CORONARY ARTERY DISEASE (CAD)































  • See definitions above for more on the table
  • Numbers represent percent of patients with criteria who will have CAD
  • Reference [9]
NON-ANGINAL CHEST PAIN
MEN WOMEN
AGE Low risk High risk Low risk High risk
35 3 35 1 19
45 9 47 2 22
55 23 59 4 25
65 49 69 9 29

  • See definitions above for more on the table
  • Numbers represent percent of patients with criteria who will have CAD
  • Reference [9]
ATYPICAL ANGINA
MEN WOMEN
AGE Low risk High risk Low risk High risk
35 8 59 2 39
45 21 70 5 43
55 45 79 10 47
65 71 86 20 51

  • See definitions above for more on the table
  • Numbers represent percent of patients with criteria who will have CAD
  • Reference [9]
TYPICAL ANGINA
MEN WOMEN
AGE Low risk High risk Low risk High risk
35 30 88 10 78
45 51 92 20 79
55 80 95 38 82
65 93 97 56 84













  • Definition of intermediate risk varied slightly between studies but was typically considered 10 - 20% on the Framingham risk calculator
  • Reference [12]
CAC score in asymptomatic intermediate risk individual Annual risk of heart disease death or heart attack
0 - 99 0.4%
100 - 399 1.3%
≥ 400 2.4%











Overview
  • There are 3 options for treating stable CAD
    • Percutaneous Coronary Intervention (PCI) - angioplasty with stenting
    • Coronary Artery Bypass Grafting (CABG)
    • Medical Therapy (MT) - typically involves aspirin, statins, and aggressive treatment of risk factors (ex. diabetes, hypertension, cholesterol)
  • These options have been compared in a number of studies involving different patient subgroups. Some of the larger trials are detailed below.
COURAGE trial - PCI + MT vs MT in Stable CAD, NEJM (2007) [PubMed abstract]
  • The COURAGE trial enrolled 2287 patients with stable coronary artery disease
Main inclusion criteria
  • 70% stenosis in at least one vessel with objective evidence of ischemia (EKG changes) or 80% stenosis in one vessel with typical angina symptoms
Main exclusion criteria
  • Left main disease
  • EF < 30%
  • Revascularization within 6 months
  • Markedly positive EST
Baseline characteristics
  • Average age 61 years
  • History of myocardial infarction - 38%
  • Previous PCI - 15%
  • Previous CABG - 11%
  • Vessel disease: One - 31% | Two - 39% | Three - 30%
Randomized treatment groups
  • Group 1 (1149 patients) - PCI + MT (93% of target lesions were successfully revascularized)
  • Group 2 (1138 patients) - MT
  • Medically therapy was defined as:
    • Aspirin (81 - 325 mg a day) or clopidogrel 75 mg a day
    • Statin - target LDL of 60 - 85 mg/dl
    • Blood pressure control with one or a combination of the following: ACE/ARB (78% of patients), beta blocker (86% of patients), calcium channel blocker (52% of patients)
    • Angina control with nitrates (57% of patients)
Primary outcome: Composite of death from any cause and non-fatal heart attack
Results

Duration: Median of 4.6 years
Outcome PCI + MT MT Comparisons
Primary outcome 19% 18.5% HR 1.05, 95%CI [0.87 - 1.27], p=0.62
Overall mortality 7.6% 8.3% HR 0.87, 95%CI [0.65 - 1.16], p=0.38
Nonfatal myocardial infarction 13.2% 12.3% HR 1.13, 95%CI [0.89 - 1.43], p=0.33
  • In the MT group, 32.6% of patients eventually underwent PCI or CABG
  • In the PCI + MT group, 21.1% of patients underwent additional PCI or CABG after baseline intervention [17]

Findings: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy.
COURAGE trial extended follow-up, NEJM (2015) [PubMed abstract]
  • A follow-up to the COURAGE trial was published in 2015. It tracked 1211 patients from the original trial for up to 15 years.

Duration: Median of 6.2 years
Outcome PCI + MT MT Comparisons
Death from any cause 25% 24% HR 1.03, 95%CI [0.83 - 1.21], p=0.76

