Diabetes Mellitus and Multi-vessel Disease. Judith Walsh, MD, MPH. Professor of Medicine. Division of General Internal Medicine

Transcription

1 TITLE: Percutaneous Coronary Intervention as an Alternative to Coronary Artery Bypass Grafting in Patients with Diabetes Mellitus and Multi-vessel Disease AUTHOR: Judith Walsh, MD, MPH Professor of Medicine Division of General Internal Medicine Department of Medicine University of California San Francisco PUBLISHER: California Technology Assessment Forum DATE OF PUBLICATION: March 6, 2013 PLACE OF PUBLICATION: San Francisco, CA 1

2 PERCUTANEOUS CORONARY INTERVENTION AS AN ALTERNATIVE TO CORONARY ARTERY BYPASS GRAFTING IN PATIENTS WITH DIABETES MELLITUS AND MULTI- VESSEL DISEASE A Technology Assessment Introduction The California Technology Assessment Forum is requested to review the scientific evidence for the use of percutaneous coronary intervention as an alternative to coronary artery bypass grafting in patients with diabetes mellitus. This topic is being addressed because of recent publication of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease (FREEDOM) trial. This is the first time that CTAF has addressed this topic. Background Coronary heart disease (CHD) is the number one cause of death in both men and women in the U.S. Untreated CHD typically leads to progressive angina, myocardial infarction, left ventricular (LV) dysfunction and congestive heart failure (CHF) and sudden death. The goals of therapy in CHD are alleviation of anginal symptoms, to delay or prevent progression of CHD and to prevent myocardial infarction (MI) or death. 2

3 CHD treatment typically starts with medical therapy, including aggressive risk factor reduction. Therapy includes aspirin, reaching treatment goals for hypertension and hyperlipidemia, smoking cessation, and for patients with diabetes, control of serum glucose. Medical therapy is the foundation of CHD treatment. All patients need medical treatment regardless of whether they have had revascularization. Coronary heart disease is a significant contributor to morbidity and mortality in patients with diabetes mellitus. CHD is more common in patients with diabetes than in patients without diabetes, and it is more likely to be multi-vessel. Patients with diabetes are more likely to have silent ischemia compared to patients without diabetes. In addition, patients with diabetes with CHD have lower survival rates than patients with CHD who do not have diabetes. Diabetic and non-diabetic patients with multi-vessel coronary artery disease are often considered for revascularization. In the U.S., approximately 700,000 patients undergo revascularization each year. 1,2 The two main indications for revascularization are 1) unacceptable angina and 2) where a survival benefit might be expected from revascularization. Revascularization: Coronary Artery Bypass Grafting The first revascularization treatment developed and used was coronary artery bypass grafting (CABG). When compared with medical management, CABG clearly relieves symptoms and it also improves survival in some patents with stable angina. The Coronary Artery Surgery Study (CASS), which was done in the late 1970s and early 1980s, showed that more patients remained symptom free after CABG than with medical therapy at one year (66% vs 30%) and at five years (63% vs 38%). 3 3

4 Although for many patients with coronary artery disease (CAD) who undergo CABG, there is no mortality benefit, 4-7 certain subgroups do have a mortality benefit from CABG. Patients who have a mortality benefit from CABG compared with medical therapy include those with left main disease or left main equivalent disease, three vessel coronary disease especially in the presence of reduced ejection fraction (EF) and two vessel disease when there is a <75% stenosis in the left anterior descending artery (LAD) proximal to the first septal artery. 6,8-11 The 2011 Recommendations of the American College of Cardiology Foundation/American Heart Association ACCF/AHA on CABG recommend a strong preference for CABG in the following groups of patients: Unprotected left main coronary artery stenosis ( 50%); Significant (>70% stenosis) three vessel disease with or without proximal LAD disease; Two vessel disease with proximal LAD disease (>75% stenosis in the LAD proximal to the first major septal artery); and Patients with one or more significant coronary artery stenosis amenable to revascularization and disabling angina while on maximal medical therapy 12 A weak recommendation for CABG is made for the following groups: Two vessel disease without significant proximal LAD disease but with extensive ischemia; Significant proximal LAD disease and evidence of extensive ischemia if a left internal mammary artery bypass graft can be placed; and Mild to moderate left ventricular systolic dysfunction (EF: 35% - 50%) and significant multi-vessel CAD or proximal LAD stenosis when viable myocardium is present in the region of intended revascularization. 12 4

5 Revascularization recommendations for patients with diabetes are essentially the same as for those patients who do not have diabetes. However, the short term and long term results with either PCI or CABG are typically worse in patients with diabetes than in patients without diabetes. 13 Revascularization: Percutaneous Coronary Interventions Percutaneous coronary interventions (PCIs) are therapeutic procedures where a balloon or catheter is inserted into a coronary artery. PCIs are non-surgical treatments and are potentially less invasive options for the treatment of CAD when compared with CABG. PCI is typically preferred to CABG for single vessel disease but its role in more severe forms of CAD has been less clear. Initial PCI procedures included balloon angioplasty where a balloon was used to open up the stenotic artery. Although balloon angioplasty was the initial type of PCI, high rates of restenosis led to adding a stent after the artery was opened. The initial stents that were used were bare metal stents (BMS) but BMS were still associated with a significant restenosis risk. The current standard for PCI is angioplasty with the addition of a drug eluting stent (DES). DES have been shown to reduce the rate of restenosis compared with BMS. DES inhibit neointimal hyperplasia, a response that may be stimulated by BMS. DES include a standard metallic stent which has a polymer coating and an anti-restenotic drug. The drug is mixed within the polymer and is released over a period of days for up to a year after the procedure. There are currently four types of approved DES. They include sirolimus-eluting, paclitaxeleluting, zotarolimus-eluting and everolimus-stents. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive and anti-proliferative properties DES were developed to prevent the proliferation of smooth muscle cells. Paclitaxel interferes 5

