Abstract
Background
The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy.
Methods
A total of 1900 diabetic subjects with MVD were randomized to PCI or CABG worldwide from April 2005–March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients.
Results
The randomized cohort was 63.1±9.1 years old and 29% female with median diabetes duration 10.2±8.9 years. Most (83%) had three-vessel disease and on average took 5.5±1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia and 26% had a prior myocardial infarction. Mean HbA1C was 7.8±1.7 mg/dl, 29% had low-density lipoprotein<70 mg/dl and mean systolic blood pressure was 134±20 mmHg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial subjects have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts.
Conclusions
The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI vs. CABG debate in diabetic subjects with MVD.
INTRODUCTION
Diabetes is increasingly prevalent worldwide and is an important risk factor for coronary artery disease and atherothrombotic events.1 Many diabetic patients require coronary revascularization. Therefore, defining the most suitable approach, coronary bypass grafting (CABG) or percutaneous intervention (PCI), is central to the optimal care of these patients.
An analysis of the Balloon Angioplasty Revascularization Investigation (BARI)2 study, a randomized trial comparing balloon angioplasty with CABG in patients with multi-vessel coronary artery disease (CAD), showed increased mortality among the subgroup of diabetic patients randomized to angioplasty. Similar results in the EAST (Emory Angioplasty versus Surgery) and CABRI (Coronary Angioplasty versus Bypass Revascularization Investigation) trials led to guidelines recommending CABG as the preferred approach to revascularization over angioplasty in diabetic patients with multivessel coronary disease (MVD)3. On the other hand reports regarding diabetic sub-groups from the Duke registry, the ARTS (Arterial Revascularization Study), ERACI (Argentine randomized trial of angioplasty vs. Surgery), SOS (Stent or Surgery) and MASS (Medicine, Angioplasty or Surgery) trials showed comparable mortality rates for the two strategies and the AWESOME (Angina with Extremely Serious Operative Mortality Evaluation) trial even showed that PCI may in fact fare better than bypass surgery.4–9.
Since these studies were reported, there have been immense technological advances in PCI, including most prominently, the evolution of stents and adjunctive drug therapy, which are now central to most PCI procedures10. These changes call into question the applicability of the earlier trial results to current practice. However, to date, definitive guidance based on randomized trial data is lacking, especially for diabetic subjects, who have comprised less than a quarter of the patients randomized in these studies. To address the need for compelling data, the randomized FREEDOM trial was designed to compare a strategy of CABG to a strategy of PCI with drug-eluting stents (DES) in diabetic patients with MVD using PCI.
The aims of this report are to: 1) Describe the baseline characteristics of subjects in the trial and 2) compare the baseline profile of the FREEDOM trial cohort with that of cohorts from other trials with multivessel and/or diabetic patients.
METHODS
Trial Design
The FREEDOM trial was designed as a two-armed superiority trial to assess the effectiveness of multi-vessel PCI with DESs relative to CABG in preventing the composite endpoint of all cause mortality, non-fatal MI or stroke at a mean follow-up of 4.37 years (Fig 1). Minimum follow-up on all subjects is 2 years. The design of the FREEDOM trial has been presented previously11. Briefly, FREEDOM recruited adult subjects with diabetes (type I or II) that met American Diabetes Association criteria. Trial eligibility required baseline values greater than 126 mg/dl for fasting glucose and >200 mg/dl for random glucose, or for patients to be undergoing pharmacological or non-pharmacological treatments for diabetes. In addition, patients were required to have MVD, defined as angiographically confirmed MVD (>70% lesions in ≥ 2 major epicardial vessels and in ≥ 2 separate coronary artery territories). All patients had an indication for revascularization based upon anginal symptoms or objective evidence of myocardial ischemia. Broadly, FREEDOM excluded subjects with prior CABG or valve surgery, left main disease, ST-elevation myocardial infarction (STEMI) in the past 72 hours or prior PCI in past 6 months. Institutional review boards at all participating sites approved the protocol and patients provided written informed consent. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study; all study analyses, the drafting and editing of the paper and its final contents.
Figure 1.