Findings: During an extended-follow-up of up to 15 years, we did not find a difference in survival between an initial strategy of PCI plus medical therapy and medical therapy alone in patients with stable ischemic heart disease.
BARI 2D Study - PCI or CABG + MT vs MT in Diabetics with CAD, NEJM (2009) [PubMed abstract]
  • The BARI 2D trial enrolled 2368 patients with diabetes and CAD
Main inclusion criteria
  • Type 2 diabetes
  • ≥ 50% stenosis of ≥ one major coronary vessel with a positive stress test or ≥ 70% stenosis of ≥ one major vessel and typical angina
  • Candidate for PCI or CABG
Main exclusion criteria
  • Left main disease
  • Serum creatinine > 2 mg/dl
  • HgA1C > 13%
  • NYHA Class III or IV heart failure
  • Prior PCI or CABG within 12 months
Baseline characteristics
  • Average age 62 years
  • Average HgA1C - 7.7%
  • Average duration of diabetes - 10.4 years
  • History of myocardial infarction - 32%
  • Prior revascularization - 24%
  • Triple vessel disease - 31%
Randomized treatment groups
  • Group 1 (1192 patients) - MT only
  • Group 2 (1176 patients) - PCI or CABG within 4 weeks + MT
  • MT was not explicitly defined, but meds taken were as follows:
    • Aspirin (94% of patients), clopidogrel or ticlopidine (21% of patients)
    • Statins (95% of patients) - target LDL < 100 mg/dl
    • Ace inhibitor or ARB (92% of patients)
    • Beta blocker (88% of patients)
  • CABG or PCI was determined before randomization based on whichever procedure was more appropriate for the individual patient
  • In Group 2, 65% of patients underwent PCI and 30% underwent CABG
  • Patients were treated to a target HgA1C of < 7%
  • Another factor in the trial randomized patients to insulin-sensitizing therapy or insulin therapy
Primary outcome: Overall mortality
Results

Duration: 5 years
Outcome MT PCI or CABG + MT Comparisons
Primary outcome 12.2% 11.7% diff 0.5%, 95%CI [-2 to 3.1], p=0.97
Composite of death, heart attack, or stroke 24.1% 22.8% diff 1.3%, 95%CI [-2.2 to 4.9], p=0.70
  • In the MT only group, 42.1% of patients eventually underwent PCI or CABG

Findings: Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision.
STICH - CABG + MT vs MT in Heart Failure, NEJM (2011) [PubMed abstract]
  • The STICH trial enrolled 1212 patients with CAD and an EF ≤ 35%
Main inclusion criteria
  • CAD suitable for revascularization
  • EF ≤ 35%
Main exclusion criteria
  • Left main disease
  • Severe angina
  • Recent myocardial infarction
  • Plan for PCI
  • > 1 prior CABG procedures
Baseline characteristics
  • Median age 59 years
  • Previous myocardial infarction - 77%
  • Previous CABG - 3%
  • Median ejection fraction - 27.5%
  • Vessel disease: One - 9% | Two - 30% | Three - 60%
Randomized treatment groups
  • Group 1 (602 patients) - MT as determined by the patient's cardiologist
  • Group 2 (610 patients) - CABG within 2 weeks + MT
  • Actual MT given was as follows:
    • Aspirin or warfarin - 93%
    • Clopidogrel - 16%
    • Statins - 87%
    • Ace inhibitors or ARBs - 89%
    • Beta blockers - 90%
    • Nitrates - 38%
Primary outcome: Overall mortality
Results

Duration: Median of 4.6 years
Outcome MT CABG + MT Comparisons
Primary outcome 41% 36% HR 0.86, 95%CI [0.72 - 1.04], p=0.12
Death from cardiovascular causes 33% 28% HR 0.81, 95%CI [0.66 - 1.00], p=0.05
Death or hospitalization for heart failure 54% 48% HR 0.84, 95%CI [0.71 - 0.98], p=0.03
  • In the MT group, 17% of patients eventually underwent CABG. In the CABG + MT group, 9% of patients did not undergo CABG.

Findings: In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes.
STICH Trial 10-year Results, NEJM (2016) [PubMed abstract]
  • A follow-up study to the STICH trial was published in 2016. It included results from the original 1212 patients.

Duration: Median of 9.8 years
Outcome CABG + MT MT Comparisons
Overall mortality 58.9% 66.1% HR 0.84, 95%CI [0.73 - 0.97] p=0.02
Death from cardiovascular causes 40.5% 49.3% HR 0.79, 95%CI [0.66 - 0.93], p=0.006
Death or hospitalization for heart failure 66.2% 74.8% HR 0.81, 95%CI [0.71 - 0.93], p=0.002
  • In the MT group, 19.8% of patients had undergone CABG during the long-term follow-up

Findings: In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone.
SYNTAX - CABG vs PCI in Multivessel disease and Left Main Disease, NEJM (2009) [PubMed abstract]
  • The SYNTAX trial enrolled 1800 patients with 3-vessel disease or left main disease
Main inclusion criteria
  • 3-vessel disease (significant disease was defined as 50% stenosis) or left main disease
Main exclusion criteria
  • Previous PCI or CABG
  • Acute myocardial infarction
Baseline characteristics
  • Average age 65 years
  • Previous myocardial infarction - 32%
  • Left main disease - 39%
  • Average number of lesions - 4.3
Randomized treatment groups
  • Group 1 (903 patients) - PCI with drug-eluting stent
  • Group 2 (897 patients) - CABG
Primary outcome: Composite of major adverse cardiac or cerebrovascular event (ex. death from any cause, stroke, myocardial infarction, or repeat revascularization) at 12 months after randomization
Results

