General description of procedure, equipment, technique
Rising rates of obesity and metabolic syndrome are leading to a pandemic of diabetes across the world. Advances in management of diabetes and other risk factors for cardiovascular disease have led to reduction in mortality from cardiovascular disease in diabetics. However, cardiovascular disease remains the leading cause of mortality among diabetics.
Management of stable coronary artery disease (CAD) in diabetics can be broadly categorized into medical management and coronary revascularization therapies. Control of risk factors for CAD, such as management of hypertension, dyslipidemia, and hyperglycemia are important in preventing the progression of CAD but are beyond the scope of this chapter.
Medical treatment or revascularization
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial enrolled diabetic subjects with documented coronary narrowing by angiography who were deemed suitable for either revascularization plus medical therapy or medical therapy alone by the treating cardiologist. These subjects were randomized to one of the two groups of medical therapy alone or medical therapy with revascularization.
The choice of revascularization—coronary bypass surgery (CABG) or percutaneous coronary intervention (PCI)—was decided by the treating cardiologist. Generally patients with more extensive CAD (3 vessel) were sent for CABG, whereas those with less extensive disease (1 or 2 vessel) underwent PCI. Medical treatment was aimed at treating angina, as well as intensive treatment of CAD risk factors.
Overall, the study showed no difference in 5-year mortality between medical therapy alone versus medical therapy plus revascularization (12% vs. 12%, P = .97). Nor was the combined event rate (death, myocardial infarction, and stroke) different between the groups (23% vs. 24%, P = .70). However, subjects undergoing CABG plus medical therapy did better compared to medical therapy for the composite outcome (22% vs. 31%, P = .01), whereas no such benefit was seen in the subgroup assigned to PCI plus medical therapy.
COURAGE was a randomized trial of 2,287 patients who had objective evidence of ischemia and significant coronary artery disease by coronary angiography. Patients were required to have at least one or more lesion(s) of 70% stenosis accompanied by a positive stress imaging study or a lesion of 80% or more in the presence of typical symptoms of angina.
Of note all patients had angiography before randomization, hence their coronary anatomy was known. One third of the patients enrolled had diabetes. Patients were randomized to PCI plus optimal medical therapy or optimal medical therapy alone. At an average follow-up of 4.6 years, there was no difference in the primary composite outcome (all-cause mortality plus nonfatal MI) between the two groups. There was no significant interaction between treatment effect and a baseline diagnosis of diabetes.
It is important to note that during the follow-up period of BARI-2D, about 40% of the subjects initially randomized to medical therapy alone underwent revascularization due to progression of symptoms or acute coronary syndrome. This is similar to what happened in the PCI versus medical therapy trial for stable CAD in the general population—the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. One third of the patients in the optimal medical therapy group underwent PCI during the follow-up period.
Effect on health status and quality of life
Comorbidities worsen quality of life in patients with stable coronary disease in general and diabetes adds to this especially in insulin-dependent subjects. Analysis of quality of life after PCI in the overall population was compared to medical therapy in the COURAGE trial. Although in the short-term quality of life was better in the PCI arm, at 36 months there was no difference between the two groups. In general subjects with more severe angina achieved greater benefit from PCI.
The BARI-2D trial looked at health status using the Duke Activity Status Index and modified RAND instruments for Energy/Fatigue, Health Distress, and Self Rated Health. Depression was measured with the Center for Epidemiological Studies Depression Scale.
Compared with medical therapy, revascularization was associated with a small but significantly greater improvement in health status. The differences were seen by the end of 1 year of follow-up and maintained at 4 years. The Duke Activity Status Index improvement was significantly larger in the subgroup that underwent CABG compared to the PCI group.
Summary and recommendations for revascularization
Subjects with diabetes and stable coronary artery disease should receive optimal medical therapy similar to nondiabetics. This includes aggressive risk factor modification and specific antianginal therapy. It is important to note diabetics may present more often with atypical symptoms of angina than nondiabetics. But once the diagnosis of CAD is made, the therapy is similar for diabetics and nondiabetics.
While BARI-2D and COURAGE show that optimal medical therapy is similar to revascularization as far as mortality and cardiovascular events are concerned, it is important to remember the patient selection criteria for these trials and be careful while generalizing results.