FREEDOM Trial Design
Statistical Methods
Descriptive statistics are presented as mean± standard deviation and median for continuous variables and frequency with percentage for categorical variables. Baseline characteristics of enrolled and eligible non-enrolled patients were compared using a Fisher exact test for categorical variables, the Wilcoxon rank sum test for continuous variables with a skewed distribution, and Student’s t-test for other continuous variables. A p-value less than 0.05 was considered significant. All analyses were conducting using SAS version 9.2 (Statistical Analysis System, SAS Institute, Inc., Cary, NC).
Changes in trial design since publication of design manuscript
Upon recommendation by the independent Data and Safety Monitoring Committee, sample size was changed from 2,058 to 1,900 subjects. Trial duration was changed from 6.75 to 7.0 yrs. The recruitment period was extended from 4.25 to 5.0 yrs. Minimum follow-up was changed from 2.5 yrs to 2.0 yrs. Average follow-up has increased from 4.07 yrs to 4.37 yrs. Assuming 4-year rate of the primary outcome measure to be 21.5% in the trial arm with a higher event rate, with 1% crossover rate and 1% loss to follow-up rate, and up to 3 interim looks at the data, a sample size of 1,900 provides 80% power to detect a relative reduction in the rate of the primary endpoint as low as 27.0% (4.65% absolute rate difference).
Baseline Measurement
Cardiovascular risk factors (blood pressure, lipid panel, HbA1c, renal function) and anthropometric measures were carried out for all subjects using standardized methodology. All patients screened for eligibility for the FREEDOM Trial underwent coronary angiography and the studies from eligibile subjects were submitted to an independent angiographic core laboratory for assessment.
Disease-specific health status was assessed using the Seattle Angina Questionnaire (SAQ), a 19 item instrument that yields five measures of health status related to coronary artery disease; scores range from 0 to 100, with higher scores indicating fewer symptoms and better health status12,13. The EuroSCORE14 was calculated using data available from the medical history close to the time of randomization. The Syntax score15 was performed by the independent angiographic core laboratory from the baseline angiogram, and all angiographic data such as LVEF and the presence vs. absence of a chronic total occlusion (CTO) are based on core laboratory determination16. The Duke jeopardy score was calculated using the method described by Califf et al.17
RESULTS
Patient recruitment
A total of 32,966 patients were screened, of whom 3309 (10%) subjects met clinical and angiographic inclusion criteria and 1900 (57% consent rate) were randomized at 140 sites worldwide between April 2005 and March 2010. Table 1 compares randomized subjects to those who were eligible for randomization but not randomized and those who were ineligible. The enrolled cohort is representative with respect to gender but was slightly younger (mean 63.1 vs. 64.4 years), more often Hispanic, and less often Asian than the eligible, non-consenting patients.
Table I.
Baseline Characteristics for N=32966 Patients Screened for FREEDOM Trial Eligibility
| Characteristic | Ineligible | Eligible | p-value*** | |
|---|---|---|---|---|
| Not Enrolled | Enrolled | |||
| N | 29657 | 1409 | 1900 | |
| Mean Age at Screening, yr | 65.2 ± 10.8 | 64.4 ± 9.6 | 63.1 ± 9.1 | <0.0001 |
| Male | 64.7 ± 10.5 | 63.7 ± 9.4 | 62.6 ± 9.0 | 0.005 |
| Female | 66.2 ± 11.2 | 66.4 ± 9.7 | 64.4 ± 9.2 | 0.002 |
| Male | 67.7% | 72.8% | 71.4% | 0.38 |
| Did not meet angiographic Inclusion Criteria* | 85.6% | NA | NA | NA |
| Clinical Exclusion Present | 57.7% | NA | NA | NA |
| Prior cardiac surgery or planned cardiac surgery** | 32 % | NA | NA | NA |
| Race/Ethnicity | <.0001 | |||
| White, Non-Hispanic | 69.6% | 51.3% | ||
| Black or African American, Non-Hispanic | 4.7% | 2.7% | ||
| Asian, Non-Hispanic | 13.3% | 9.7% | ||
| Other, Non-Hispanic | 4.3% | 1.8% | ||
| Hispanic | 8.2% | 34.5% | ||
| Planned Management Strategy | ||||
| PCI | 51.8% | 50% | NA | |
| CABG | 33.6% | 50% | ||
| Medical therapy alone | 5.8% | |||
| Unknown | 8.8% | |||
Subjects needed to have multi-vessel CAD defined as critical (≥70%) lesions in at least two major epicardial vessels. Angiographic characteristics needed to be amenable to both PCI/DES and CABG. Left main disease, in-stent restenosis and >1 chronic total occlusion were excluded.