6 with microtubule function that are responsible for chromosome segregation during cell division. They also prevent smooth muscle proliferation. Everolimus is a sirolimus derivate as is zotarolimus. DES have similar safety profiles when compared with BMS. However, DES have a higher risk of late stent thrombosis than BMS and they require longer and more consistent antiplatelet therapy. In terms of efficacy, DES are generally preferred given that they significantly lower the rate of target lesion revascularization when compared with BMS. Currently the standard of care when performing PCI is to use a DES rather than a BMS in most patients given the evidence for increased efficacy with DES. When comparing CABG to PCI, many of the earlier studies compared CABG to balloon angioplasty or BMS, whereas the more recent studies compare CABG to DES. Revascularization In Patients With Diabetes Among patients undergoing revascularization, approximately 25%-30% have diabetes. The indications for revascularization are similar in patients with diabetes and patients without diabetes, although the outcomes in patients with diabetes are typically worse. Most of the studies in patients with diabetes comparing PCI with CABG have been subgroup analyses of larger studies. Given that patients with diabetes have worse short and long term outcomes with any revascularization, it is important to compare the efficacy of CABG with the efficacy of PCI specifically in diabetic populations. The goal of this assessment is to evaluate PCI as an alternative to CABG in patients with diabetes with multi-vessel CAD. 6

7 TECHNOLOGY ASSESSMENT (TA) TA Criterion 1: The technology must have final approval from the appropriate government regulatory bodies. The U.S. Food and Drug Administration (FDA) defines a coronary stent as a device made of a metal scaffold placed via a delivery catheter during PCI into the coronary artery or saphenous vein graft to widen or maintain the opening of the narrowed coronary vessels. Coronary artery stents are classified as Class III devices and approved only via the pre-market approval (PMA) process. Manufacturers with FDA approved coronary artery stents and systems include Cordis Corporation, - a subsidiary of Johnson & Johnson, Co., Abbot Vascular, Boston Scientific Corporation, Medtronic, and Medinol, Ltd. TA Criterion 1 is met. TA Criterion 2: The scientific evidence must permit conclusions concerning the effectiveness of the technology regarding health outcomes. The Medline database, Cochrane clinical trials database, Cochrane reviews database and Database of Abstracts of Reviews of Effects (DARE) were searched using the search terms coronary artery bypass, CABG, percutaneous coronary intervention, PCI stents and coronary artery disease, and diabetes mellitus or diabetes. The search was performed for the period from database inception 7

8 through December, The bibliographies of systematic reviews and key articles were manually searched for additional references and references were requested form the device manufacturer. The abstracts of citations were reviewed for relevance and all potentially relevant articles were reviewed in full. Inclusion criteria were: Study had to evaluate PCI and CABG in patients with diabetes and multivessel disease; Study had to measure clinical outcomes; Included only humans; and Published in English as a peer reviewed article Studies were excluded if they only focused on non-clinical outcomes. A total of 373 potentially relevant articles were identified. These 373 abstracts were evaluated and 331 were excluded. Reasons for exclusion included not addressing the study question, not reporting clinical outcomes, and not comparing PCI to CABG. After evaluation of the remaining 42 abstracts, exclusion of duplicate publications and review of articles, a total of 14 published clinical trials are included in this evaluation. Details of the clinical trials are described in Table 1. There were five trials comparing CABG to balloon angioplasty These five trials included a total of 640 patients with diabetes. In all these studies, patients with diabetes were a subgroup of the total number of patients. An additional five studies compared BMS with CABG These studies included a total of 684 patients with diabetes who were again a subgroup of all patients. Four trials compared DES with CABG. 22,24-32 These studies included 3,021 patients, 1,900 of whom came from one study, the FREEDOM trial. 27,32 In two of the studies, patients with diabetes were a subgroup of the total 8

9 number of patients included. 22,26,29-31 Two of the studies included only patients with diabetes. 27,28,32 Study outcomes included mortality, non-fatal MI, Q wave MI, CVA and rates of revascularization. Composite endpoints were frequently used. Typical composite endpoints included MACCE (major cardiovascular and cerebrovascular events) defined as death, CVA, MI and repeat revascularization, and MACE (major cardiovascular events) defined as death, MI and repeat revascularization. Other included outcomes were angina class at one year and freedom from angina pectoris at one year. Level of Evidence: 1,2 TA Criterion 2 is met. 9

10 Table 1: Description of Studies of PCI vs CABG in Patients with Diabetes Mellitus Name of study Outcomes reported specifically for patients with diabetes N Patients with diabetes Inclusion Criteria Intervention Balloon Angioplasty vs CABG BARI 18 Yes 353 Multi-vessel CAD and Balloon angioplasty candidates for PTCA or vs CABG CABG CABRI 17 Yes 124 Multi-vessel CAD and PTCA vs CABG eligible for revascularization EAST 14 Yes 90 Multi-vessel CAD who could PTCA vs CABG undergo either procedure GABI 15 Yes 41 Symptomatic multi-vessel disease PTCA vs CABG All cause mortality New MI Main Outcomes Mortality and angina class at one year Composite: death, Q wave MI or major ischemic thallium defect at three year follow-up Freedom from angina pectoris at one year RITA-1 16 Yes 62 Single or multi-vessel disease and revascularization appropriate Bare Metal Stenting vs CABG ARTS-I 22 Yes 208 Multi-vessel CAD including LAD and at least one other lesion in another major PTCA vs CABG BMS vs CABG Death or non-fatal MI Composite: MACCE -death, CVA, MI and repeat revascularization 10