In BARI-2D subjects with left main disease or 3-vessel CAD with left ventricular dysfunction were excluded from the trial. Major exclusion criteria for COURAGE were subjects with persistent Canadian Cardiovascular Society class IV angina, markedly positive stress test (substantial ST segment depression in stage I of Bruce protocol or hypotensive response to exercise), refractory heart failure, and ejection fraction <30%.
The most updated guidelines for myocardial revascularization come from the European Society of Cardiology. The main indication for revascularization is persistent symptoms despite optimal medical therapy. Other indications are less common and include having a high-risk profession such as a pilot.
Data for improving prognosis is less convincing using PCI than CABG. A small nuclear substudy of the COURAGE trial showed that if the ischemic burden is >10%, PCI lowered the risk of death or MI. This will be discussed further below in the choice between PCI and CABG. Table 1 shows the indications for coronary revascularization.
Revascularization technique: PCI versus surgery
The goals of revascularization for significant coronary disease vary between patients. At one end of the spectrum they include quality of life issues, such as reducing symptoms of angina or exertional dyspnea, and improving exercise tolerance.
Revascularization might also decrease the cost of care by reducing event rates (congestive heart failure (CHF), NSTEMI, unstable angina) and thereby recurrent hospitalizations. In most situations the most important goal is reducing mortality over time. There are fundamental differences in the procedure related risk, recovery time, and durability between PCI and surgery that may make one procedure preferable to the other for a given clinical setting.
Survival after surgery or PCI
Multiple registry studies and subset analyses have shown an absolute survival benefit over time for surgical revascularization compared to PCI in diabetic patients with multivessel coronary disease, although the differences were not always statistically significant. A subset analysis of the BARI trial demonstrated this in 1997.
When the 353 patients (19% of the randomized population) with treated diabetes mellitus were compared, 80.6% of patients treated by surgery and 65.5% of patients treated with angioplasty survived for 5 years (P = .003). Analysis of the New York State cardiac registries in 2005 showed superior 3-year survival rates for surgical treatment of diabetics with two or three vessel coronary artery disease when the LAD was involved.
A meta-analysis of 10 clinical trials published in 2009 showed a significant reduction in mortality among 615 diabetics treated with CABG when compared to 618 diabetics who received PCI using either balloon angioplasty or bare metal stents (HR 0.70, CI 0.56-0.87). A subset analysis of diabetic subjects enrolled in the SYNergy Between PCI With TAXUS and Cardiac Surgery (SYNTAX) trial was published after 3 years of follow-up. Mortality was 8.7 % among 221 patients treated with surgery and 13.6% for the 231 patients treated with drug eluting stents (P = .113).
In BARI-2D there was also a small, but not statistically significant survival time advantage for surgery versus medical therapy at 5 years (86.4% vs. 83.6%, P = 0.33). While it did not specifically report outcomes for diabetic patients undergoing revascularization, the recent American College of Cardiology Foundation-The Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization sTrategies (ASCERT) study also showed significantly better survival for surgery compared to PCI for multivessel disease (83.6% vs. 79.2% at 4 years, risk ratio 0.79). The report did indicate that the difference was maintained across multiple subgroups, including diabetes.
Three randomized trials have addressed outcomes of surgery versus PCI with either bare metal or drug eluting stents. The 5-year results of CARDia were presented at the 2012 ESC. All-cause mortality was only marginally better with CABG (12.6% vs. 14% for PCI, HR 1.17, CI 0.73 to 1.87).
The recently published the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial has now confirmed superior survival for surgery at 5 years (89.1% vs. 83.7%, P = .049) when compared with treatment using early generation drug eluting (sirolimus or paclitaxel) stents. VA CARDS also showed better survival in diabetics treated with surgery rather than PCI after 2 years of follow-up (95% vs. 79%, P = .0106).
None of these randomized studies comparing PCI to surgery among diabetics were powered for a mortality endpoint alone. The finding of a significant reduction in all-cause mortality with surgery in two of three randomized trials, two large database studies and a large meta-analysis, as well as trends toward improved survival in other subset analyses is strong evidence for superior survival outcomes with surgery.
