Given the limitations of the trials described above, the National Heart, Lung, and Blood Institute sponsored the FREEDOM trial—an appropriately powered, randomized comparison of PCI (with drug-eluting stents) and CABG (using arterial grafting) in patients with diabetes and multivessel coronary artery disease using contemporary techniques and concomitant optimal medical therapy.⁸

FREEDOM study design

The FREEDOM trial enrolled 1,900 patients with diabetes and angiographically confirmed multivessel coronary artery disease (83% with three-vessel disease) with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary-artery territories. The main exclusion criteria were severe left main coronary artery stenosis (≥ 50% stenosis), class III or IV congestive heart failure, and previous CABG or valve surgery. For CABG surgery, arterial revascularization was encouraged.

Dual antiplatelet therapy was recommended for at least 12 months in patients receiving a drug-eluting stent, and optimal medical management for diabetes, hypertension, and hyperlipidemia was strongly advocated.

Between April 2005 and April 2010, 32,966 patients were screened, of whom 3,309 were eligible for the trial and 1,900 consented and were randomized (953 to the PCI group and 947 to the CABG group). The patients were followed for a minimum of 2 years and had a median follow-up time of 3.8 years. Outcomes were measured with an intention-to-treat analysis.

Study results

Patients. The groups were comparable with regard to baseline demographics and cardiac risk factors.

The mean age was 63; 29% of the patients were women, and 83% had three-vessel coronary artery disease. The mean hemoglobin A_1c was 7.8%, and the mean ejection fraction was 66%. The mean SYNTAX score, which defines the anatomic complexity of lesions, was 26 (≤ 22 is mild, 23–32 is intermediate, and ≥ 33 is high). The mean EURO score, which defines surgical risk, was 2.7 (a score ≥ 5 being associated with a lower rate of survival).

The primary composite outcome (death, nonfatal myocardial infarction, or nonfatal stroke) occurred less frequently in the CABG group than in the PCI group (Table 2). CABG was also associated with significantly lower rates of death from any cause and of myocardial infarction. Importantly, survival curves comparing the two groups diverged at 2-year follow-up. In contrast to other outcomes assessed, stroke occurred more often in the CABG group. The 5-year rates in the CABG group vs the PCI group were:

• Primary outcome—18.7% vs 26.6%, P = .005
• Death from any cause—10.9% vs 16.3%, P = .049
• Myocardial infarction—6% vs 13.9%, P < .0001
• Stroke—5.2% vs 2.4%, P = .03.

The secondary outcome (death, nonfatal myocardial infarction, nonfatal stroke, or repeat revascularization at 30 days or 12 months) had occurred significantly more often in the PCI group than in the CABG group at 1 year (16.8% vs 11.8%, P = .004), with most of the difference attributable to a higher repeat revascularization rate in the PCI group (12.6% vs 4.8%, P < .001).

Subgroup analysis. CABG was superior to PCI across all prespecified subgroups, covering the complexity of the coronary artery disease. Event rates with CABG vs PCI, by tertiles of the SYNTAX score:

• SYNTAX scores ≤ 22: 17.2% vs 23.2%
• SYNTAX scores 23–32: 17.7% vs 27.2%
• SYNTAX scores ≥ 33: 22.8% vs 30.6%.

Cost-effectiveness. Although up-front costs were higher with CABG, at $34,467 for the index hospitalization vs $25,845 for PCI (P < .001), when the in-trial results were extended to a lifetime horizon, CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI.³⁵ Traditionally, therapies are considered costeffective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.

WHY MAY CABG BE SUPERIOR IN DIABETIC PATIENTS?

The major advantage of CABG over PCI is the ability to achieve complete revascularization. Diabetic patients with coronary artery disease tend to have diffuse, multifocal disease with several stenotic lesions in multiple coronary arteries. While stents only treat the focal area of most significant occlusion, CABG may bypass all proximal vulnerable plaques that could potentially develop into culprit lesions over time, truly bypassing the diseased segments (Figure 1).

In addition, heavy calcification may not allow optimal stenting in these patients.

Use of multiple stents increases the risk of restenosis, which could lead to a higher incidence of myocardial infarction and need for repeat revascularization. This was evident in the FREEDOM trial, in which the mean number of stents per patient was 4.2. Also, some lesions need to be left untreated because of the complexity involved.

The major improvement in outcomes after CABG has resulted from using arterial conduits such as the internal mammary artery rather than the saphenous vein.³⁶ The patency rates of internal mammary artery grafts exceed 80% over 10 years.³⁷ Internal mammary artery grafting was done in 94% of patients receiving CABG in the FREEDOM trial.

WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis^38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.⁴⁰

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

CASE A 34-year-old, otherwise healthy man presented at our emergency department (ED) complaining of severe, acute,high-thoracic back pain. He had left-sided chest pain radiating to his left arm and nonspecific paresthesias that did not track along a specific dermatome. The pain started 2 days earlier while the patient was lifting a heavy object at work. He was initially seen by his family physician, who diagnosed acute back pain, prescribed a COX-2 selective nonsteroidal anti-inflammatory agent, and advised him to stay home from work. This treatment did not improve the patient’s pain, which became more severe shortly before his arrival in our ED.

On physical examination, we found the patient in general good health, with no evidence of distress. His blood pressure was 128/78 mm Hg, his respiratory rate was 16 breaths/min,and his oral temperature was 36.5°C (97.7°F). An electrocardiogram(EKG) showed a normal sinus rhythm with no evidence of ischemia. Troponin I was 0 ng/mL, and complete blood count,C-reactive protein, and erythrocyte sedimentation rate were within normal range. After observation, the patient was discharged for ambulatory follow-up, with a diagnosis of acute back pain and nonischemic chest pain.

Two days later, the patient returned to the ED. He said that the pain had not gotten better, and he reported the gradual development of numbness in both legs, along with urinary retention. Re-examination revealed an ASIA D paraplegia at T4,with 650 mL postvoid residual urine volume. (ASIA D paraplegia means no sensory loss below the level of the injury and a motorfunction score above 3/5, which indicates active joint movement is possible against gravity but not against resistance.)

An emergent magnetic resonance imaging (MRI) scan was ordered; it revealed a large left-sided epidural mass spanning the length of T4 and T5 vertebrae with severe cord displacement and compression (FIGURE 1). On a T1-weighted MRI, the mass appeared hyperintense only on the periphery,indicating the presence of extracellular methemoglobin—a radiographic manifestation of early subacute hemorrhage.¹

Surgery. We started the patient on IV dexamethasone and performed an urgent T3-T5 laminectomy, which revealed a large brown epidural mass adhering to the duramater (FIGURE 2). We removed the mass and sent it to pathology, which confirmed an epidural hematoma.

The patient’s postoperative course was uneventful, and he was discharged from the hospital with complete motor strength in both legs and complete urinary control. The patient rapidly regained all sensory function, and we re-examined him one month postop in our outpatient clinic. He was intact neurologically and completely free of pain and dysesthesia. A follow-up MRI 3 months postop revealed no residual compression or signal abnormalities within the spinal cord.