Prior bypass surgery or valvular surgery or valve surgery planned.
Test of significance for difference between enrolled patients and eligible but not enrolled patients
Demographic Characteristics
The mean age of the FREEDOM trial sample was 63.1± 9.1 years with over half of the subjects being white males (Table I). Seven hundred and four (37%) subjects were enrolled from North America, 520 (27%) from South America, 480 (25%) from Europe and 196 from Australasia (11%).
Clinical Presentation
In keeping with the inclusion criteria, 31% of subjects in FREEDOM had recent (>72 hours) acute coronary syndromes with normalizing biomarkers of myocardial ischemia upon trial enrollment, and the rest had stable coronary disease with anginal symptoms and/or inducible ischemia with stress testing (Table II). The overall mean angina frequency score on the Seattle Angina Questionnaire (SAQ) was 71, indicating mild angina (angina on a weekly basis), and 23% of patients had no angina at baseline (angina frequency score of 100). The mean (SAQ) physical limitations score was 69 indicating mild limitations, and mean SAQ quality of life score was 48 (fair). SAQ results indicate that physical limitation and angina frequency are mild to moderate (means of 69 and 71 out of 100 with 100 indicating better health), and angina stability and quality of life being on an average lower (mean 43 and 48, respectively.) Out of the 69% with stable disease, approximately 41% underwent ischemia testing. Seventy five percent subjects were found to have moderate or severe ischemia.
Table II.
History of Presenting Illness
| Overall (N=1900) |
|
|---|---|
| HISTORY OF PRESENTING ILLNESS (Indication for coronary angiography) | |
| Stable coronary heart disease (1317 subjects) | 69.3% |
| Acute Coronary Syndrome (ACS) (584 subjects) | 30.7% |
| ST elevation MI (>72 hrs prior to admission) | 20.2% |
| Non-ST elevation ACS (466 subjects) | 79.8% |
| No recurrent/provocable ischemia | 33.3% |
| Provocable ischemia only | 23.4% |
| Spontaneous recurrent ischemia | 41.3% |
| Refractory ischemia | 1.9% |
More than 95% of subjects had type-2 diabetes. Complications associated with longstanding diabetes were relatively frequent (18%, table III); 85% had hypertension, 84% from hyperlipidemia and 55% of subjects had tobacco exposure. One-quarter (26%) of subjects had a prior MI, 3% had a prior stroke and 11% had known peripheral arterial disease. Less than 1% (11 subjects) had a PCI between 6 and 12 months before enrollment in the trial (Table III).
Table III.
Past Medical and Surgical History (N=1900)
| Overall | ||
|---|---|---|
| PAST MEDICAL HISTORY | ||
| Diabetes Mellitus: | Type I | 4.5% |
| Type II | 95.5% | |
| Complications associated with diabetes* | 18.0% | |
| Diabetic foot ulcer | 9.3% | |
| Extremity amputation | 3.8% | |
| Diabetic retinopathy/blindness | 39.4% | |
| Diabetic nephropathy | 32.7% | |
| Diabetic neuropathy | 54.5% | |
| History of high blood pressure | 84.8% | |
| History of hyperlipidemia | 83.7% | |
| Prior myocardial infarction | 25.6% | |
| Prior stroke | 3.2% | |
| Peripheral arterial disease | 11.2% | |
| History of valvular heart disease | 1.3% | |
| History of arrhythmia | 4.8% | |
| If yes: Permanent Pacemaker Implanted | 20.9% | |
| AICD | 0.0% | |
| History of chronic renal insufficiency | 6.8% | |
| History of dialysis | 0.4% | |
| History of chronic obstructive pulmonary disease (COPD) or asthma | 10.2% | |
| Ever smoked | 54.5% | |
| If yes (n=91): Current smoker | 28.8% | |
| Ex-smoker (quit >12 months ago) | 65.8% | |
| History of gastrointestinal ulcer/bleed | 4.7% | |
| Aspirin daily for last 7 days or longer | 71.7% | |
| History of renal artery stenosis | 0.5% | |
| PAST SURGICAL HISTORY | ||
| Prior PTCA (balloon angioplasty or atherectomy) within 12 months prior | 0.6% | |
| Prior PCI w/stent within the last 12 months | 0.6% | |
Percentages for the 5 diabetic complications are calculated based on the 343 subjects with complications
Physical Exam and Laboratory evaluations
Mean duration of diabetes was 10.2±8.9 years. At baseline, the mean HbA1C was 7.8±1.7%, LDL was 92.7 ± 36.3 mg/dl and systolic BP was 133.7 ± 19.8 mmHg. At baseline 36% of FREEDOM subjects hada HbA1C<7%, 62% had a LDL<100 mg/dl, 19% had a systolic blood pressure of <120 mmHg, 53% had a diastolic blood pressure of <80 mmHg for, and 16% were current smokers (Table IV). Almost half (42%) of subjects were obese based on body mass index, 59% met the abnormal waist circumference criterion, 48% had a triglyceride level ≥150 mg/dl and 75% had a low HDL.