11 epicardial artery AWESOME 20 Yes 144 Medically refractory unstable angina and at high risk for CABG SOS 23 Yes 142 Revascularization clinically indicated and appropriate by either strategy ERACI II 19 Yes 78 Multi-vessel CHD and clinical indication for revascularization MASS II 21 Yes 115 Multi-vessel CAD and eligible for each strategy Drug eluting stents vs CABG ARTS-II 22,24,25 Yes 159 Multi-vessel CAD including LAD and at least one other lesion in another major epicardial artery BMS vs CABG PCI (any commercially available BMS) vs CABG PCI with stent placement vs CABG PCI with stent vs CABG Sirolimus eluting stent single arm compare with historical controls 30 day, six month and 36 month survival Mortality Rate of repeat revascularization Freedom from major adverse cardiovascular events (MACE) at 30 days, one year, three years and five years Composite: Mortality, Q wave MI, and refractory angina requiring revascularization Composite: MACCE -death, CVA, MI and repeat revascularization CARDia 28 No 510 Diabetic patients with multivessel or complex single vessel CAD SYNTAX 26,29-31 Yes: prespecified 452 Left main and or three vessel disease PCI plus stenting (69% sirolimus and 31% BMS) vs CABG TAXUS express DES (paclitaxel) vs CABG Composite: all cause mortality, MI and stroke Composite: all cause mortality, CVA, MI or repeat revascularization 11

12 FREEDOM 27,32 No 1,900 Multi-vessel coronary disease suitable for either PCI or CABG Drug eluting stent (sirolimus or paclitaxel) Composite: all cause mortality, nonfatal MI and non-fatal stroke ARTS-I: Arterial Revascularization Study I AWESOME: Angina With Extremely Serious Operative Mortality Evaluation BARI: Bypass Angioplasty Revascularization Investigation CABG: Coronary Artery Bypass Graft CABRI: Coronary Angioplasty versus Bypass Revascularization CAD: Coronary Artery Disease CARDia: Coronary Artery Revascularization in Diabetes CHD: Coronary Heart Disease EAST: Emory Angioplasty vs Surgery Trial ERACI II: Argentine Randomized Study-Coronary Angioplasty with Stenting Versus Coronary Bypass Surgery in Multi- Vessel Disease FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease GABI: German Angioplasty Bypass Surgery Investigation MACCE: Major Adverse Cardiac and Cerebrovascular Events MACE: Major Adverse Cardiac Events MASS II: Medicine, Angioplasty or Surgery Study MI: Myocardial Infarction PCI: Percutaneous Coronary Intervention PTCA: Percutaneous Transluminal Coronary Angioplasty RITA-1: Randomized Intervention Treatment of Angina SOS: Surgery or Stent Study 12

13 SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery 13

14 Table 2: Outcomes of Studies of PCI vs CABG in Patients with Diabetes Mellitus Name Length of follow-up Results Balloon Angioplasty vs CABG BARI years Five year survival 80.6% for CABG and 65.5% for PTCA (p=0.003) CABRI One year Overall mortality at one year follow-up similar in both groups (2.7% CABG and 3.9% PTCA: NS) EAST Three years Overall composite: 27.3% CABG vs 28.8% PTCA; NS Five year survival 26/29 (89.7%) PCI vs 27/30 CABG 90%): NS Comments Patients with diabetes not analyzed separately GABI Overall freedom from angina: 74% CABG vs 71% PTCA; NS Patients with diabetes not analyzed separately RITA years Primary outcome: 5/29 PTCA vs 12/33 CABG: p=.055 Bare Metal Sten tenting vs CABG ARTS-I Five years MACCE higher in patients with BMS compared with CABG (53.8% vs 23.4%: p= 0.001) AWESOME 20 Three years Survival at 36 months: 72% CABG vs 81% PCI: NS (36 months) SOS 23 Six year 17.6% of PCI patients died vs 5.4% in CABG group (HR 3.53: 95% C.I to 10.95) ERACI-II Five years PCI mortality 10% vs CABG mortality 10.2%: NS) MASS-II Five years Overall composite: 21.2% in CABG group vs 32.7% in PCI No difference in treatment effect between diabetic and non-diabetic subgroups 14

15 Name Length of Results Comments follow-up (p=0.0026) 5 year survival: PCI: 47/56 (83.9%) vs CABG: 50/59 (84.7%): NS Drug Eluting Stents vs CABG ARTS-II 24,25 Five years MACCE lower in CABG than DES (23.4% vs 40.5%: p<0.001) Comparison with historical control Onuma, 2010; CARDia 28 One year No difference in composite outcome (death/mi/stroke) 10.5% When subgroup that received DES CABG vs 13.0% PCI (HR 1.25: 95% C.I. 0.75,2.09: p=0.39) Secondary outcome: death, MI stroke or revascularization (69%) compared with CABG, still no difference 11.3% CABG vs 19.3% PCI (HR 1.77:95% C.I : p=0.02) SYNTAX 26,29-31 Three years No difference in composite safety endpoint (death/stroke/mi) at one year between two groups: (10.3% CABG vs 10.1% DES; p=0.96) Repeat revascularization rates higher with DES (20.3% vs 6.4%; p<0.0010) At three years, composite endpoint 22.9% CABG vs 27.0% DES: p=0.002 FREEDOM years Composite outcome at five years more common in PCI group: 26.6% in PCI and 18.7% in CABG: p=0.005 Stroke rate at five years more common in CABG group (5.2% vs 2.4%: p=0.030) ARTS-I: Arterial Revascularization Study I AWESOME: Angina With Extremely Serious Operative Mortality Evaluation BARI: Bypass Angioplasty Revascularization Investigation CABG: Coronary Artery Bypass Graft 15