Caveats to the survival benefit of surgery
It is important to note that the survival benefit of surgery generally is not immediate. One-year mortality in CARDia (3.2% PCI vs. 3.2% CABG) and 2-year survival rate in FREEDOM (6.7% PCI vs. 6.3% CABG) were virtually identical between treatment arms and not statistically different at 1 year in VA CARDS (8.2% PCI vs. 5.0% CABG).
Survival curves from BARI-2D show about a 2.5-year delay before a survival effect begins to arise for surgery compared to aggressive medical treatment. This delayed survival effect is similar to what was seen in early trials comparing surgery to medical management among all patients with coronary artery disease.
A greater delay to a net survival benefit would be expected where surgical risk is high or the risk with continued medical therapy is low. One of the important concerns about surgical management is the risk of stroke.
Overall, there appears to be a greater risk of stroke after surgery compared with PCI. The risk of stroke with surgery increases with advanced age, presence of significant cerebrovascular disease, and a history of previous cerebrovascular events.
What lessons can be learned from the recent trials comparing surgery to PCI with drug eluting stents? First, the magnitude of survival benefit for surgery tends to track the underlying risk of future events in the patient population being studied.
An important aspect of BARI-2D was that all patients were considered to be stable enough to continue medical therapy rather than proceeding to revascularization. Of the three published randomized trials conducted exclusively in diabetics, CARDia had the lowest overall mortality over time; VA CARDS had the highest observed mortality and FREEDOM was intermediate.
The net survival benefit for surgery was 1.4% at 5 years for CARDia, 5.4% at 5 years for FREEDOM, and 16% at 2 years for VA CARDS. This suggests that the greatest effect occurs where the underlying risk is highest.
The angiographic entry criteria for these trials may provide some clues as to where the benefit is greater. Both CARDIA and FREEDOM enrolled patients with 2- or 3-vessel disease deemed suitable for either treatment, but neither required involvement of the anterior wall (LAD territory), whereas this was an entry requirement of VA CARDS.
About 8% of patients enrolled in FREEDOM did not have significant disease of the LAD. The number of patients without LAD disease is not stated in the CARDia reports, but CARDia did allow single vessel disease not involving the LAD when a complex bifurcation lesion was present, a cohort where a survival benefit for revascularization versus medical therapy is questionable.
A second lesson from these trials is that there is a significant regional variation in treatment effect. This was demonstrated in FREEDOM with greater advantage for surgery among sites in North America compared with Europe.
This variation may also help to explain the differences between CARDia and VA CARDS since CARDia was entirely a European study and VA CARDS was conducted completely within the U.S. Whether the regional disparity in results comes from differences in how the treatments are performed or from unknown factors in the underlying patient populations cannot be determined.
The regional variation, however, also follows the general observation that higher event rates result in greater advantage for surgery. The overall event rates in FREEDOM were significantly higher in North American sites than elsewhere.
Reducing future event rates
Composite endpoints have favored bypass surgery over PCI among diabetics to a greater extent than mortality alone. The event rates, however, are generally driven by an increased risk of repeat revascularization for PCI.
The greater risk of repeat PCI is likely to be an acceptable tradeoff in situations where survival benefit is small and surgical risk is high but could drive decisions when surgical risk is low. No solid economic comparisons are available as yet, but the higher long-term event rates and higher cost of drug eluting stents compared to bare metal stents suggest that surgery may be a cost-effective alternative to stenting when a sufficient number of sites are involved.
Stenting has generally been as effective in controlling angina as surgery when employed in patients with less complex disease. Thus, while the SYNTAX score has not been useful in determining which patients might derive a survival advantage from stenting, it may be useful to identify patients likely to have more sustained symptom relief since it is essentially a composite of the complexity of coronary lesions and correlates well with the need for repeat revascularization.
None of the trials conducted exclusively in diabetics have randomized patients with left main coronary artery disease. Thus, there are no solid comparative data for either PCI versus CABG or revascularization versus intensive medical management in diabetic patients.