Diagnosis remains a challenge

Spinal epidural hematoma (SEH) is an uncommon entity, with an estimated incidence of 0.1/100,000 per year.²  Because there are no studies that look at a large series of patients in the literature, our knowledge of the disorder is limited to case reports and small case series.

In most reports, SEH is linked to predisposing factors such as an underlying coagulopathy or anticoagulant therapy, epidural venous malformation, spinal trauma, inflammatory spine disease, pregnancy or neoplastic encroachment, and bleeding into the spinal canal.³ Spontaneous spinal epidural hematoma (SSEH) with no recognizable underlying predisposing factor is even rarer,⁴ and the paucity of published data makes it difficult to estimate the true incidence.

In the largest study to date, Zhong etal⁵ found 7 of 30 cases of SSEH were not associated with bleeding risk factors, making the calculated incidence approximately 0.023/100,000 per year. However, it is impossible to estimate how many cases remain undetected because neurological loss does not occur, and the pain is labeled a nonspecific backache that resolves spontaneously.

The typical patient will present with nothing more than severe midline spinal pain located anywhere from the head to the buttocks. Patients with acute onset of axial back pain with no distinguishing signs or symptoms (“red flags”) are seen daily in every practice. Commonly accepted guidelines from the American College of Physicians (ACP) and the American Pain Society (APS) direct the physician away from MRI scanning that can confirm the diagnosis.⁶

As our patient’s case illustrates, acute pain in the axial spine is a very common complaint, and usually has a benign etiology. Compression of one or more of the exiting thoracic nerve roots can cause thoracic radiculopathy, which might confound the diagnosis even further and lead to an unnecessary cardiothoracic work-up.⁴ That was the case for our patient. Only when neurological loss is evident will the need for an MRI become clear, and the diagnosis became apparent.

Definitive treatment is elusive

Several authors advocate emergent surgical decompression and evacuation of the hematoma, because the neurological outcome could be catastrophic,⁷ resulting in complete quadri/paraplegia. This approach is equivocal, however, as spontaneous resolution of neurological symptoms has been described in many cases.^1,7-11 Therefore, the decision whether to operate largely depends on the individual’s surgical risk factors and clinical course. In a high-risk patient who is improving neurologically, watchful waiting may be prudent, while in neurologically deteriorating low-risk cases little is lost with immediate surgical decompression.¹²

The prognosis of SSEH is also difficult to estimate. Several reports confirm that cervical and cervicothoracic hematomas carry a worse prognosis than thoracolumbar and lumbosacral hematomas.^3,5 A rapid onset of neurological deterioration (less than12 hours) also heralds graver consequences, as does spinal cord edema on initial MRI.⁵

Two windows of opportunity
Two time periods stand out as possible course-changing opportunities for clinicians.The first occurs when the patient initially complains of an acute backache. At this point, ACP/APS guidelines direct us to look for red flags that focus attention on the more troubling etiologies for backache.⁶ Unfortunately, SSEH has no specific red flag, and itis misleading to suggest that such an esoteric diagnosis should routinely be considered.

A better approach would be to look for the unusual: very sharp, acute-onset, highly localized back pain that does not respond well to analgesics (TABLE [developed by NR]),along with any dysesthesia or unusual radicular complaint. A positive l’hermitte sign—anelectrical sensation that runs down the back and into the limbs—on physical examination might also warrant placing SSEH in the differential diagnosis.

The second time when swiftness might be crucial is from diagnosis to surgery. In a neurologically deteriorating patient, time is of utmost importance, and taking action at this juncture can produce a marked difference in the final outcome.³

CORRESPONDENCE
Nimrod Rahamimov, MD, Department of Orthopedics Band Spine Surgery, Western Galilee Hospital, PO Box 21, Naharia 22100, Israel; [email protected]

CASE A 34-year-old, otherwise healthy man presented at our emergency department (ED) complaining of severe, acute,high-thoracic back pain. He had left-sided chest pain radiating to his left arm and nonspecific paresthesias that did not track along a specific dermatome. The pain started 2 days earlier while the patient was lifting a heavy object at work. He was initially seen by his family physician, who diagnosed acute back pain, prescribed a COX-2 selective nonsteroidal anti-inflammatory agent, and advised him to stay home from work. This treatment did not improve the patient’s pain, which became more severe shortly before his arrival in our ED.

On physical examination, we found the patient in general good health, with no evidence of distress. His blood pressure was 128/78 mm Hg, his respiratory rate was 16 breaths/min,and his oral temperature was 36.5°C (97.7°F). An electrocardiogram(EKG) showed a normal sinus rhythm with no evidence of ischemia. Troponin I was 0 ng/mL, and complete blood count,C-reactive protein, and erythrocyte sedimentation rate were within normal range. After observation, the patient was discharged for ambulatory follow-up, with a diagnosis of acute back pain and nonischemic chest pain.

Two days later, the patient returned to the ED. He said that the pain had not gotten better, and he reported the gradual development of numbness in both legs, along with urinary retention. Re-examination revealed an ASIA D paraplegia at T4,with 650 mL postvoid residual urine volume. (ASIA D paraplegia means no sensory loss below the level of the injury and a motorfunction score above 3/5, which indicates active joint movement is possible against gravity but not against resistance.)

An emergent magnetic resonance imaging (MRI) scan was ordered; it revealed a large left-sided epidural mass spanning the length of T4 and T5 vertebrae with severe cord displacement and compression (FIGURE 1). On a T1-weighted MRI, the mass appeared hyperintense only on the periphery,indicating the presence of extracellular methemoglobin—a radiographic manifestation of early subacute hemorrhage.¹

Surgery. We started the patient on IV dexamethasone and performed an urgent T3-T5 laminectomy, which revealed a large brown epidural mass adhering to the duramater (FIGURE 2). We removed the mass and sent it to pathology, which confirmed an epidural hematoma.

The patient’s postoperative course was uneventful, and he was discharged from the hospital with complete motor strength in both legs and complete urinary control. The patient rapidly regained all sensory function, and we re-examined him one month postop in our outpatient clinic. He was intact neurologically and completely free of pain and dysesthesia. A follow-up MRI 3 months postop revealed no residual compression or signal abnormalities within the spinal cord.

Diagnosis remains a challenge

Spinal epidural hematoma (SEH) is an uncommon entity, with an estimated incidence of 0.1/100,000 per year.²  Because there are no studies that look at a large series of patients in the literature, our knowledge of the disorder is limited to case reports and small case series.

In most reports, SEH is linked to predisposing factors such as an underlying coagulopathy or anticoagulant therapy, epidural venous malformation, spinal trauma, inflammatory spine disease, pregnancy or neoplastic encroachment, and bleeding into the spinal canal.³ Spontaneous spinal epidural hematoma (SSEH) with no recognizable underlying predisposing factor is even rarer,⁴ and the paucity of published data makes it difficult to estimate the true incidence.