16 CABRI: Coronary Angioplasty versus Bypass Revascularization CAD: Coronary Artery Disease CARDia: Coronary Artery Revascularization in Diabetes CHD: Coronary Heart Disease EAST: Emory Angioplasty vs Surgery Trial ERACI II: Argentine Randomized Study-Coronary Angioplasty with Stenting Versus Coronary Bypass Surgery in Multi- Vessel Disease FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease GABI: German Angioplasty Bypass Surgery Investigation MACCE: Major Adverse Cardiac and Cerebrovascular Events MACE: Major Adverse Cardiac Events MASS II: Medicine, Angioplasty or Surgery Study MI: Myocardial Infarction PCI: Percutaneous Coronary Intervention PTCA: Percutaneous Transluminal Coronary Angioplasty RITA-1: Randomized Intervention Treatment of Angina SOS: Surgery or Stent Study SYNTAX: Synergy between PCI with Taxus and Cardiac Surgery 16

17 TA Criterion 3: The technology must improve net health outcomes. In order to determine whether PCI improves net health outcomes, the potential benefits and potential risks must be assessed. Potential Benefits CABG has been the standard technique used to treat obstructions in coronary arteries. In order to get the blood to the myocardium, either veins (typically the saphenous) or arteries (internal mammary) are used to bypass the diseased vessels. CABG can relieve symptoms and can prolong life for some individuals but is a major surgical procedure requiring sternotomy and associated with surgical morbidity and mortality as well as a prolonged convalesence. The main potential benefits of PCI are the ability to open a stenotic artery while avoiding the need for a major operation with a sternotomy. The procedure requires a groin incision using local anaesthetic and so avoids the need for major surgery. Patients can often go home on the same day as the procedure. 33 Thus, the main potential benefit is that revascularizaiton can be achieved without the patient needing to undergo major cardiac surgery. Potential Risks 1. Long Term Mortality Most individual trials did not have the power to assess an impact on mortality, A meta-analysis done in 2007 compared the effectiveness of PCI vs CABG in patients in whom revascularization was clinically indicated 34. A total of 23 studies were included: of them; six studies included patients with diabetes and had available data for analysis. Five year survival was similar in 17

18 patients with diabetes who received PCI or who received CABG (79.2% vs 82.2%: NS). In a more recent meta-analysis, Hlatky and colleagues pooled data from ten randomized trials to compare the effectiveness of CABG and PCI according to patients baseline clinical characteristics 35 The main outcome was all cause mortality. Ten trials provided information on 7,812 patients. In six of the trials, the intervention was PCI with balloon angioplasty and in four of the trials, the PCI intervention used BMS. There were a total of 615 patients with diabetes who had CABG and 618 patients with diabetes who unnderwent PCI. Among patients with diabetes, mortality was lower in the CABG group than in the PCI group (HR 0.70: 95% C.I ); however there was no difference in mortality between groups in patients who did not have diabetes (HR 0.98: ). Patient age was a modifying factor in that mortality was higher in patients aged 65 and over who received PCI compared with CABG but treatment effect was not modified by other factors. Thus, mortality is higher in patients with diabetes after PCI than after CABG. Restenosis, Stent Failure, and Need For Revascularization Important long term risks with PCI are restenosis, stent failure and the need for revascularization. In the era of balloon angioplasty, the rate of restenosis was significantly higher than it is currently in the DES era. The main reason for the current use of DES is to reduce the risk of restenosis. Although restenosis can still happen, the rates are lower than with BMS or PTCA. One large meta-analysis of 38 studies showed a reduction in target lesion revascularization with DES as compared with BMS by about 12% at four year folllow-up. 36 In a large registry study that included patients with 18

19 complex coronary lesions, the rate of target vessel revascularization at two years was 7.4% for those who received DES compared with 10.7% for those who received BMS (p<0.001). 37 In the FREEDOM trial, the randomized controlled trial (RCT) of PCI with DES versus CABG in patients with diabetes, the rate of repeat revascularization events at one year was 12.6% in the PCI group vs 4.8% in the CABG group (HR 2.74: 95% C.I ). Thus, although the rate of restenosis requiring revascularization has decreased with the use of DES, it still remains a significant long term risk associated with PCI. 2. Peri-Procedural Procedural PCI risks include those that are related to cardiac catheterization and diagnostic angiography as well as those that are related to the particular stent and/or wires that are used. Since the current standard of PCI includes the use of stents rather than balloon angioplasty alone, the complications that are currently seen are more likely to be stent related than those related to balloon angioplasty. The risk of peri-procedural complications has decreased over time as devices have improved, stents have been used and the use of anti-platelet therapy has become more standard. In general, rates of major peri-procedural complications are low. 3. Major complications An important complication which is frequently monitored is the need for emergent CABG after PCI, if the PCI was not successful. The rate of emergent PCI after CABG has been decreasing over time. In one study, it decreased from 2.95% in 1979 to 1994 to 0.3% in In the American College of Cardiology 19