Table IV.
Cardiovascular Risk Factor Profile of the FREEDOM Cohort *
| Variable | Mean ± SD or % |
|---|---|
| LDL (mg/dl) | 92.7 ± 36.6 |
| LDL <100 | 62.4% |
| LDL <70 | 29.1% |
| HbA1c, % | 7.8 ± 1.7 |
| HbA1c (%) | |
| <7.0 | 36.0% |
| 7.0%–8.0 | 25.4% |
| ≥8.0 | 38.7% |
| SBP mmHg | 133.8 ± 19.8 |
| SBP (mmHg) | |
| <120 | 18.9% |
| 120–140 | 43.0% |
| ≥140 | 38.2% |
| DBP mmHg | 76.0 ± 11.1 |
| DBP (mmHg) | |
| <80 | 53.2% |
| 80–90 | 33.1% |
| ≥ 90 | 13.7% |
| Triglycerides (mg/dl) | 177.9 ±132.1 (148.0) |
| Triglycerides ≥ 150 | 48.0% |
| HDL (mg/dl) | 39.2±11.2 |
| HDL ≤ 40 (men), ≤ 50 (women) | 75.4% |
| Waist (cm) | 102.6±14.2 |
| Waist ≥102(men), ≥88 (women) | 59.4% |
| Current Smoker, % | 15.7% |
| Hemoglobin (g/dl) | 13.6±1.6 |
| Creatinine (mg/dl) | 1.1±0.5 |
| Presence of microalbuminuria (>30 mg/g) | 40.3% |
N ranges from 1750 to 1899 for each measure.
Continuous variables are presented as mean ± standard deviation. Medians are presented in () after the standard deviation for skewed measures.
Medications
Participants in the FREEDOM trial were taking an average of 1.5±0.8 medications for diabetes (range 0–5) and 5.5±1.7 medications (range 0–11) daily for secondary prevention.. At baseline 93% were receiving antiplatelet therapy, 88% anti-anginal agents, 86% lipid-lowering agents and 78% a renin-angiotensin system inhibiting agent. In terms of diabetes treatments, 32% of subjects were being treated with insulin, 56% were receiving biguanides, 44% sulfonylureas and 8% were receiving thiazolidinediones (Table V).
Table V.
Baseline Medications (N=1900)
| Overall | |
|---|---|
| Medication | |
| Antiplatelet agent | |
| Aspirin | 90.7% |
| Clopidogrel | 23.9% |
| Ticlopidine | 1.1% |
| Cilostazol | 0.1% |
| Anti-anginal agent | |
| Beta blocker | 75.3% |
| Calcium-channel antagonist | 31.9% |
| Nitrate | 39.4% |
| Lipid –lowering agent | |
| Statin | 82.3% |
| Fibrate | 4.8% |
| Other Cardiovascular Medications | |
| ACE inhibitor | 64.3% |
| Angiotensin II antagonist | 16.3% |
| ACE inhibitor or ARB | 78.2% |
| Aldosterone antagonist | 2.8% |
| Loop diuretics | 10.3% |
| Thiazide diuretic | 13.0% |
| Diabetes Medication | |
| Insulin | 32.3% |
| Sulfonylurea | 43.7% |
| Biguanides | 55.8% |
| Alpha-glucosidase inhibitor | 1.3% |
| Thiazolidinedione | 8.2% |
| Rosiglitazone | 4.7% |
| Pioglitazone | 3.5% |
| NSAID | 5.3% |
| PPI* | 14.4% |
ACE=angiotensin-converting enzyme; ARB=angiotensin II receptor blocker; NSAID=Nonsteroidal anti-inflammatory drug.