In the largest study to date, Zhong etal⁵ found 7 of 30 cases of SSEH were not associated with bleeding risk factors, making the calculated incidence approximately 0.023/100,000 per year. However, it is impossible to estimate how many cases remain undetected because neurological loss does not occur, and the pain is labeled a nonspecific backache that resolves spontaneously.

The typical patient will present with nothing more than severe midline spinal pain located anywhere from the head to the buttocks. Patients with acute onset of axial back pain with no distinguishing signs or symptoms (“red flags”) are seen daily in every practice. Commonly accepted guidelines from the American College of Physicians (ACP) and the American Pain Society (APS) direct the physician away from MRI scanning that can confirm the diagnosis.⁶

As our patient’s case illustrates, acute pain in the axial spine is a very common complaint, and usually has a benign etiology. Compression of one or more of the exiting thoracic nerve roots can cause thoracic radiculopathy, which might confound the diagnosis even further and lead to an unnecessary cardiothoracic work-up.⁴ That was the case for our patient. Only when neurological loss is evident will the need for an MRI become clear, and the diagnosis became apparent.

Definitive treatment is elusive

Several authors advocate emergent surgical decompression and evacuation of the hematoma, because the neurological outcome could be catastrophic,⁷ resulting in complete quadri/paraplegia. This approach is equivocal, however, as spontaneous resolution of neurological symptoms has been described in many cases.^1,7-11 Therefore, the decision whether to operate largely depends on the individual’s surgical risk factors and clinical course. In a high-risk patient who is improving neurologically, watchful waiting may be prudent, while in neurologically deteriorating low-risk cases little is lost with immediate surgical decompression.¹²

The prognosis of SSEH is also difficult to estimate. Several reports confirm that cervical and cervicothoracic hematomas carry a worse prognosis than thoracolumbar and lumbosacral hematomas.^3,5 A rapid onset of neurological deterioration (less than12 hours) also heralds graver consequences, as does spinal cord edema on initial MRI.⁵

Two windows of opportunity
Two time periods stand out as possible course-changing opportunities for clinicians.The first occurs when the patient initially complains of an acute backache. At this point, ACP/APS guidelines direct us to look for red flags that focus attention on the more troubling etiologies for backache.⁶ Unfortunately, SSEH has no specific red flag, and itis misleading to suggest that such an esoteric diagnosis should routinely be considered.

A better approach would be to look for the unusual: very sharp, acute-onset, highly localized back pain that does not respond well to analgesics (TABLE [developed by NR]),along with any dysesthesia or unusual radicular complaint. A positive l’hermitte sign—anelectrical sensation that runs down the back and into the limbs—on physical examination might also warrant placing SSEH in the differential diagnosis.

The second time when swiftness might be crucial is from diagnosis to surgery. In a neurologically deteriorating patient, time is of utmost importance, and taking action at this juncture can produce a marked difference in the final outcome.³

CORRESPONDENCE
Nimrod Rahamimov, MD, Department of Orthopedics Band Spine Surgery, Western Galilee Hospital, PO Box 21, Naharia 22100, Israel; [email protected]

CASE A 34-year-old, otherwise healthy man presented at our emergency department (ED) complaining of severe, acute,high-thoracic back pain. He had left-sided chest pain radiating to his left arm and nonspecific paresthesias that did not track along a specific dermatome. The pain started 2 days earlier while the patient was lifting a heavy object at work. He was initially seen by his family physician, who diagnosed acute back pain, prescribed a COX-2 selective nonsteroidal anti-inflammatory agent, and advised him to stay home from work. This treatment did not improve the patient’s pain, which became more severe shortly before his arrival in our ED.

On physical examination, we found the patient in general good health, with no evidence of distress. His blood pressure was 128/78 mm Hg, his respiratory rate was 16 breaths/min,and his oral temperature was 36.5°C (97.7°F). An electrocardiogram(EKG) showed a normal sinus rhythm with no evidence of ischemia. Troponin I was 0 ng/mL, and complete blood count,C-reactive protein, and erythrocyte sedimentation rate were within normal range. After observation, the patient was discharged for ambulatory follow-up, with a diagnosis of acute back pain and nonischemic chest pain.

Two days later, the patient returned to the ED. He said that the pain had not gotten better, and he reported the gradual development of numbness in both legs, along with urinary retention. Re-examination revealed an ASIA D paraplegia at T4,with 650 mL postvoid residual urine volume. (ASIA D paraplegia means no sensory loss below the level of the injury and a motorfunction score above 3/5, which indicates active joint movement is possible against gravity but not against resistance.)

An emergent magnetic resonance imaging (MRI) scan was ordered; it revealed a large left-sided epidural mass spanning the length of T4 and T5 vertebrae with severe cord displacement and compression (FIGURE 1). On a T1-weighted MRI, the mass appeared hyperintense only on the periphery,indicating the presence of extracellular methemoglobin—a radiographic manifestation of early subacute hemorrhage.¹

Surgery. We started the patient on IV dexamethasone and performed an urgent T3-T5 laminectomy, which revealed a large brown epidural mass adhering to the duramater (FIGURE 2). We removed the mass and sent it to pathology, which confirmed an epidural hematoma.

The patient’s postoperative course was uneventful, and he was discharged from the hospital with complete motor strength in both legs and complete urinary control. The patient rapidly regained all sensory function, and we re-examined him one month postop in our outpatient clinic. He was intact neurologically and completely free of pain and dysesthesia. A follow-up MRI 3 months postop revealed no residual compression or signal abnormalities within the spinal cord.

Diagnosis remains a challenge

Spinal epidural hematoma (SEH) is an uncommon entity, with an estimated incidence of 0.1/100,000 per year.²  Because there are no studies that look at a large series of patients in the literature, our knowledge of the disorder is limited to case reports and small case series.

In most reports, SEH is linked to predisposing factors such as an underlying coagulopathy or anticoagulant therapy, epidural venous malformation, spinal trauma, inflammatory spine disease, pregnancy or neoplastic encroachment, and bleeding into the spinal canal.³ Spontaneous spinal epidural hematoma (SSEH) with no recognizable underlying predisposing factor is even rarer,⁴ and the paucity of published data makes it difficult to estimate the true incidence.

In the largest study to date, Zhong etal⁵ found 7 of 30 cases of SSEH were not associated with bleeding risk factors, making the calculated incidence approximately 0.023/100,000 per year. However, it is impossible to estimate how many cases remain undetected because neurological loss does not occur, and the pain is labeled a nonspecific backache that resolves spontaneously.

The typical patient will present with nothing more than severe midline spinal pain located anywhere from the head to the buttocks. Patients with acute onset of axial back pain with no distinguishing signs or symptoms (“red flags”) are seen daily in every practice. Commonly accepted guidelines from the American College of Physicians (ACP) and the American Pain Society (APS) direct the physician away from MRI scanning that can confirm the diagnosis.⁶

As our patient’s case illustrates, acute pain in the axial spine is a very common complaint, and usually has a benign etiology. Compression of one or more of the exiting thoracic nerve roots can cause thoracic radiculopathy, which might confound the diagnosis even further and lead to an unnecessary cardiothoracic work-up.⁴ That was the case for our patient. Only when neurological loss is evident will the need for an MRI become clear, and the diagnosis became apparent.