20 National Cardiovascular Data registry, which includes over 100,000 PCI procedures, performed between 1998 and 2000 of which 77% received stents, low rates of periprocedural complications including in-hospital MI (0.4%), urgent CABG (1.9%) or death (1.4%) were reported Coronary Artery Complications Coronary artery complications include dissection, perforation, intramural hematoma and occlusion of branch vessels. Dissection and resulting abrupt closure are much less common in the DES era than they were with PTCA. Stents reduce the risk of abrupt closure and although dissection still occurs, the consequences are mitigated by the stent. Coronary artery perforation is similarly much less common in the stent era but can still occur. In a large series of over 10,000 PCIs performed from (of which 6,836 patients received stents ), the risk of perforation was 0.84%. 40 The mortality rate after coronary artery perforation is five to ten percent. 41,42 5. Vascular Complications Vascular complications at the femoral artery insertion site can occur in about six percent of patients 43,44 Peripheral vascular complications after conventional and complex percutaneous coronary interventional procedure include hematomas, formation of pseudoaneurysms, occlusion, creation of AV fisutas and retroperitoneal hematomas. 44 Use of the radial artery (which is more compressible) for access as compared with the femoral artery was associated with a reduced risk of major bleeding in a 2009 meta-analysis, 45 but not overall in a large RCT Radial vs Femoral Access for Coronary Angiography and Intervention in Patients with 20

21 Acute Coronary Syndromes (RIVAL) - although there were some subgroups who did achieve a bleeding reduction in RIVAL Stroke Stroke is a relatively rare complication of PCI with a rate of approximately 0.07% to 0.4% of procedures Since stroke also occurs with the main alternative to PCI, CABG, it is important to compare the risk of the two procedures. Most individual trials have not shown a signfiicant difference in risk between the two procedures but most did not have adequate power to detect differences in that relatively rare outcome. A recent meta-analysis compared the risk of stroke with CABG to the risk with PCI. 49 The meta-analysis included 10,944 patients in 19 trials, only some of whom had patients with diabetes. Patients with diabetes were not analyzed separately. The primary end point was 30 day risk of stroke. The 30 day risk of stroke was signficantly higher in those who underwent CABG compared with those who underwent PCI (1.20% vs 0.34%: OR 2.94: 95% C.I to 5.09: p = ). Similar results were seen after a median follow-up of 12.1 months (1.83% vs 0.99%: OR 1.67:95% C.I to 2.56: p = 0.02). Thus although stroke remains a risk with PCI, the risk is significantly lower than it would be with the main alternative, CABG. 7. Other Complications Other complications that can rarely occur as a result of PCI are atheroembolic disease, acute kidney injury and anticoagulation associated bleeding. 21

22 Summary In summary, PCI has several potential benefits, especially in the current era of PCI with DES. These benefits include revascularization without the need for a major surgical procedure and its associated morbidity and mortality and need for recuperation. The major risk is the potential need for revasascularization after the procedure. Although procedural complications can occur, overall the risks are relatively low. Although stroke is a potentially important complication of PCI, the risk of stroke is significantly lower than the risk seen with CABG. Thus, overall, net health outcomes are improved with PCI, especially in the current era of DES. TA Criterion 3 is met TA Criterion 4: The technology must be as beneficial as any established alternatives. The main established alternative to PCI is CABG. PCI treatments have evolved over time. Initial studies compared balloon angioplasty with CABG. After the introduction of stents, studies began to compare BMS with CABG. Finally, with the introduction of DES, most recent studies have compared DES with CABG. Early studies of balloon angioplasty vs CABG: subgroup analysis Percutaneous transluminal coronary angioplasty (PTCA) was first introduced in Initially it was used in patients with single vessel disease but over time also began to be used in those with multi-vessel disease. In 1987, the NIH Heart, Lung, and Blood Institute (NHLBI) initiated the Bypass Angioplasty Revascularization 22

23 Investigation (BARI). The goal of BARI was to test the hypothesis that a revascularization strategy involving PTCA did not result in poorer clnical outcomes than CABG at five year follow-up. 51 BARI prespecified some subgroup analyses, although evaluation of the impact on patients with diabetes was not prespecified in the protocol. However, diabetes was added by the Data Safety and Monitoring Board (DSMB) as a prespecified group prior to any outcome analyses. A total of 1,829 patients with multi-vessel disease were randomized to either CABG or PTCA and were followed for an average of 5.4 years. Of these, 353 had treated diabetes at baseline. Overall, in the entire study cohort, the five year survival rate was 89.3% for those assigned to CABG and 86.3% for those assigned to PTCA (p = 0.19). Among patients with diabetes who were receiving diabetic treatment at baseline, the five year survial was 80.6% for CABG and 65.5% for PTCA (p = 0.003). The results of this study suggest that five year survival in patients with diabetes may be better after CABG than after PTCA, but since the analysis in patients with diabetes was not a prespecified subgroup analysis, these results should be seen as hypothesis generating rather than clearly causal. Four other studies of balloon angioplasty vs CABG all included some patients with diabetes The number of patients with diabetes in each study ranged from However, in only one of the studies - RITA-I: Randomized Intervention Treatment of Angina - were patients with diabetes analyzed separately. The primary outcome (death or MI) was not statistically significantly different between the two groups although the numbers were very small, given that there were only 62 diabetic patients in the RITA-1 study. 16 Bare Metal Stents vs CABG 23

