CORONARY REVASCULARIZATION IN DIABETES MELLITUS AND MULTIVESSEL CAD :REVISITING THE EVIDENCE

Dr. Satyam Rajvanshi

Introduction Coronary artery disease (CAD) is a major

cause of morbidity and mortality among patients with diabetes mellitus

Compared to nondiabetic patients, patients with diabetes are more likely to have CAD, which is most often multivessel, and to have episodes of silent ischemia

Diabetic patients with CAD have a lower longterm survival rate than nondiabetic patients with CAD

Diabetics comprise 25 to 30 percent of those who undergo revascularization

The indications for revascularization, are generally similar in patients with and without diabetes

Short and longterm results of revascularization with PCI or CABG are often worse in diabetics

CURRENT RECOMMENDATIONS

Trial basis: PCI vs CABG

Trial basis: PCI vs CABG in DM

1st RCT of coronary revascularization in diabetic patients with complex CAD

510 patients multivessel or complex single-vessel CAD randomized to PCI plus stenting (and routine abciximab) or CABG

BMS used initially, later switched to Cypher (sirolimus drug-eluting) stents was made when these became available

Primary outcome - CE of all-cause mortality, MI, and stroke

Secondary outcome - repeat revascularization added to the primary outcome events

At 1 year NS for CE of death, MI, and stroke NS for all-cause mortality Significantly less frequent CE of death, MI,

stroke, or repeat revascularization in CABG (driven by less repeat revasc. but more strokes with CABG)

[Overall, Just like SYNTAX]

But PCI could not meet the prespecified Non-inferiority criteria to CABG!

SYNTAX: The Diabetic cohort 25% of 1800 study participants had diabetes “ALL-comers” design - consecutive

enrollment of all eligible patients with three-vessel or left main coronary artery disease – One of its kind!

Inclusion – Previously untreated CAD (≥50% target vessel stenosis) with stable/unstable angina or atypical chest pain

Exclusion – previous PCI or CABG, acute MI, or need for concomitant cardiac surgery

Primary outcome – CE of MACCE (death from any cause, stroke, MI, or repeat revascularization)

Follow-up upto 60 months

AT 5 yrs CABG vs PCI in DM NS in CE of all-cause death, MI, or stroke NS in individual components - all-cause death,

stroke, or MI MACCE (including repeat revascularization) less

with CABG driven by less Repeat revascularization Low SYNTAX score (≤ 22) subgroup

Rates of MACCE similar but repeat revascularization remained less frequent with CABG

Odds were stacked against PCI – at the beginning itself!

More complete revascularization in CABG Hard end points combined with soft end

points! Had Repeat Revascularization been a

separate (Secondary) outcome – it would have been a negative study!

DM with complex CAD randomized to drug-eluting stents or surgery

Inclusion – only those lesions whose revascularization known to increase survival (Symptom mitigating revascularization excluded)

Extremely slow recruitement, early termination to only 25% of intended participants!

Severely underpowered for its primary endpoint

NS in CE of All-cause death, Nonfatal MI

No firm conclusions about the comparative effectiveness of CABG and PCI made

Freedom from confusion..….?

……. Apparently not!

FREEDOM

Purpose of FREEDOM To determine the superior approach to

revascularization in patients with diabetes and multivessel CAD - contemporary PCI with DES or CABG techniques, both with currently recommended ancillary medical therapies

Methods 2 arm superiority RCT Unblinded, no placebo F/U upto 5 years Sites: 140 worldwide NHLBI funded

Patient Selection: Inclusion Criteria

Diabetes mellitus (Type 1 or Type 2), defined according to the American Diabetes Association as either: fasting plasma glucose elevation on more

than one occasion of ≥ 126 mg/dL classic symptoms of diabetes mellitus with

unequivocal elevation of plasma glucose (2 hour postprandial or random of greater than 200 mg/dL) or

Currently undergoing pharmacological or non-pharmacological treatment for diabetes

Angiographically confirmed multivessel CAD critical (greater than or equal to 70%) lesions in at least two major epicardial vessels in at least two separate coronary artery

territories (LAD, LCX, RCA)] Angiographic characteristics amenable to

both PCI/DES and CABG Indication for revascularization based upon

symptoms of angina and/or objective evidence of myocardial ischemia

Exclusion Criteria Severe congestive heart failure (class III or

IV according to New York Heart Association [NYHA] or pulmonary edema)

Prior CABG surgery; Prior valve surgery; Prior PCI with stent implantation within 6 months of study entry