Definitive treatment is elusive

Several authors advocate emergent surgical decompression and evacuation of the hematoma, because the neurological outcome could be catastrophic,⁷ resulting in complete quadri/paraplegia. This approach is equivocal, however, as spontaneous resolution of neurological symptoms has been described in many cases.^1,7-11 Therefore, the decision whether to operate largely depends on the individual’s surgical risk factors and clinical course. In a high-risk patient who is improving neurologically, watchful waiting may be prudent, while in neurologically deteriorating low-risk cases little is lost with immediate surgical decompression.¹²

The prognosis of SSEH is also difficult to estimate. Several reports confirm that cervical and cervicothoracic hematomas carry a worse prognosis than thoracolumbar and lumbosacral hematomas.^3,5 A rapid onset of neurological deterioration (less than12 hours) also heralds graver consequences, as does spinal cord edema on initial MRI.⁵

Two windows of opportunity
Two time periods stand out as possible course-changing opportunities for clinicians.The first occurs when the patient initially complains of an acute backache. At this point, ACP/APS guidelines direct us to look for red flags that focus attention on the more troubling etiologies for backache.⁶ Unfortunately, SSEH has no specific red flag, and itis misleading to suggest that such an esoteric diagnosis should routinely be considered.

A better approach would be to look for the unusual: very sharp, acute-onset, highly localized back pain that does not respond well to analgesics (TABLE [developed by NR]),along with any dysesthesia or unusual radicular complaint. A positive l’hermitte sign—anelectrical sensation that runs down the back and into the limbs—on physical examination might also warrant placing SSEH in the differential diagnosis.

The second time when swiftness might be crucial is from diagnosis to surgery. In a neurologically deteriorating patient, time is of utmost importance, and taking action at this juncture can produce a marked difference in the final outcome.³

CORRESPONDENCE
Nimrod Rahamimov, MD, Department of Orthopedics Band Spine Surgery, Western Galilee Hospital, PO Box 21, Naharia 22100, Israel; [email protected]

Initial outcomes data for SHM's Project BOOST show a reduction in 30-day hospital readmission rates to 12.7% from 14.7% among a select group of 11 participating hospitals.

Results were reported online July 22 in the Journal of Hospital Medicine. “Participation in Project BOOST appeared to be associated with a decrease in readmission rates,” the study authors cautiously observe, although two accompanying editorials label the results as "limited" and "disappointing."

The research compares outcomes data for clinical acute-care units at 11 of 30 hospitals in the first two BOOST cohorts, started in 2008 and 2009, with clinically matched non-BOOST control units for all-patient, 30-day readmissions. Each BOOST site adopted two or more of the recommended interventions from the program’s toolkit for improving care transitions, with the support of an expert mentor. Reporting clinical outcomes was voluntary and uncompensated, and 19 of the hospitals in the initial cohorts did not share their data—cited as a serious limitation by authors of the editorials.

"You can look at our study on a couple of different levels," says lead author and BOOST lead analyst Luke Hansen, MD, MHS, of the division of hospital medicine at Northwestern University Feinberg School of Medicine in Chicago. "One is the sites that gave us data, and in that group there were statistically significant results. But I think the more important question is: Will that be enough? What is the magnitude of the effect, and is it enough to give hospitals the impetus they need to prevent avoidable readmissions?"

Listen to more of our interview with Dr. Luke Hansen, Project BOOST's lead analyst.

Project BOOST is one of SHM's national QI programs aimed at improving care transitions through such strategies as readmission risk assessments, medication reconciliation, patient coaching, and post-discharge follow-up calls. For hospitals and HM groups searching for solutions to the 30-day readmission dilemma—and thereby avoid Medicare reimbursement penalties, clear answers remain elusive.

"BOOST is one of a number of care transitions improvement methodologies that have been applied to the problem of readmissions, each of which has evidence to support their effectiveness in their initial settings, but has proven difficult to translate to other sites," JHM Editor-in-Chief Andrew D. Auerbach, MD, MPH, SFHM, a professor of medicine in residence at the University of California at San Francisco's division of hospital medicine, and co-authors note in an accompanying editorial.

Dr. Auerbach notes in his editorial that research problems limited the study's robustness but that "the authors provide the necessary start down the road towards a fuller understanding of real-world efforts to reduce readmissions."

In the other editorial, Ashish K. Jha, MD, MPH, of the Harvard School of Public Health, Health Policy, and Management suggests that readmissions ultimately may be the wrong target. A better goal, Dr. Jha says, is to improve transitions of care and demonstrate better processes in achieving those results—even though that might not significantly alter readmission rates. "We need to get clearer on what we’re trying to achieve," he adds.

Visit our website for more information on hospital readmission studies.

Initial outcomes data for SHM's Project BOOST show a reduction in 30-day hospital readmission rates to 12.7% from 14.7% among a select group of 11 participating hospitals.

Results were reported online July 22 in the Journal of Hospital Medicine. “Participation in Project BOOST appeared to be associated with a decrease in readmission rates,” the study authors cautiously observe, although two accompanying editorials label the results as "limited" and "disappointing."

The research compares outcomes data for clinical acute-care units at 11 of 30 hospitals in the first two BOOST cohorts, started in 2008 and 2009, with clinically matched non-BOOST control units for all-patient, 30-day readmissions. Each BOOST site adopted two or more of the recommended interventions from the program’s toolkit for improving care transitions, with the support of an expert mentor. Reporting clinical outcomes was voluntary and uncompensated, and 19 of the hospitals in the initial cohorts did not share their data—cited as a serious limitation by authors of the editorials.

"You can look at our study on a couple of different levels," says lead author and BOOST lead analyst Luke Hansen, MD, MHS, of the division of hospital medicine at Northwestern University Feinberg School of Medicine in Chicago. "One is the sites that gave us data, and in that group there were statistically significant results. But I think the more important question is: Will that be enough? What is the magnitude of the effect, and is it enough to give hospitals the impetus they need to prevent avoidable readmissions?"

Listen to more of our interview with Dr. Luke Hansen, Project BOOST's lead analyst.

Project BOOST is one of SHM's national QI programs aimed at improving care transitions through such strategies as readmission risk assessments, medication reconciliation, patient coaching, and post-discharge follow-up calls. For hospitals and HM groups searching for solutions to the 30-day readmission dilemma—and thereby avoid Medicare reimbursement penalties, clear answers remain elusive.

"BOOST is one of a number of care transitions improvement methodologies that have been applied to the problem of readmissions, each of which has evidence to support their effectiveness in their initial settings, but has proven difficult to translate to other sites," JHM Editor-in-Chief Andrew D. Auerbach, MD, MPH, SFHM, a professor of medicine in residence at the University of California at San Francisco's division of hospital medicine, and co-authors note in an accompanying editorial.

