N Engl J Med. 2012 Dec 20;367(25):2375-84. doi: 10.1056/NEJMoa1211585. Epub 2012

Nov 4

Journal Club Presentation: Nick Bosch

Revascularization and DiabetesPatients with DM and multivessel CAD, what

is optimal method of revascularization?Atherosclerosis and diabetes700,000 patients undergo multivessel

coronary revascularization yearly25% of these patients are diabetic

N Engl J Med. 2012 Dec 20;367(25):2375-84. doi: 10.1056/NEJMoa1211585. Epub 2012 Nov 4

HistoryBypass Angioplasty Revascularization

Investigation trial (BARI) in 1997Patients w/ multivessel disease assigned

randomly to CABG or PTCA; average follow-up 5.4 yrs

No difference in mortality overallDiabetic subgroup undergoing CABG lived

longerLed to ACCF/AHA Guideline recommendations:

CABG preferred for revascularization of multivessel disease in diabetics

Circulation.2011; 124: e652-e735Published online before print November 7, 2011,doi: 10.1161/ CIR.0b013e31823c074e

N Engl J Med. 2012 Dec 20;367(25):2375-84. doi: 10.1056/NEJMoa1211585. Epub 2012 Nov 4

History ContinuedOutcomes from both PCI and CABG have improved

with stents, antithrombotic therapy, arterial conduits

Coronary Artery Revascularization in Diabetes (CARDia) Study in 2005Diabetics (~500) with Multivessel or complex single

vessel disease randomized to PCI w/ stent or CABG (used both BMS and DES; became available during study)

1 yr results: no difference in mortality, lower rates of revascularization in CABG group

Underpowered

J Am Coll Cardiol. 2010 Feb 2;55(5):432-40. doi: 10.1016/j.jacc.2009.10.014.

History ContinuedSynergy between PCI with TAXUS and

Cardiac Surgery (SYNTAX) Study in 2009Randomized 1800 patients w/ 3-vessel or left

main disease to CABG or PCI w/ DESSignificantly more major cardiac or

cerebrovascular events at 12 months in PCI group; driven by increase in rate of revascularization

No difference in all-cause mortality for patients after 1 year

N Engl J Med. 2009 Mar 5;360(10):961-72. doi: 10.1056/NEJMoa0804626. Epub 2009 Feb 18

Purpose of FREEDOMTo determine if contemporary PCI with DES

or CABG techniques, both with currently recommended ancillary medical therapies, is the superior approach to revascularization in patients with diabetes and multivessel CAD.

Methods continued2 arm superiority trialUnblinded, no placeboTrial Duration 7 years w/ recruitment period

of 5 years (minimum follow-up of 2 years)Stats

Log-rank test to compare distributions of the time to first event

Cox proportional-hazards regression for hazard ratios for outcomes and subgroup analysis

Sites: 140 worldwide

MethodsPatient Selection

Multivessel CAD Stenosis >70% in 2 or more epicardial vessels

involving at least two separate coronary artery territories confirmed with angiography

Indication for revascularization based on symptoms of angina or objective evidence of myocardial ischemia

Diabetics Type 1 or 2 diabetics meeting ADA criteria: fasting

BS >126, random BS > 200, or pharmacological or nonpharmacological treatments for diabetes

Methods continuedExclusion criteria

Prior CABG or valve surgeryLeft main diseaseST-elevation MI in last 72 hoursPrior PCI in 6 months

Methods continuedDES: majority sirolimus or paclitaxel eluting.

Newer generations could be used if approved for use. ASA and clopidogrel for at least 12 months.

CABG: encouraged arterial revascularization when able

Medical therapy goals for both groups:LDL <70BP <130/80HgbA1c <7%

Methods continuedOutcomes

Primary Composite of death from any cause, nonfatal MI,

nonfatal strokeSecondary

Major adverse cardiovascular and cerebrovascular events 30 days and 12 months after procedure (includes components of primary end point + revascularization)

Annual all-cause and cardiovascular mortality

Characteristic Ineligible Eligible P value‡

Not enrolled Enrolledn 29657 1409 1900Mean age at screening, y

65.2 ± 10.8 64.4 ± 9.6 63.1 ± 9.1 <.0001

 Male 64.7 ± 10.5 63.7 ± 9.4 62.6 ± 9.0 .005 Female 66.2 ± 11.2 66.4 ± 9.7 64.4 ± 9.2 .002Male 67.7% 72.8% 71.4% .38Did 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%

Table I. Baseline characteristics for N = 32966 patients screened for FREEDOM trial eligibility

⁎Participants needed to have multivessel CAD defined as critical (≥70%) lesions in at least 2 major epicardial vessels. Angiographic characteristics needed to be amenable to both PCI/DES and CABG. Left main disease, in-stent restenosis, and >1 CTO 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

Overall (n = 1900)

History of presenting illness (indication for coronary angiography)

Stable coronary heart disease (1317 participants)

69.3%

ACS (584 participants) 30.7%

 ST-elevation MI (>72 h before admission)

20.2%

 Non–ST-elevation ACS (466 participants)