PPI=Proton pump inhibitor; Total available N=369. PPI was added onto the data collection form in February, 2009
Baseline Angiographic Findings
Triple vessel disease was present in 83% of subjects in FREEDOM, with a mean of 5.7±2.2 lesions (of >50% diameter stenosis) per patient and a mean total burden of disease (total length of all lesions) of 77.6±33.5 mm. Left main disease was an exclusion criterion. Almost all (99%) subjects had LAD involvement. The target lesion was located in the proximal LAD for 14%. Mean left ventricular ejection fraction (LVEF) was 66.2 ± 11.3%, with only 1% of subjects having LVEF<35%. Among all 11,226 lesions, 6% were total occlusions, 22% were bifurcation lesions, 21% were calcific lesions and 46% were ACC/AHA grade C lesions. The mean Duke jeopardy score was high at 9.3 (Table VI).17
Table VI.
Baseline Angiographic Profile for 1888 Subjects with a Centrally Interpreted Angiogram
| Variable | Mean± SD or% | |
|---|---|---|
| No. of Diseased Vessels | 1 | 0.1% |
| 2 | 16.6% | |
| 3 | 83.3% | |
| Location of disease | LAD | 98.9% |
| LCX | 92.6% | |
| RCA | 91.7% | |
| Proximal LAD involvement (Target lesion=LAD located in proximal) | 13.8% | |
| # Lesions per patient | 5.7 ± 2.2 (1888) | |
| Extent of disease per patient (Total length of lesions, mm) | 77.6 ± 33.8 (1888) | |
| Duke Jeopardy Score | 9.3 ± 3.1 (1874) | |
| Left ventricular ejection fraction, % | 66.2 ± 11.3 (1291) | |
| Left ventricular ejection fraction | >50% | 90.9% |
| 35%–50% | 8.0% | |
| < 35% | 1.1% |
LAD=left anterior descending artery; LCX=left circumflex artery; RCA=right coronary artery DS=diameter stenosis
There were 1857 subjects with a calculable EuroSCORE and 1887 subjects with a calculable SYNTAX score. The EuroSCORE distribution was highly positively skewed and has a median of 1.9 (interquartile range, 1.3 to 3.1) for FREEDOM subjects (Fig. 2). The EuroSCORE was significantly higher for black and non-Hispanic subjects, for those with longer diabetes duration, and those with 3VD. The Syntax score distribution was symmetric with a mean of 26.2±8.6 and median of 26.0 (interquartile range, 20.0 to 31.5) (Fig. 3). The SYNTAX score was also significantly higher for black and non-Hispanic subjects and not surprisingly for those with CTOs and 3VD. There were 395 subjects (20.9%) with a high SYNTAX score (>32), 839 (44.0%) with an intermediate score (22–32) and 662 (35.1%) with a low score (<22)18. The observed tertiles of the SYNTAX score in the FREEDOM cohort were 22 and 29.
Figure 2.
EuroSCORE Distribution for FREEDOM Subjects at Randomization (N=1857)
Figure 3.
Syntax Score Distribution for FREEDOM Subjects at Randomization (N=1887)
FREEDOM cohort compared to other trial cohorts
We compared the baseline clinical and angiographic characteristics of subjects enrolled in the FREEDOM trial with those from other published contemporary studies such as Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2-D), Coronary Artery Revascularization in Diabetes (CARDia), SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) and the Bypass Angioplasty Revascularization Investigation (BARI) as a historical comparator (Table VII and Fig. 4–5). The BARI 2-D trial randomized 2,368 diabetic patients with stable documented coronary disease or myocardial ischemia to early or deferred revascularization in the presence of aggressive medical therapy with either insulin sensitizing or insulin providing agents. CARDia studied 510 diabetic subjects with multi-vessel coronary disease and compared the strategies of PCI with DES versus CABG. SYNTAX evaluated 1800 subjects with left main or MVD, of which 452 had medically treated diabetes. This trial, like FREEDOM, compared PCI with DES to CABG. The clinical profiles of the patients in these studies conducted worldwide are remarkably similar to each other and to the FREEDOM cohort. FREEDOM stands out in having the largest proportion of patients with 3-vessel disease. Compared with the BARI trial, which randomly assigned 1,829 subjects (456 diabetic subjects) to PCI versus CABG in the 1980s, the FREEDOM cohort had a significantly lower LDL (93 mg/dl versus 140mg/dl in BARI), and the prevalence of hypertension and hyperlipidemia in FREEDOM were almost double that of the BARI trial.