Dr. Auerbach notes in his editorial that research problems limited the study's robustness but that "the authors provide the necessary start down the road towards a fuller understanding of real-world efforts to reduce readmissions."

In the other editorial, Ashish K. Jha, MD, MPH, of the Harvard School of Public Health, Health Policy, and Management suggests that readmissions ultimately may be the wrong target. A better goal, Dr. Jha says, is to improve transitions of care and demonstrate better processes in achieving those results—even though that might not significantly alter readmission rates. "We need to get clearer on what we’re trying to achieve," he adds.

Visit our website for more information on hospital readmission studies.

Initial outcomes data for SHM's Project BOOST show a reduction in 30-day hospital readmission rates to 12.7% from 14.7% among a select group of 11 participating hospitals.

Results were reported online July 22 in the Journal of Hospital Medicine. “Participation in Project BOOST appeared to be associated with a decrease in readmission rates,” the study authors cautiously observe, although two accompanying editorials label the results as "limited" and "disappointing."

The research compares outcomes data for clinical acute-care units at 11 of 30 hospitals in the first two BOOST cohorts, started in 2008 and 2009, with clinically matched non-BOOST control units for all-patient, 30-day readmissions. Each BOOST site adopted two or more of the recommended interventions from the program’s toolkit for improving care transitions, with the support of an expert mentor. Reporting clinical outcomes was voluntary and uncompensated, and 19 of the hospitals in the initial cohorts did not share their data—cited as a serious limitation by authors of the editorials.

"You can look at our study on a couple of different levels," says lead author and BOOST lead analyst Luke Hansen, MD, MHS, of the division of hospital medicine at Northwestern University Feinberg School of Medicine in Chicago. "One is the sites that gave us data, and in that group there were statistically significant results. But I think the more important question is: Will that be enough? What is the magnitude of the effect, and is it enough to give hospitals the impetus they need to prevent avoidable readmissions?"

Listen to more of our interview with Dr. Luke Hansen, Project BOOST's lead analyst.

Project BOOST is one of SHM's national QI programs aimed at improving care transitions through such strategies as readmission risk assessments, medication reconciliation, patient coaching, and post-discharge follow-up calls. For hospitals and HM groups searching for solutions to the 30-day readmission dilemma—and thereby avoid Medicare reimbursement penalties, clear answers remain elusive.

"BOOST is one of a number of care transitions improvement methodologies that have been applied to the problem of readmissions, each of which has evidence to support their effectiveness in their initial settings, but has proven difficult to translate to other sites," JHM Editor-in-Chief Andrew D. Auerbach, MD, MPH, SFHM, a professor of medicine in residence at the University of California at San Francisco's division of hospital medicine, and co-authors note in an accompanying editorial.

Dr. Auerbach notes in his editorial that research problems limited the study's robustness but that "the authors provide the necessary start down the road towards a fuller understanding of real-world efforts to reduce readmissions."

In the other editorial, Ashish K. Jha, MD, MPH, of the Harvard School of Public Health, Health Policy, and Management suggests that readmissions ultimately may be the wrong target. A better goal, Dr. Jha says, is to improve transitions of care and demonstrate better processes in achieving those results—even though that might not significantly alter readmission rates. "We need to get clearer on what we’re trying to achieve," he adds.

Visit our website for more information on hospital readmission studies.

A new report that shows ever-growing Medicare spending for chronically ill patients in the last two years of life can serve as a reminder for hospitalists to properly gauge patients’ wishes for end-of-life care, one of the authors says.

The brief from the Dartmouth Atlas Project [PDF] shows that from 2007 to 2010, average spending per patient in the last two years of life increased 15.2% to $69,947, and average spending in the last six months of life rose 13.4% to $36,392.

During the same three-year period, patients in their last six months of life were less likely to be hospitalized and logged more time in hospice care—21 days versus 18.3 days—reflecting the wishes of most patients to spend their last days in a homelike environment, the report notes. Accordingly, chronically ill Medicare patients were less likely to die in the hospital by the end of the study period.

David Goodman, MD, MS, co-principal investigator for Dartmouth Atlas of Health Care, says the growing use of hospice care and decreased hospitalization stays “aligns more closely with patients’ preferences.”

“The focus really needs to be on better diagnosis of patients’ preferences to reduce what has been well-documented as overutilization from the patient’s perspective,” Dr. Goodman says.

While costs and trends vary widely among regions and health-care systems, Dr. Goodman attributes the differences to local supplies of hospital beds and practice styles. For example, in regions with more beds, patients are more likely to spend time in the hospital near the end of life, he says. “There is definitely a national trend away from hospital care near the end of life,” he adds. “But that rate of change varies a lot from place to place. It’s helpful for hospitalists to understand where they fit on the spectrum.”

Visit our website for more information on end of life care.

A new report that shows ever-growing Medicare spending for chronically ill patients in the last two years of life can serve as a reminder for hospitalists to properly gauge patients’ wishes for end-of-life care, one of the authors says.

The brief from the Dartmouth Atlas Project [PDF] shows that from 2007 to 2010, average spending per patient in the last two years of life increased 15.2% to $69,947, and average spending in the last six months of life rose 13.4% to $36,392.

During the same three-year period, patients in their last six months of life were less likely to be hospitalized and logged more time in hospice care—21 days versus 18.3 days—reflecting the wishes of most patients to spend their last days in a homelike environment, the report notes. Accordingly, chronically ill Medicare patients were less likely to die in the hospital by the end of the study period.

David Goodman, MD, MS, co-principal investigator for Dartmouth Atlas of Health Care, says the growing use of hospice care and decreased hospitalization stays “aligns more closely with patients’ preferences.”

“The focus really needs to be on better diagnosis of patients’ preferences to reduce what has been well-documented as overutilization from the patient’s perspective,” Dr. Goodman says.

While costs and trends vary widely among regions and health-care systems, Dr. Goodman attributes the differences to local supplies of hospital beds and practice styles. For example, in regions with more beds, patients are more likely to spend time in the hospital near the end of life, he says. “There is definitely a national trend away from hospital care near the end of life,” he adds. “But that rate of change varies a lot from place to place. It’s helpful for hospitalists to understand where they fit on the spectrum.”

Visit our website for more information on end of life care.

A new report that shows ever-growing Medicare spending for chronically ill patients in the last two years of life can serve as a reminder for hospitalists to properly gauge patients’ wishes for end-of-life care, one of the authors says.

The brief from the Dartmouth Atlas Project [PDF] shows that from 2007 to 2010, average spending per patient in the last two years of life increased 15.2% to $69,947, and average spending in the last six months of life rose 13.4% to $36,392.

During the same three-year period, patients in their last six months of life were less likely to be hospitalized and logged more time in hospice care—21 days versus 18.3 days—reflecting the wishes of most patients to spend their last days in a homelike environment, the report notes. Accordingly, chronically ill Medicare patients were less likely to die in the hospital by the end of the study period.