24 The development of BMS was a significant advance over balloon angioplasty in the treatment of coronary artery diseaes. Adding the BMS could reduce the chance of restenosis by minimizing early arterial recoil and contraction. A total of five studies have compared BMS to CABG. Four of these five studies reported results in patients with diabetes separately. The Medicine, Angioplasty or Surgery S Study II (MASS-II) included 115 patients with diabetes but did not report the results in patients with diabetes separately Arterial Revascularization Study I (ARTS-I) In ARTS-I, patients with multi-vessel CAD including the LAD and at least one other lesion in another major epicardial artery were randomized to receive BMS vs CABG. The main endpoint was a composite endpoint- death, MI and repeat revascularization or MACCE (major adverse cardiac and cerebrovascular events). In the subgroup analysis of 208 patients with diabetes, at five years, the rate of MACCE was higher in patients treated with BMS than in those treated with CABG (53.8% vs 23.4%: p = 0.001). 2. Angina With Extrememly Serious Operative Mortality Evaluation (AWESOME) In the AWESOME trial, patients with medically refractory unstable angina and at high risk for CABG were randomized to either BMS vs CABG. Study outcomes included 30 day, six month and 36 month survival. Among the 144 included patients with diabetes, 36 month survival was similar in the two groups (72% CABG vs 81% PCI: NS). 3. Surgery or Stent (SOS) Trial 24

25 The SOS trial randomized patients in whom revascularization was clinically indicated and appropriate by either strategy to receive PCI with any commercially available BMS vs CABG. The main study outcome was rate of repeat revascularizaiton. A total of 142 patients with diabetes were included in this study. At six year follow-up, a total of 17/65 of the PCI patients had died vs 5.4% of those in the CABG group (HR 3.53: 95% C.I to 10.95). There was no difference in treatment effect between diabetic and non-diabetic subgroups. 4. Argentine Randomized Study-coronar coronary Angioplasty with Stenting II (ERACI II) In the ERACI II trial, patients with multi-vessel CHD and clinical indications for revascularization were randomized to either receive PCI with stent placement or CABG. The main outcome was freedom from major adverse cardiovascular events (MACE) at 30 days, one year, three years and five years. At five year follow-up, mortality among the 78 included patients with diabetes was 10% in the PCI group vs 10.2% in the CABG group, not significantly different between the two groups. Drug Eluting Stents vs CABG Many of the earlier studies using either balloon angioplasty or BMS were done before the current era where the standard for PCI is to use DES. Four studies have compared drug eluting stents and CABG for the treatment of multi-vessel disease in patients with diabetes. A total of 3,021 patients have been included in these four studies- 1,900 of the patients came from the FREEDOM study. Two of the studies were subgroup analyses of larger studies 22,24-26,29-31 and the other two studies included only patients with diabetes ARTS-II 25

26 The ARTS-II study was a single arm study. All participants received DES. ARTS I was a randomized controlled trial comparing surgery and BMS. Patients in the ARTS-II study were compared to the surgical arm of the ARTS-I as a historical control. In order to be sure that the population was comparable to the ARTS-I trial, patients were stratified by clinical site with the goal of ensuring that at least 1/3 of patients had three vessel disease. Among the 607 patients included in ARTS-II study, 159 of them had diabetes. Investigators compared DES with BMS and also compared DES with CABG. At three year follow-up, there was no significant difference in the main outcome (MACCE) between those who received DES and those who received CABG. However, at five year follow-up, the rate of MACCE was lower in CABG than in DES (23.4% vs 40.5%: p< 0.001). Thus, CABG appeared safer at five year follow up. Caution should be used in drawing conclusions, since this was a subgroup analysis using a group of historical controls. 2. Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) SYNTAX was a large randomized controlled trial including 1,800 patients and conducted at 85 sites. 26 The study was designed to compare CABG and DES (paclitaxel) in patients with three vessel or left main coronary disease. The main outcome was major adverse cardiac and cerebrovascular events (MACCE). Overall, rates of MACCE were significantly higher in those who received DES than those who received CABG. This study was designed as a non-inferiority trial but because of the significant difference in MACCE between groups, the criteria for noninferiority were not met. A subgroup analysis of SYNTAX in patients with diabetes was prespecified. A total of 452 of the trial participants had diabetes. At one year follow-up, there was no difference between the two groups but at three year follow-up patients with 26

27 diabetes who received CABG had a 22.9% rate of MACCE and patients with diabetes who received DES had a rate of 37.0% (p = 002). 29,31 Thus, in this prespecified subgroup analysis, the rate of adverse events was lower in those who received CABG than in those who received DES. 3. Coronary Artery Revascularization in Diabetes Study (CARDia) The CARDia study was the first randomized controlled trial that specifically focused on the role of PCI with DES and CABG in patients with diabetes with multivessel coronary artery disease. 28 This was a non-inferiority trial designed to show whether or not PCI was or was not non-inferior to CABG. Patients were included if they had diabetes and either multi-vessel coronary artery disease or complex single vessel disease (ostial or proximal left anterior descending artery disease). Patients had to be eligible to receive either PCI or CABG in order to be included. Patients were randomized to either receive PCI or CABG. The trial started out with patients receiving BMS, but when DES became available, patients received DES. The primary endpoint was a composite end point assessed at one year after randomization. The composite end point included death, MI and stroke. A major secondary endpoint was repeat revascularization at one-year follow-up. Among those who received stents, 69% received DES and 31% received BMS. At one-year follow-up, there was a trend toward a reduction in the composite end point in those who received CABG compared with PCI but this reduction was not statistically significant (10.5% CABG vs 13.0% PCI: HR 1.25: 95% C.I : p = 0.39). The rate of all cause mortality was 3.2% in each group. The combined endpoint of MACCE was 11.3% in the CABG group and 19.3% in the PCI group (HR 1.77: 95% C.I : p = 0.02). When the patients who received CABG were 27