Stroke within 6 months of study entry; if stroke occurred more than 6 months prior to study entry, must have significant residual neurologic involvement, as reflected in a Rankin Score of greater than 1

Instent restenosis of a target vessel Two or more chronic total occlusions in

major coronary territories Left main stenosis (at least 50%

diameter stenosis) Acute ST elevation MI (Qwave) within 72

hours of study entry requiring revascularization

Abnormal creatine kinase level (greater than twice the normal limit); or abnormal CKMB level at study entry

Intolerance to aspirin or both clopidogrel and ticlopidine

Planned simultaneous surgical procedure unrelated to coronary revascularization (e.g., valve surgery, aneurysmectomy, carotid endarterectomy, or carotid stent)

Prior history of significant bleeding (within 6 months of study entry) that may occur during CABG or PCI/DES related anticoagulation

Significant leukopenia, neutropenia, thrombocytopenia, anemia, or known bleeding diathesis

Pregnancy Severe degree of comorbidities (COPD, CKD, CLD,

Dementia)

Methods continued DES: 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 <70 BP <130/80 HbA1c <7%

Methods continued Outcomes

Primary Composite of death from any cause, nonfatal

MI, nonfatal stroke Secondary

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 SCORE Tool to score complexity of CAD based on

anatomy There 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

Results Primary outcome analysis for DES type

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

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

events than CABG No difference in 30 day major bleeding

event(P=0.13) ARF requiring dialysis at 30 days significantly

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

Limitations Unblinded

Investigators 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 randomizedPI stated that of the eligible patients who

declined randomization, most requested PCI as reason for not wanting randomization

“

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

Evidence: Limitations

Endpoint definitions Differ in different trials

SYNTAX used conventional MI definition FREEDOM – used 2 different definitions

Periprocedural MI – within 30 days of procedure – used conventional definition

18% of total MIsPost 30 days MI – included

asymptomatic elevation of Troponins as MI!

82% of total MIs in trial period - ?significance

Generalisability of results Most trials - only 10% or less of

screening population eligible – too many exclusion criteria

Generalisability of results FREEDOM excluded

LMCHFLow EF (Only 5% patients)Prior CABG and Valve surgeriesISRCTOs (Only 5% patients)Common comorbidities

Many excluded cohorts make CABG outcome less favourable

Generalisability of results Mean EUROSCORE in FREEDOM – 2.8

Mean in most registries of CABG in real world population is higher

3.7 ± 2.5 Circulation.2008; 118: S199-S2093.5 ± 2.5 Neth Heart J. 2010 Aug; 18(7-8): 355–359.5.0 ± 3.5 Interactive CardioVascular and Thoracic Surgery 3 (2004) 562–565

Euroscore > 5 indicates increased risk of mortalityLower risk and less representative population for

CABG!

Treatment not Uptodate FREEDOM

Only about half continued on DAPT > 1 yearNewer antiplatelets not used1st gen DES only

Aorta No-Touch CABG not usedMIDCAB not used

Treatment not Uptodate A Catch-22 situation

Shorter smaller more concurent trials….dismissed as they are small and

short duration!Longer Larger trials

…sidelined if the treatment is fast evolving – by the time results are produced – ‘intervention’ is old!

Is there a rescue?

SYNTAX and SYNTAX II The category based risk approach of the

anatomical based SYNTAX Score – i.e. ‘low’, ‘intermediate,’ or ‘high’ SYNTAX Scores – to guide decision making between CABG or PCI is potentially misleading

Post hoc analysis of the SYNTAX trial - low and high risk subjects existed in higher and lower SYNTAX Score tertiles, which appeared to have implications for the most appropriate revascularisation modality (CABG and PCI)

The SYNTAX Score II was designed to improve decision making between CABG and PCI, by allowing for a long term, individualized risk assessment of patients with complex coronary artery disease.

Combines the anatomical based SYNTAX Score with clinical variables

These variables include Unprotected LM-CAD female gender Chronic obstructive pulmonary disease Age left ventricular ejection fraction CrCl PVD

SYNTAX Score II was developed in SYNTAX Trial Validated in the multicentre DELTA Registry

(n=2891) DELTA Registry - multinational,

nonrandomised, allcomers registry, conducted in 14 centres in Europe, US and South Korea. The study population was heterogeneous, and included complex coronary artery disease – anatomical SYNTAX Score ≥33 existed in 30%, and 3VD in 26%

During development and validation of the SYNTAX Score II, it was shown that

…diabetes did not improve decision making between CABG and PCI - when age, kidney function and left ventricular ejection fraction are accounted for!

HYBRID procedures!