Table VII.
Comparison of Baseline Characteristics in Contemporary Trials.18
| Variable | FREEDOM | BARI-2D | CARDia | BARI |
|---|---|---|---|---|
| Percentage or mean ± SD | ||||
| No. of subjects | 1900 | 2368 | 510 | 1829 |
| Duration of diabetes (yr) | 10.2±8.9 | 10.4±8.7 | 10 | N/A |
| LDL (mg/dl) | 92.7 ± 36.3 | 92 | 75.66 | 140 |
| Systolic BP (mmHg) | 133.7 ± 19.8 | 131.7±20 | 137±19 | 130 |
| Diastolic BP (mmHg) | 76.0 ± 11.1 | 74.5±11.2 | 73.5 | 76 |
| Triglycerides (mg/dl) | 177.9±132.1 | 148 | 167.32 | 191 |
| HDL (mg/dl) | 39.2±11.2 | 37 | 45.63 | 38.2 |
| HbA1c (%) | 7.8 ± 1.7 | 7.7±1.6 | 7.9 | N/A |
| Triglycerides > 150 mg/dl | 48.0% | 31% | N/A | N/A |
| Low HDL (mg/dl) | 75.4% | 72.4% | N/A | N/A |
| HbA1>7% | 64.0% | 58.3% | N/A | N/A |
| Chronic renal insufficiency | 6.8% | N/A | 4.7% | N/A |
| LV Ejection Fraction (%) | 66.2 ±11.3 | N/A | 59.5 | 57.3% |
BP=blood pressure; LDL=low-density lipoprotein; HDL=high-density lipoprotein; LV=left ventricular; N/A: not available in published literature
Figure 4.
Comparison of Contemporary Trials
Figure 5.
Comparison of Evidence-Based Medication Use Across Trials
DISCUSSION
Over the last decade, the advent of DES, vast improvements in adjunctive medical therapies, significant advances in operative techniques (total arterial revascularization, off-pump surgery, minimally invasive robotic surgery) and better peri-operative care, has rekindled the revascularization debate regarding the optimal strategy for coronary revascularization in diabetic patients. Recent large studies such the VA-CARDS and the CARDIA trial19 were terminated before complete recruitment of the target sample size and were therefore unable or underpowered to provide a definitive answer. The FREEDOM trial has recruited an adequate sample size to provide a definitive answer with regard to superiority of one revascularization strategy over another with 80% power to detect a 27.0% relative reduction in the primary endpoint attributable to the superior strategy. The trial will report its primary outcome of the composite (earliest occurring of) death, non-fatal MI and non-fatal stroke at mean 4.37 years of follow-up in 2012.
Only 3309 subjects out of the screened 32,966 (10%), subjects met angiographic eligibility criteria for FREEDOM (Table I). While this posed a great challenge for recruitment, we believe that this “low” incidence of multi-vessel disease in diabetic subjects is a result of successes in medical therapy, such as increasing use of statin and renin-angiotensin system (RAS) inhibitor therapies. The FREEDOM trial cohort is notable for the high prevalence of multiple cardiovascular risk factors such as hypertension, obesity and dyslipidemia in addition to long-standing diabetes. With enrollment criteria including a history of having suffered an acute coronary syndrome or having inducible ischemia, and the fact that 83% subjects enrolled in FREEDOM have 3 vessel disease and 99% have LAD involvement, there can be no doubt that this is a cohort at very high risk for future cardiovascular events. Challenges in achieving near-complete revascularization in subjects with a mean aggregate lesion length of 78 mm and high myocardial jeopardy scores add to the complexity of the FREEDOM patient cohort. The EuroSCORE calculation is skewed with a low median score, probably due to the fact that FREEDOM, by virtue of its design, either excludes subjects with significant co-morbidities or does not fully capture data related to previous cardiac surgery, critical pre-operative state, pulmonary hypertension, active endocarditis and other complications related to thoracic surgery (components of the EuroSCORE). The SYNTAX score, being an anatomical angiographic score, is very normally distributed, with almost 45% subjects having scores in what is considered the intermediate range (22–32). Subjects with such scores and concomitant diabetes have been the subject of recent interesting speculation regarding the relative efficacy of PCI versus CABG.