79.8%

 No recurrent/provocable ischemia

33.3%

 Provocable ischemia only 23.4%

 Spontaneous recurrent ischemia

41.3%

 Refractory ischemia 1.9%

Table II. History of presenting illness

OverallMedical historyDiabetes mellitus Type 1 4.5%

Type 2 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 BP 84.8%History of hyperlipidemia 83.7%Prior MI 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 COPD or asthma 10.2%Ever smoked 54.5% If yes (n = 91): current smoker 28.8% Ex-smoker (quit >12 m ago) 65.8%History of gastrointestinal ulcer/bleed 4.7%Aspirin daily for last 7 d or longer 71.7%History of renal artery stenosis 0.5%

Surgical historyPrior PTCA (balloon angioplasty or atherectomy) within 12 m prior

0.6%

Prior PCI w/stent within the last 12 m 0.6%

Variable Mean ± SD or %LDL (mg/dL) 92.7 ± 36.6LDL <100 62.4%LDL <70 29.1%HbA1c (%) 7.8 ± 1.7HbA1c (%) <7.0 36.0% 7.0-8.0 25.4% ≥8.0 38.7%SBP (mm Hg) 133.8 ± 19.8SBP (mm Hg) <120 18.9% 120-140 43.0% ≥140 38.2%DBP (mm Hg) 76.0 ± 11.1DBP (mm Hg) <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 ± 1.6Creatinine (mg/dL) 1.1 ± 0.5Presence of microalbuminuria (>30 mg/g)

40.3%

Table IV. Cardiovascular risk factor profile of the FREEDOM cohort

OverallMedicationAntiplatelet agent Aspirin 90.7% Clopidogrel 23.9% Ticlopidine 1.1% Cilostazol 0.1%Antianginal agent β-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% α-Glucosidase inhibitor 1.3% Thiazolidinedione 8.2% Rosiglitazone 4.7% Pioglitazone 3.5% NSAID 5.3% PPI⁎ 14.4%

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%

No. of 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)

LVEF (%) 66.2 ± 11.3 (1291)

LVEF >50% 90.9%

35%-50% 8.0%

<35% 1.1%

Table VI. Baseline angiographic profile for 1888 participants with a centrally interpreted angiogram

SYNTAX SCORETool to score complexity of CAD based on

anatomyThere were 395 participants (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).

Results

Results

Results

Results

Results

Results

Primary composite outcome - subgroups

ResultsPrimary outcome analysis for DES type

compared to CABG (898 pts)Sirolimus-eluting (469 pts) at 5 yrs: 6.7% more

events than CABGPaclitaxel-eluting (394 pts) at 5 yrs: 6.5% more

events than CABGNo difference in 30 day major bleeding event:

P=0.13ARF requiring dialysis at 30 days significantly

higher in CABG group (P=0.02): 8 pts compared to 1 patient

DiscussionPatients undergoing CABG had significantly lower

rates of the primary endpoint including death from any cause

Results consistent with reports from smaller, retrospective, cohort, underpowered and subgroup analyses in the past

Previous results had shown major adverse events were driven by rates of revascularization. This study shows CABG benefit driven by decreased MI and death from any cause.

Increased rate of stroke consistent in almost all previous studies and meta-analyses

DiscussionSimilar rates of medical therapy in each

group90% use of dual antiplatelet therapy at 12

months for PCI groupsShowed benefit of CABG over PCI with DES

using current technology/medical advancesReinforce vs. change clinical practice

Already recommendedIncrease level of evidence: IIa, level of

evidence B -> I?

Discussion - limitationsLow-prevalence subgroups

Low statistical power to detect interactions between subgroups

UnblindedInvestigators argue that this is less important given

objective outcomes and similar medical therapy between groups

Generalizability: only 10% of screening population eligible, only half of those randomizedLate Breaking Clinic Trial 2012: PI stated that of the

eligible patients who declined randomization, most requested PCI as reason for not wanting randomization

Equipoise candidates for each procedure often not the case. Likely explains significant number of patients screened but not eligible for randomization

“Main Results of the Future REvascularization Evaluation in Patients with Diabetes Mellitus: Optimal management of Multivessel disease (FREEDOM) Trial”; Scientific Sessions 2012, late breaking trials AHA

Discussion - limitations 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%

No. of 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)

LVEF (%) 66.2 ± 11.3 (1291)

LVEF >50% 90.9%

35%-50% 8.0%

<35% 1.1%

Discussion - limitationsType 1 Diabetics: only 4.5% of patientsLonger term follow-up: saphenous vein grafts

failure?

Cost-effectivenessCost-Effectiveness of PCI with Drug Eluting Stents vs.

Bypass Surgery for Patients with Diabetes and Multivessel CAD: Results from the FREEDOM Trial. Elizabeth A. Magnuson et al. Presentation from Late Breaking Clinical Trials Scientific Sessions 2012, 11/4/2012. Total cost for index hospitalization of CABG was $8622

higher per patient compared to PCI Over next 5 years, follow-up costs were higher for PCI

mostly due to repeat revascularization but cumulative 5 year costs remained $3641 higher per patient with CABG

Model expanding results over lifetime: CABG more economically attractive compared to DES-PCI driven mostly by increase in survival.

CABG had an incremental cost-effectiveness ratio of $8,132 per quality-adjusted life-year gained vs PCI. Traditionally, therapies are considered cost-effective if the incremental cost-effectiveness ratio is less than $50,000 per quality-adjusted life-year gained.