David Goodman, MD, MS, co-principal investigator for Dartmouth Atlas of Health Care, says the growing use of hospice care and decreased hospitalization stays “aligns more closely with patients’ preferences.”

“The focus really needs to be on better diagnosis of patients’ preferences to reduce what has been well-documented as overutilization from the patient’s perspective,” Dr. Goodman says.

While costs and trends vary widely among regions and health-care systems, Dr. Goodman attributes the differences to local supplies of hospital beds and practice styles. For example, in regions with more beds, patients are more likely to spend time in the hospital near the end of life, he says. “There is definitely a national trend away from hospital care near the end of life,” he adds. “But that rate of change varies a lot from place to place. It’s helpful for hospitalists to understand where they fit on the spectrum.”

Visit our website for more information on end of life care.

Identification of monosodium urate crystals, either in a joint fluid sample or in a tophi aspirate, should be performed for a definite diagnosis of gout, according to new multinational evidence-based recommendations on the diagnosis and management of the disease.

When identification of monosodium urate (MSU) crystals is not possible, the diagnosis can be supported by classical clinical features such as podagra, tophi, or rapid response to colchicine, or by characteristic imaging findings, Dr. Francisca Sivera of Hospital General Universitario de Elda (Spain) and her colleagues reported on behalf of the 2011 3e (Evidence, Expertise, Exchange) Initiative. The initiative is a multinational collaboration tasked with promoting evidence-based practice in rheumatology through the development of practical recommendations that address relevant clinical issues.

The MSU identification recommendation is one of 10 recommendations developed by 474 rheumatologists from 14 countries who participated in the 2011 3e Initiative. In keeping with 3e protocol, a panel of 78 experts representing the 14 countries developed 10 key clinical questions pertinent to the diagnosis and management of gout, each of which was investigated via extensive literature review. Recommendations for each of the questions were then formulated, debated, and voted on by Initiative participants, and each recommendation was graded based on the level of evidence.

In addition to diagnosis, the gout recommendations address comorbidity screening, acute gout treatment, lifestyle counseling, urate-lowering therapy, flare prophylaxis, the effect of comorbidities on drug selection, patient monitoring, tophi treatment, and management of asymptomatic hyperuricemia (Ann. Rheum. Dis. 2013 July 18 [doi: 10.1136/annrheumdis-2013-203325]).

Specifically, with a high level of agreement that ranged from a mean of 8.1 to 9.2 on a 1-10 scale, the 3e Initiative participants recommended:

• Assessing renal function and cardiovascular risk factors in patients with gout and/or hyperuricemia.

• Treating acute gout with low-dose colchicine, nonsteroidal anti-inflammatory drugs, and/or glucocorticoids, depending on comorbidities and the risk of adverse effects.

• Advising patients about health lifestyle choices.

• Using allopurinol first-line as urate-lowering therapy, and considering uricosurics as alternatives when necessary.

• Educating patients on the risk and management of flares – and using prophylaxis – when introducing urate-lowering therapy.

• Using allopurinol with close monitoring, and starting at a low dose with slow titration, in patients with mild to moderate renal impairment.

• Setting the treatment target for serum urate at below 0.36 mmol/L (6 mg/dL) with eventual absence of gout attacks and resolution of tophi.

• Treating tophi medically by achieving a sustained reduction in serum uric acid, preferably below 0.30 mmol/L (5 mg/dL) and reserving surgery for select cases, such as those involving nerve compression, mechanical impingement, or infection.

• Forgoing pharmacological treatment of asymptomatic hyperuricemia.

The ultimate goal of these recommendations, which were based on 1a-5 evidence levels, and which received recommendation grades ranging from B to D, is to improve patient care, Dr. Sivera said in an interview. The level of evidence and grade of recommendation were made according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Gout affects up to 2% of men in Western countries, and is associated with morbidity, disability, and poorer quality of life. Despite the availability of a number of guidelines and recommendations, management of the condition is often suboptimal, she said.

"Gout is a curable disease, but evidence shows that many patients are mismanaged with regard to both treatment and diagnosis. Even in a rheumatology clinic, only about a quarter of the patients have a diagnosis of gout established by MSU crystal identification, and in a U.K. study, only one in three patients with a diagnosis of gout were taking urate-lowering therapy," she said.

Research shows that when guidelines are implemented, they improve the quality of care. Educational outreach has an effect on implementation, she said, noting that "both dissemination and education – in both gout and in evidence-based medicine – are an integral part of the 3e Initiative, so these multinational recommendations have the potential to positively influence the standard of care."

The 3e recommendations follow those published in 2012 on behalf of the American College of Rheumatology, which centered on the treatment and prophylaxis of acute gout flares and the appropriate use of urate-lowering therapy.

"Some of the recommendations provided are similar, such as treating to a target serum uric acid level, and the ‘start low, go slow’ approach to allopurinol therapy. This highlights the general consensus on many aspects of the optimal standard of gout management," Dr. Sivera said.

Where the 3e recommendation and the ACR guidelines overlap, there is, indeed, general agreement, Dr. John FitzGerald of the University of California, Los Angeles, said in an interview.

Both processes benefited from Delphi consensus methodologies and systematic literature reviews to inform decision making. However, the two diverge with respect to other aspects of the methodology and presentation, he noted.

"The RAND/UCLA methodology used by ACR resulted in guidelines that were evidence based to be the most efficacious recommendations. As noted, the RAND/UCLA methodology excludes cost of therapy (as typically there are insufficient head-to-head therapeutic cost-efficacy studies on which to base recommendations). The ACR guidelines therefore leave it to the practitioner to use the efficacy-based recommendations, along with their clinical and practical knowledge, to then provide recommendations for specific patients. As an example, allopurinol and febuxostat have relatively similar efficacy but significant cost differences," said Dr. FitzGerald, who co-led the ACR guidelines development project.

"The 3e approach incorporates that next step in decision making to provide evidence-based and practical recommendations to the practitioner," he said.

The ACR effort addressed four specific domains of gout management: treatment of acute gouty attacks, management of urate-lowering therapy, management of chronic tophaceous gout, and prophylaxis of acute gouty attacks. Although the 3e effort focused on 10 specific, clinically relevant questions, it is valuable for other reasons as well, such as the inclusion of diagnosis as part of the recommendations, and the fact that asymptomatic hyperuricemia is addressed, he said, noting that neither of these was addressed by the ACR guidelines.

The 3e recommendations also address the use of benzbromarone, a uricosuric agent that is not available in the United States.

While the 3e effort lacks the extent of detail included in the ACR guidelines, such as the inclusion of specific information on allopurinol dosing, the 3e group is to be commended for the size of the effort, Dr. FitzGerald said, stressing the value of the input from nearly 500 rheumatologists from 14 countries.