In comparing the baseline characteristics of FREEDOM with recent landmark studies such as CARDia19, BARI-2D20, 21, and SYNTAX22 (Fig. 4, Table VII), it becomes evident that our subjects are comparable in terms of the clinical and angiographic characteristics, as are the rates of use of evidence-based medications for secondary prevention of atherosclerotic disease. In aggregate, these studies are markedly different from the historical BARI trial, with twice as much hypertension and hyperlipidemia noted in the recent trials.
The FREEDOM trial is unique in many ways. FREEDOM is the largest randomized trial of MVD treatments dedicated to diabetic subjects only. The mean values for blood pressure, lipids (LDL) and HbA1C upon entry into the trial are relatively favorable, and these risk factors are being aggressively targeted in the trial. From the inception of the trial, the importance of achieving optimal medical therapy in both arms has been emphasized. We firmly believe that in the post COURAGE23 and BARI-2D world, there is no place for evaluating revascularization strategies with sub-optimal medical therapy. The trial has fostered teamwork, coordination and communication between the cardiologist, interventionalist, cardiac surgeon and the diabetologist. We have taken special effort from the initiation of the trial to ensure an adequate multi-ethnic representation and equitable recruitment from sites in North and South Americas, Europe and Australasia.
The baseline data from the FREEDOM trial establish that the trial has successfully recruited a high-risk diabetic multi-vessel coronary disease cohort to test the optimal revascularization strategy. FREEDOM will contribute towards a definitive answer to the twodecade long debate regarding the merits of PCI vs. CABG for diabetic patients with multivessel disease. Simultaneously, it will also serve as a rich database to generate additional hypotheses regarding the role of optimal medical therapy in the management of these complex subjects for the reduction of long-term macro-vascular events.
Acknowledgments
Supported by U01 grant #01HL071988 from the National Heart, Lung, and Blood Institute. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute
Footnotes
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Clinical Trial Registration #:NCT00086450
REFERENCES
- 1.Bonow RO, Gheorghiade M. The diabetes epidemic: a national and global crisis. Am J Med. 2004;116(Suppl 5A):2S–10S. doi: 10.1016/j.amjmed.2003.10.014. [DOI] [PubMed] [Google Scholar]
- 2.Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. N Engl J Med. 1996;335(4):217–225. doi: 10.1056/NEJM199607253350401. [DOI] [PubMed] [Google Scholar]
- 3.Bansilal S, Farkouh ME, Fuster V. Optimal treatment of the diabetic patient with multivessel disease. Curr Cardiol Rep. 2008;10(4):272–284. doi: 10.1007/s11886-008-0045-x. [DOI] [PubMed] [Google Scholar]
- 4.Barsness GW, Peterson ED, Ohman EM, Nelson CL, DeLong ER, Reves JG, et al. Relationship between diabetes mellitus and long-term survival after coronary bypass and angioplasty. Circulation. 1997;96(8):2551–2556. doi: 10.1161/01.cir.96.8.2551. [DOI] [PubMed] [Google Scholar]
- 5.Serruys PW, Ong AT, van Herwerden LA, Sousa JE, Jatene A, Bonnier JJ, et al. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial. J Am Coll Cardiol. 2005;46(4):575–581. doi: 10.1016/j.jacc.2004.12.082. [DOI] [PubMed] [Google Scholar]
- 6.Rodriguez AE, Baldi J, Fernandez Pereira C, Navia J, Rodriguez Alemparte M, Delacasa A, et al. Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II) J Am Coll Cardiol. 2005;46(4):582–588. doi: 10.1016/j.jacc.2004.12.081. [DOI] [PubMed] [Google Scholar]
- 7.Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet. 2002;360(9338):965–970. doi: 10.1016/S0140-6736(02)11078-6. [DOI] [PubMed] [Google Scholar]