Although a subgroup of SYNTAX patients had both diabetes and left main stenosis, this subgroup has not been reported independently and is likely to be underpowered for any meaningful comparison. In the overall population, SYNTAX demonstrated a slight absolute improvement in major adverse cardiac or cerebrovascular event (MACCE) for PCI in the lowest tercile of SYNTAX scores compared with surgical revascularization.
This was not, however, statistically significant (P = .33). Since the presence of diabetes seems to accentuate the benefits for surgery versus PCI, surgery should be considered the preferred treatment for almost all diabetic patients with left main disease until more definitive data is available.
One of the issues that cannot be addressed by randomized clinical trials is the best treatment option for patients at highest risk for complications from a particular treatment modality. High-risk patients are generally excluded from trials at the screening phase.
In the FREEDOM trial, the Euroscore estimates of surgical risk were quite low. Thus, information regarding outcomes for high-risk patients is only available in registries or case series.
Because of the inherent selection bias of these types of studies, accurate comparative efficacy is difficult to ascertain. One of the messages from the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) trial was that one or two major surgical risk factors can negate a survival benefit for surgery compared to balloon angioplasty.
The basic message from SYNTAX is that increasing complexity of PCI (assessed by SYNTAX score) drives down long-term success rates for PCI, but has no correlation with surgical outcomes. How to balance patients at high risk for complications from both procedures has not been addressed in any systematic fashion.
Although both BARI-2D and COURAGE suggest that an initial strategy of medical management is reasonable for diabetic patients with stable coronary artery disease, a significant portion of patients in both of these trials proceeded with revascularization during follow-up. Thus, neither of these trials actually assess outcomes with pure medical management. Importantly, the trials do not provide any information regarding the optimal timing of a switch in strategy.
Another important issue for diabetic patients with coronary artery disease is the presence of diffuse disease of moderate angiographic severity. The diffuse nature of the disease can make grading of lesions problematic due to a lack of a good reference point.
There are no clear data regarding when diffuse disease is severe enough to warrant a revascularization strategy. There are, however, important differences in the criteria used for the three randomized trials that may provide some insight.
CARDia had the least stringent entry criteria, requiring only a 50% stenosis in two or more territories, a complex bifurcation lesion in any major epicardial vessel, or an isolated stenosis in the LAD prior to the first septal branch. FREEDOM required multivessel coronary disease of >70% stenosis in at least two major territories, but did not require involvement of the anterior wall. VA CARDS required involvement of the anterior wall with or without additional territories. It also required objective evidence for ischemia in at least one territory if none of the angiographic stenoses were 70% or greater.
Finally, when PCI is chosen as the original revascularization strategy, a question arises as to the appropriate strategy when repeat intervention is being contemplated. There is little information regarding outcomes of repeat PCI compared to surgery.
Factors that favor a switch to surgical strategy would include progression to significant disease in the anterior wall, interval deterioration of left ventricular function, a larger territory of ischemia, short interval to restenosis, and resistance to dual antiplatelet therapies.
Summary and recommendations
In choosing a revascularization strategy for a particular patient, there will be multiple interactions between patient and procedural factors that come into play. Generally, factors that favor better survival with surgery rather than medical management (anterior wall involvement, decreased left ventricular function, larger territories of ischemia, etc.) would favor surgery over PCI for the survival advantage at least in situations where surgical risk is acceptable.
When the expected survival benefit compared to medical therapy is modest and the complexity of lesions is low, good symptom relief may be obtained with PCI over at least an intermediate time frame. The expected use of an internal mammary artery (IMA) graft to the anterior wall in single-vessel disease and the possibility of additional arterial grafts in multivessel disease may lead to better durability for surgery regardless of the SYNTAX score, particularly when a longer time frame (5 to 15 years) is considered. A summary of decision points is given in Figure 1 as a general strategy to approach revascularization in a diabetic patient.
What’s the evidence?
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- General description of procedure, equipment, technique
- Medical treatment or revascularization
- Effect on health status and quality of life
- Summary and recommendations for revascularization
- Revascularization technique: PCI versus surgery
- Survival after surgery or PCI
- Caveats to the survival benefit of surgery
- Reducing future event rates
- Reducing symptoms
- Persistent unknowns
- Summary and recommendations
- What’s the evidence?