Indeed, the extensive effort by "a large group of practicing rheumatologists from many different countries in Europe, South America, and Australasia resulted in the recommendations addressing those aspects [of gout diagnosis and management] that rheumatologists found most clinically relevant," Dr. Sivera said.

She and her colleagues concluded that "the high level of agreement with the final recommendations and the multinational participation increase their utility and will hopefully facilitate their dissemination and implementation worldwide."

The 3e Gout Program was sponsored by AbbVie. Dr. Sivera reported receiving fees from Menarini for preparing educational presentations, and other authors reported receiving lecture or consulting fees and/or research grants from many companies, including AbbVie. Dr. FitzGerald reported receiving honoraria and grant support from the ACR.

Identification of monosodium urate crystals, either in a joint fluid sample or in a tophi aspirate, should be performed for a definite diagnosis of gout, according to new multinational evidence-based recommendations on the diagnosis and management of the disease.

When identification of monosodium urate (MSU) crystals is not possible, the diagnosis can be supported by classical clinical features such as podagra, tophi, or rapid response to colchicine, or by characteristic imaging findings, Dr. Francisca Sivera of Hospital General Universitario de Elda (Spain) and her colleagues reported on behalf of the 2011 3e (Evidence, Expertise, Exchange) Initiative. The initiative is a multinational collaboration tasked with promoting evidence-based practice in rheumatology through the development of practical recommendations that address relevant clinical issues.

The MSU identification recommendation is one of 10 recommendations developed by 474 rheumatologists from 14 countries who participated in the 2011 3e Initiative. In keeping with 3e protocol, a panel of 78 experts representing the 14 countries developed 10 key clinical questions pertinent to the diagnosis and management of gout, each of which was investigated via extensive literature review. Recommendations for each of the questions were then formulated, debated, and voted on by Initiative participants, and each recommendation was graded based on the level of evidence.

In addition to diagnosis, the gout recommendations address comorbidity screening, acute gout treatment, lifestyle counseling, urate-lowering therapy, flare prophylaxis, the effect of comorbidities on drug selection, patient monitoring, tophi treatment, and management of asymptomatic hyperuricemia (Ann. Rheum. Dis. 2013 July 18 [doi: 10.1136/annrheumdis-2013-203325]).

Specifically, with a high level of agreement that ranged from a mean of 8.1 to 9.2 on a 1-10 scale, the 3e Initiative participants recommended:

• Assessing renal function and cardiovascular risk factors in patients with gout and/or hyperuricemia.

• Treating acute gout with low-dose colchicine, nonsteroidal anti-inflammatory drugs, and/or glucocorticoids, depending on comorbidities and the risk of adverse effects.

• Advising patients about health lifestyle choices.

• Using allopurinol first-line as urate-lowering therapy, and considering uricosurics as alternatives when necessary.

• Educating patients on the risk and management of flares – and using prophylaxis – when introducing urate-lowering therapy.

• Using allopurinol with close monitoring, and starting at a low dose with slow titration, in patients with mild to moderate renal impairment.

• Setting the treatment target for serum urate at below 0.36 mmol/L (6 mg/dL) with eventual absence of gout attacks and resolution of tophi.

• Treating tophi medically by achieving a sustained reduction in serum uric acid, preferably below 0.30 mmol/L (5 mg/dL) and reserving surgery for select cases, such as those involving nerve compression, mechanical impingement, or infection.

• Forgoing pharmacological treatment of asymptomatic hyperuricemia.

The ultimate goal of these recommendations, which were based on 1a-5 evidence levels, and which received recommendation grades ranging from B to D, is to improve patient care, Dr. Sivera said in an interview. The level of evidence and grade of recommendation were made according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Gout affects up to 2% of men in Western countries, and is associated with morbidity, disability, and poorer quality of life. Despite the availability of a number of guidelines and recommendations, management of the condition is often suboptimal, she said.

"Gout is a curable disease, but evidence shows that many patients are mismanaged with regard to both treatment and diagnosis. Even in a rheumatology clinic, only about a quarter of the patients have a diagnosis of gout established by MSU crystal identification, and in a U.K. study, only one in three patients with a diagnosis of gout were taking urate-lowering therapy," she said.

Research shows that when guidelines are implemented, they improve the quality of care. Educational outreach has an effect on implementation, she said, noting that "both dissemination and education – in both gout and in evidence-based medicine – are an integral part of the 3e Initiative, so these multinational recommendations have the potential to positively influence the standard of care."

The 3e recommendations follow those published in 2012 on behalf of the American College of Rheumatology, which centered on the treatment and prophylaxis of acute gout flares and the appropriate use of urate-lowering therapy.

"Some of the recommendations provided are similar, such as treating to a target serum uric acid level, and the ‘start low, go slow’ approach to allopurinol therapy. This highlights the general consensus on many aspects of the optimal standard of gout management," Dr. Sivera said.

Where the 3e recommendation and the ACR guidelines overlap, there is, indeed, general agreement, Dr. John FitzGerald of the University of California, Los Angeles, said in an interview.

Both processes benefited from Delphi consensus methodologies and systematic literature reviews to inform decision making. However, the two diverge with respect to other aspects of the methodology and presentation, he noted.

"The RAND/UCLA methodology used by ACR resulted in guidelines that were evidence based to be the most efficacious recommendations. As noted, the RAND/UCLA methodology excludes cost of therapy (as typically there are insufficient head-to-head therapeutic cost-efficacy studies on which to base recommendations). The ACR guidelines therefore leave it to the practitioner to use the efficacy-based recommendations, along with their clinical and practical knowledge, to then provide recommendations for specific patients. As an example, allopurinol and febuxostat have relatively similar efficacy but significant cost differences," said Dr. FitzGerald, who co-led the ACR guidelines development project.

"The 3e approach incorporates that next step in decision making to provide evidence-based and practical recommendations to the practitioner," he said.

The ACR effort addressed four specific domains of gout management: treatment of acute gouty attacks, management of urate-lowering therapy, management of chronic tophaceous gout, and prophylaxis of acute gouty attacks. Although the 3e effort focused on 10 specific, clinically relevant questions, it is valuable for other reasons as well, such as the inclusion of diagnosis as part of the recommendations, and the fact that asymptomatic hyperuricemia is addressed, he said, noting that neither of these was addressed by the ACR guidelines.

The 3e recommendations also address the use of benzbromarone, a uricosuric agent that is not available in the United States.

While the 3e effort lacks the extent of detail included in the ACR guidelines, such as the inclusion of specific information on allopurinol dosing, the 3e group is to be commended for the size of the effort, Dr. FitzGerald said, stressing the value of the input from nearly 500 rheumatologists from 14 countries.

Indeed, the extensive effort by "a large group of practicing rheumatologists from many different countries in Europe, South America, and Australasia resulted in the recommendations addressing those aspects [of gout diagnosis and management] that rheumatologists found most clinically relevant," Dr. Sivera said.

She and her colleagues concluded that "the high level of agreement with the final recommendations and the multinational participation increase their utility and will hopefully facilitate their dissemination and implementation worldwide."