- 8.Soares PR, Hueb WA, Lemos PA, Lopes N, Martinez EE, Cesar LA, et al. Coronary revascularization (surgical or percutaneous) decreases mortality after the first year in diabetic subjects but not in nondiabetic subjects with multivessel disease: an analysis from the Medicine, Angioplasty, or Surgery Study (MASS II) Circulation. 2006;114(1 Suppl):I420–I424. doi: 10.1161/CIRCULATIONAHA.105.000679. [DOI] [PubMed] [Google Scholar]
- 9.Morrison DA, Sethi G, Sacks J, Henderson W, Grover F, Sedlis S, et al. Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: a multicenter, randomized trial. Investigators of the Department of Veterans Affairs Cooperative Study #385, the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) J Am Coll Cardiol. 2001;38(1):143–149. doi: 10.1016/s0735-1097(01)01366-3. [DOI] [PubMed] [Google Scholar]
- 10.Bansilal S, Farkouh M, Sharma S, Fuster V. Diabetic multivessel disease: stenting vs**coronary artery bypass grafting. Indian Heart J. 2007;59(2) Suppl B:B72–B82. [PubMed] [Google Scholar]
- 11.Farkouh ME, Dangas G, Leon MB, Smith C, Nesto R, Buse JB, et al. Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) Trial. Am Heart J. 2008;155(2):215–223. doi: 10.1016/j.ahj.2007.10.012. [DOI] [PubMed] [Google Scholar]
- 12.Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995;25(2):333–341. doi: 10.1016/0735-1097(94)00397-9. [DOI] [PubMed] [Google Scholar]
- 13.Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Fihn SD. Monitoring the quality of life in patients with coronary artery disease. Am J Cardiol. 1994;74(12):1240–1244. doi: 10.1016/0002-9149(94)90555-x. [DOI] [PubMed] [Google Scholar]
- 14.Roques F, Michel P, Goldstone AR, Nashef SA. The logistic EuroSCORE. European heart journal. 2003;24(9):881–882. doi: 10.1016/s0195-668x(02)00799-6. [DOI] [PubMed] [Google Scholar]
- 15.Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2005;1(2):219–227. [PubMed] [Google Scholar]
- 16.Genereux P, Palmerini T, Caixeta A, Cristea E, Mehran R, Sanchez R, et al. SYNTAX Score Reproducibility and Variability Between Interventional Cardiologists, Core Laboratory Technicians, and Quantitative Coronary Measurements. Circulation Cardiovascular interventions. 2011;4(6):553–561. doi: 10.1161/CIRCINTERVENTIONS.111.961862. [DOI] [PubMed] [Google Scholar]
- 17.Califf RM, Phillips HR, 3rd, Hindman MC, Mark DB, Lee KL, Behar VS, et al. Prognostic value of a coronary artery jeopardy score. J Am Coll Cardiol. 1985;5(5):1055–1063. doi: 10.1016/s0735-1097(85)80005-x. [DOI] [PubMed] [Google Scholar]
- 18.Kappetein AP, Feldman TE, Mack MJ, Morice MC, Holmes DR, Stahle E, et al. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. European heart journal. 2011;32(17):2125–2134. doi: 10.1093/eurheartj/ehr213. [DOI] [PubMed] [Google Scholar]
- 19.Kapur A, Hall RJ, Malik IS, Qureshi AC, Butts J, de Belder M, et al. Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial. J Am Coll Cardiol. 2010;55(5):432–440. doi: 10.1016/j.jacc.2009.10.014. [DOI] [PubMed] [Google Scholar]
- 20.Baseline characteristics of patients with diabetes and coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Am Heart J. 2008;156(3):528–536. 536, e1–e5. doi: 10.1016/j.ahj.2008.05.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Schwartz L, Kip KE, Alderman E, Lu J, Bates ER, Srinivas V, et al. Baseline coronary angiographic findings in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D) Am J Cardiol. 2009;103(5):632–638. doi: 10.1016/j.amjcard.2008.11.024. [DOI] [PubMed] [Google Scholar]
- 22.Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961–972. doi: 10.1056/NEJMoa0804626. [DOI] [PubMed] [Google Scholar]
- 23.Boden WE, O'Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503–1516. doi: 10.1056/NEJMoa070829. [DOI] [PubMed] [Google Scholar]