28 compared with the subset of patients who received DES, there were still no statistically significant differences. These results at one year did not show that PCI was non-inferior to CABG. Although there was a trend toward a reduction in the composite outcome among those treated with CABG compared with those treated with PCI, this was not statistically significant. This could be because there truly is no difference or could be because of inadequate power of the trial to detect a true difference. Regardless, the CARDia study alone did not answer the question of whether PCI or CABG should be preferred in patients with diabetes. 4. Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease Study (FREEDOM) The major study that addresses the role of PCI plus stenting vs CABG in patients with diabetes is the FREEDOM study. The FREEDOM study was a large multi-center RCT that compared DES to CABG in patients with multi-vessel coronary artery disease. 32 A total of 1,900 patients with diabetes at a total of 140 centers around the world were randomized to receive PCI with DES or CABG. Patients were included if they had Type I or Type 2 diabetes and had angiographically confirmed multi-vessel coronary artery disease with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary artery territories and without left main disease. Among those receiving DES, sirolimus-eluting and paclitaxel-eluting stents were most commonly used. A newer generation of drug eluting stent could be used as long as it was FDA approved. Abciximab was recommended for patients undergoing PCI. Dual antiplatelet therapy with aspirin and clopidrogel was recommended for at least 12 months after stent implantation. For CABG surgery, arterial revascularization was encouraged. Risk factor 28

29 modification was encouraged in all patients and recommended targets were set. These included a goal low density lipoprotein (LDL) of <70 mg/deciliter, a goal blood pressure of <130/80 and a goal glycosylated hemoglobin of <7%. The primary study outcome was a composite of all cause mortality, nonfatal MI and nonfatal stroke. Secondary outcomes included rate of MACCE at 30 days and 12 months after the procedure (including some components of the primary outcome and repeat revascularization). Mean patient age was 63.1 years, 29% were women and 83% had triple vessel disease. The primary composite outcome was more common at five year follow-up in the PCI group (26.6% PCI vs 18.7% CABG: p =0.005). When outcomes were analyzed individually, at five year follow-up, MI was lower in CABG group (6.0% vs 13.9%: p < 0.001) and all cause mortality was also lower in the CABG group (10.9% vs 16.3%: p = 0.049). Stroke at five year follow up was higher in the CABG group than in the PCI group (5.2% vs 2.4%: p = 0.03). This large trial with adequate power has answered the question of whether CABG or PCI with DES is superior in patients with diabetes. This study has clearly shown that for patients with diabetes and multi-vessel coronary artery disease, CABG is superior to PCI. It significantly reduced the rate of the composite endpoint (mortality, MI and stroke). In addition, overall mortality and MI were both reduced, although there was a small increased risk of stroke in those who received CABG. Thus, this study clearly shows that in patients with diabetes, PCI using the current technology of DES is inferior to CABG. PCI does not show an improvement in clinical outcomes compared with the established alternative of CABG in patients with diabetes with multi-vessel disease who are undergoing revascularization. 29

30 Summary In summary, the current standard for PCI procedure uses DES. Among the trials comparing PCI with DES to CABG, two were subgroup analyses - one showed no difference between the interventions and one showed worse outcome with PCI. Two trials evaluated PCI with DES vs CABG exclusively in patients with diabetes - one was small and underpowered. The large FREEDOM trial included 1,900 patients with diabetes and definitively showed a significant reduction in mortality and myocardial infarction with CABG compared with PCI, although was associated with a small increased risk of stroke. This study has shown us that CABG is superior to PCI for patients with diabetes with multi-vessel disease requiring revascularization. PCI, when compared with the established alternative of CABG, does not result in an improvement in health outcomes. TA Criterion 4 is not met for PCI as an alternative to CABG for patients with diabetes and multi-vessel disease. TA Criterion 5: The improvement must be attainable outside of the investigational setting. Since the improvement has not been shown in the investigational setting, an improvement cannot be obtained outside of the investigational setting. TA Criterion 5 is not met for PCI as an alternative to CABG for patients with diabetes and multi-vessel disease. 30

31 CONCLUSION In summary, PCI is being compared to CABG in patients with diabetes with multi-vessel disease. Many studies have compared PCI and CABG in patients with coronary disease. The majority of the early studies conducted subgroup analyses of patients with diabetes, most suggesting at least a trend toward improvement with CABG. In addition, PCI technology has progressed from balloon angioplasty to BMS and now to the current standardly used technology of DES. However, even using the currently used PCI technology of DES, PCI is associated with an increased mortality risk compared with CABG and does not lead to an improvement in health outcomes. 31

32 RECOMMENDATION It is recommended that PCI as an alternative to CABG in operable patients with diabetes mellitus and multivessel disease does not meet CTAF criteria 4 or 5 for safety, efficacy and improvement in health outcomes. The CTAF Panel voted twelve in favor of the recommendation as presented in the assessment and none opposed. The motion carried. March 6, 2013 This is the first review of this technology by the California Technology Assessment Forum. 32

33 RECOMMENDATIONS OF OTHERS American College of Cardiology In 2011, the American College of Cardiology released two practice guidelines. 1) In partnership with the American Heart Association (AHA) and the Society for Cardiovascular Angiography and Interventions (SCAI): 2011 ACCF/AHA/SCAI guideline for percutaneous coronary artery intervention. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions; and 2) In partnership with the American Heart Association: 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: ry: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Both sets of guidelines make the following recommendation under sections titled: Revascularization to Improve Survival: Recommendations; Non-Left Main CAD Revascularization, Class IIa: CABG is probably recommended in preference to PCI to improve survival in patients with multivessel CAD and diabetes mellitus, particularly if a LIMA graft can be anastomosed to the LAD artery. (Level of Evidence: B) American College of Cardiology (ACC), CA Chapter The ACC CA Chapter provided a written opinion on this technology and sent a representative to the meeting. American Heart Association (AHA) 33