The 3e Gout Program was sponsored by AbbVie. Dr. Sivera reported receiving fees from Menarini for preparing educational presentations, and other authors reported receiving lecture or consulting fees and/or research grants from many companies, including AbbVie. Dr. FitzGerald reported receiving honoraria and grant support from the ACR.

Identification of monosodium urate crystals, either in a joint fluid sample or in a tophi aspirate, should be performed for a definite diagnosis of gout, according to new multinational evidence-based recommendations on the diagnosis and management of the disease.

When identification of monosodium urate (MSU) crystals is not possible, the diagnosis can be supported by classical clinical features such as podagra, tophi, or rapid response to colchicine, or by characteristic imaging findings, Dr. Francisca Sivera of Hospital General Universitario de Elda (Spain) and her colleagues reported on behalf of the 2011 3e (Evidence, Expertise, Exchange) Initiative. The initiative is a multinational collaboration tasked with promoting evidence-based practice in rheumatology through the development of practical recommendations that address relevant clinical issues.

The MSU identification recommendation is one of 10 recommendations developed by 474 rheumatologists from 14 countries who participated in the 2011 3e Initiative. In keeping with 3e protocol, a panel of 78 experts representing the 14 countries developed 10 key clinical questions pertinent to the diagnosis and management of gout, each of which was investigated via extensive literature review. Recommendations for each of the questions were then formulated, debated, and voted on by Initiative participants, and each recommendation was graded based on the level of evidence.

In addition to diagnosis, the gout recommendations address comorbidity screening, acute gout treatment, lifestyle counseling, urate-lowering therapy, flare prophylaxis, the effect of comorbidities on drug selection, patient monitoring, tophi treatment, and management of asymptomatic hyperuricemia (Ann. Rheum. Dis. 2013 July 18 [doi: 10.1136/annrheumdis-2013-203325]).

Specifically, with a high level of agreement that ranged from a mean of 8.1 to 9.2 on a 1-10 scale, the 3e Initiative participants recommended:

• Assessing renal function and cardiovascular risk factors in patients with gout and/or hyperuricemia.

• Treating acute gout with low-dose colchicine, nonsteroidal anti-inflammatory drugs, and/or glucocorticoids, depending on comorbidities and the risk of adverse effects.

• Advising patients about health lifestyle choices.

• Using allopurinol first-line as urate-lowering therapy, and considering uricosurics as alternatives when necessary.

• Educating patients on the risk and management of flares – and using prophylaxis – when introducing urate-lowering therapy.

• Using allopurinol with close monitoring, and starting at a low dose with slow titration, in patients with mild to moderate renal impairment.

• Setting the treatment target for serum urate at below 0.36 mmol/L (6 mg/dL) with eventual absence of gout attacks and resolution of tophi.

• Treating tophi medically by achieving a sustained reduction in serum uric acid, preferably below 0.30 mmol/L (5 mg/dL) and reserving surgery for select cases, such as those involving nerve compression, mechanical impingement, or infection.

• Forgoing pharmacological treatment of asymptomatic hyperuricemia.

The ultimate goal of these recommendations, which were based on 1a-5 evidence levels, and which received recommendation grades ranging from B to D, is to improve patient care, Dr. Sivera said in an interview. The level of evidence and grade of recommendation were made according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Gout affects up to 2% of men in Western countries, and is associated with morbidity, disability, and poorer quality of life. Despite the availability of a number of guidelines and recommendations, management of the condition is often suboptimal, she said.

"Gout is a curable disease, but evidence shows that many patients are mismanaged with regard to both treatment and diagnosis. Even in a rheumatology clinic, only about a quarter of the patients have a diagnosis of gout established by MSU crystal identification, and in a U.K. study, only one in three patients with a diagnosis of gout were taking urate-lowering therapy," she said.

Research shows that when guidelines are implemented, they improve the quality of care. Educational outreach has an effect on implementation, she said, noting that "both dissemination and education – in both gout and in evidence-based medicine – are an integral part of the 3e Initiative, so these multinational recommendations have the potential to positively influence the standard of care."

The 3e recommendations follow those published in 2012 on behalf of the American College of Rheumatology, which centered on the treatment and prophylaxis of acute gout flares and the appropriate use of urate-lowering therapy.

"Some of the recommendations provided are similar, such as treating to a target serum uric acid level, and the ‘start low, go slow’ approach to allopurinol therapy. This highlights the general consensus on many aspects of the optimal standard of gout management," Dr. Sivera said.

Where the 3e recommendation and the ACR guidelines overlap, there is, indeed, general agreement, Dr. John FitzGerald of the University of California, Los Angeles, said in an interview.

Both processes benefited from Delphi consensus methodologies and systematic literature reviews to inform decision making. However, the two diverge with respect to other aspects of the methodology and presentation, he noted.

"The RAND/UCLA methodology used by ACR resulted in guidelines that were evidence based to be the most efficacious recommendations. As noted, the RAND/UCLA methodology excludes cost of therapy (as typically there are insufficient head-to-head therapeutic cost-efficacy studies on which to base recommendations). The ACR guidelines therefore leave it to the practitioner to use the efficacy-based recommendations, along with their clinical and practical knowledge, to then provide recommendations for specific patients. As an example, allopurinol and febuxostat have relatively similar efficacy but significant cost differences," said Dr. FitzGerald, who co-led the ACR guidelines development project.

"The 3e approach incorporates that next step in decision making to provide evidence-based and practical recommendations to the practitioner," he said.

The ACR effort addressed four specific domains of gout management: treatment of acute gouty attacks, management of urate-lowering therapy, management of chronic tophaceous gout, and prophylaxis of acute gouty attacks. Although the 3e effort focused on 10 specific, clinically relevant questions, it is valuable for other reasons as well, such as the inclusion of diagnosis as part of the recommendations, and the fact that asymptomatic hyperuricemia is addressed, he said, noting that neither of these was addressed by the ACR guidelines.

The 3e recommendations also address the use of benzbromarone, a uricosuric agent that is not available in the United States.

While the 3e effort lacks the extent of detail included in the ACR guidelines, such as the inclusion of specific information on allopurinol dosing, the 3e group is to be commended for the size of the effort, Dr. FitzGerald said, stressing the value of the input from nearly 500 rheumatologists from 14 countries.

Indeed, the extensive effort by "a large group of practicing rheumatologists from many different countries in Europe, South America, and Australasia resulted in the recommendations addressing those aspects [of gout diagnosis and management] that rheumatologists found most clinically relevant," Dr. Sivera said.

She and her colleagues concluded that "the high level of agreement with the final recommendations and the multinational participation increase their utility and will hopefully facilitate their dissemination and implementation worldwide."

The 3e Gout Program was sponsored by AbbVie. Dr. Sivera reported receiving fees from Menarini for preparing educational presentations, and other authors reported receiving lecture or consulting fees and/or research grants from many companies, including AbbVie. Dr. FitzGerald reported receiving honoraria and grant support from the ACR.