34 The AHA did not send an opinion on this technology nor send a representative to the meeting. See above for guideline(s). Society for Cardiovascular Angiography and Interventions (SCAI) SCAI sent a written opinion on this technology and sent a representative to the meeting. See above for guideline(s). Agency for Healthcare Research and Quality (AHRQ) AHRQ s Effective Health Care Program published in 2007 its report: Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Grafting for Coronary Artery Disease. One of the key questions in the report was to determine the evidence of comparative effectiveness of PCI and CABG based on coronary diseases risk factors, diabetes or other comorbid disease. The report notes the following: six RCTs reporting survival of diabetic patients at one and five years. One RCT - Bypass Angioplasty Revascularization Investigation (BARI) trial - found significantly better survival for diabetic patients assigned to CABG while none of the other five trials found significant differences in survival between diabetic patients with PCI vs. CABG. However, the pooled data from all the trials showed no significant difference in survival after PCI or CABG. Blue Cross Blue Shield Association (BCBSA) No assessments on this technology were found on the BCBSA TEC website. Canadian Agency for Drugs and Technologies in Health (CADTH) On October, 2012, CADTH issued its Rapid Response Report: Drug Eluting Stents for Patients with Diabetes and Coronary Artery Disease: A Review of the 34

35 Clinical Evidence E and Guidelines to determine the clinical effectiveness and drug safety of drug eluting stents in adults with both diabetes and coronary artery disease and to find any evidence guidelines on this topic. Based on its findings, CADTH wrote the following: In adults with diabetes and coronary artery disease, findings from both randomized and non- randomized controlled trials showed consistently that the clinical effectiveness, as measured by the need for a repeat revascularization of the target vessel, is the best with CABG, followed by DES (drug eluting stents), then BMS (bare metal stents). Findings on safety outcomes such as risk of death and myocardial infarction are similar between DES and BMS up to 2.5 years follow-up and in favour of DES with longer follow-up times. Findings on comparisons between DES and CABG are inconsistent on safety outcomes. There was no evidence found on guidelines for the use of DES in adult patients with both diabetes and coronary artery disease. National Institute for Health and Clinical Excellence (NICE) NICE clinical guideline 126: Management of Stable Angina (issued on July 2011 and last modified on December 2012) noted the following in the section: Key Priorities for Implementation: When either procedure would be appropriate, take into account the potential survival advantage of CABG over PCI for people with multivessel disease whose symptoms are not satisfactorily controlled with optimal medical treatment and who: have diabetes or are over 65 years or have anatomically complex three-vessel disease, with or without involvement of the left main stem. Centers for Medicare and Medicaid Services (CMS) 35

36 National Coverage Determination (NCD) guidelines are available for Percutaneous Transluminal Angioplasty (PTA) procedures under Section 20.7 in the Medicare National Determination Coverage Manual. However, there is no NCD for drug eluting coronary stents themselves used in PTA or PCI.. Local Medicare carriers have discretion on coverage decisions of coronary stents. American Association for Thoracic Surgery (AATS) AATS did not send a written opinion on this technology but did send a representative to the CTAF public meeting. Society of Thoracic Surgeons (STS) STS provided a written opinion on this technology and sent a representative to the CTAF public meeting. 36

37 ABBREVIATIONS ARTS-I: AV: Arterial Revascularization Study I Arterio Venous AWESOME: Angina With Extremely Serious Operative Mortality Evaluation BARI: BMS: CABG: CABRI: CAD: CARdia: CASS: CVA: CHD: CHF: C.I.: DARE: DES: DSMB: EAST: EF: ERACI II: Bypass Angioplasty Revascularization Investigation Bare Metal Stents Coronary Artery Bypass Graft Coronary Angioplasty versus Bypass Revascularization Coronary Artery Disease Coronary Artery Revascularization in Diabetes Coronary Artery Surgery Study Cerebrovascular Accident Coronary Heart Disease Congestive Heart Failure Confidence Interval Database of Abstracts of Reviews of Effects Drug Eluting Stent(s) Data Safety and Monitoring Board Emory Angioplasty vs Surgery Trial Ejection Fraction Argentine Randomized Study-coronary Angioplasty with Stenting Versus coronary Bypass surgery in Multi-Vessel Disease FDA: Food and Drug Administration FREEDOM: Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease GABI: German Angioplasty Bypass Surgery Investigation 37

38 HR: LAD: LDL: LV: MACCE: Hazard Ratio Left Anterior Descending Low Density Lipoprotein Left Ventricle or Ventricular Major Adverse Cardiovascular and Cerebrovascular Events (Death, CVA, MI and repeat revascularization) MACE: Major Adverse Cardiovascular Events (death, MI and repeat revascularization) MASS II: MI: NHLBI: OR: PCI: PTCA: RCT: RITA: RIVAL: Medicine, Angioplasty or Surgery Study Myocardial Infarction National Institutes of Health (NIH) Heart, Lung, and Blood Institute Odds Ratio Percutaneous Coronary Intervention Percutaneous Transluminal Coronary Angioplasty Randomized Controlled Trial Randomized Intervention Treatment of Angina Radial vs Femoral Access for Coronary Angiography and Intervention in Patients with Acute Coronary Syndromes SOS: SYNTAX: Surgery or Stent Study Synergy between PCI with Taxus and Cardiac Surgery 38