Duration: 12 months
Outcome PCI CABG Comparisons
Primary outcome 17.8% 12.4% RR 1.44, 95%CI [1.15 - 1.81]. p=0.002
Overall mortality 4.4% 3.5% RR 1.24, 95%CI [0.78 - 1.98]. p=0.37
Stroke 0.6% 2.2% RR 0.25, 95%CI [0.09 - 0.67]. p=0.003
Myocardial infarction 4.8% 3.3% RR 1.46, 95%CI [0.92 - 2.33]. p=0.11
Repeat revascularization 13.5% 5.9% RR 2.29, 95%CI [1.67 - 3.14]. p<0.001
Primary outcome (patients with left main disease) 15.8% 13.7% p=0.44

Findings: CABG remains the standard of care for patients with three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year.
SYNTAX Trial 5-year Results, Lancet (2013) [PubMed abstract]
  • A follow-up study to the SYNTAX trial was published in 2013. It included results from 1676 of the original 1800 patients.

Duration: 5 years
Outcome PCI CABG Comparisons
Primary outcome 37.3% 26.9% p<0.0001
Overall mortality 13.9% 11.4% p=0.10
Stroke 2.4% 3.7% p=0.09
Myocardial infarction 9.7% 3.8% p<0.0001
Repeat revascularization 25.9% 13.7% p<0.0001
Primary outcome (patients with left main disease) 36.9% 31% p=0.12

Findings: CABG should remain the standard of care for patients with complex lesions (high or intermediate SYNTAX scores). For patients with less complex disease (low SYNTAX scores) or left main coronary disease (low or intermediate SYNTAX scores), PCI is an acceptable alternative. All patients with complex multivessel coronary artery disease should be reviewed and discussed by both a cardiac surgeon and interventional cardiologist to reach consensus on optimum treatment.
SYNTAX Trial 10-year Mortality Results, Lancet (2019) [PubMed abstract]
  • Another follow-up study to the SYNTAX trial was published in 2019. It included overall mortality results from 1689 of the original 1800 patients.

Duration: 10 years
Outcome PCI CABG Comparisons
Overall mortality 27% 24% HR 1.17, 95%CI [0.97 - 1.41] p=0.092
Overall mortality (3-vessel disease group) 28% 21% HR 1.41, 95%CI [1.10 - 1.80]
Overall mortality (left main disease group) 26% 28% HR 0.90, 95%CI [0.68 - 1.20]

Findings: At 10 years, no significant difference existed in all-cause death between PCI using first-generation paclitaxel-eluting stents and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with left main coronary artery disease.
FREEDOM Trial - CABG vs PCI in Diabetics with Multivessel Disease, NEJM (2012) [PubMed abstract]
  • The FREEDOM trial enrolled 1900 patients with diabetes and multivessel disease
Main inclusion criteria
  • Diabetes
  • > 70% stenosis in ≥ 2 epicardial vessels
Main exclusion criteria
  • Left main disease
Baseline characteristics
  • Average age 63 years
  • Average A1C - 7.8%
  • Previous myocardial infarction - 26%
  • 3-vessel disease - 83%
  • Average number of lesions - 5.7
Randomized treatment groups
  • Group 1 (953 patients) - PCI with drug-eluting stent (predominantly sirolimus and paclitaxel)
  • Group 2 (947 patients) - CABG
  • All patients received optimal medical therapy
  • Dual antiplatelet therapy was recommended for 12 months after stenting
Primary outcome: Composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke
Results

Duration: Median of 3.8 years
Outcome PCI CABG Comparisons
Primary outcome (5-year estimate) 26.6% 18.7% p=0.005
Overall mortality (5-year estimate) 16.3% 10.9% p=0.049
Myocardial infarction (5-year estimate) 13.9% 6% p<0.001
Stroke (5-year estimate) 2.4% 5.2% p=0.03
Acute renal failure requiring dialysis within 30 days of procedure 1 patient 8 patients p=0.02

Findings: For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke.
BEST Trial - CABG vs PCI with Everolimus-eluting Stents in Multivessel Disease, NEJM (2015) [PubMed abstract]
  • The BEST trial enrolled 880 patients with multivessel disease
Main inclusion criteria
  • > 70% stenosis in ≥ 2 major epicardial vessels
  • Candidate for PCI and CABG
Main exclusion criteria
  • Left main disease
  • NYHA III or IV heart failure
  • Previous CABG
  • Prior PCI with drug-eluting stent within 1 year
  • Significant bleeding within 6 months
Baseline characteristics
  • Average age 64 years
  • History of myocardial infarction - 6%
  • Diabetes - 41%
  • Vessel disease: Two - 23% | Three - 77%
  • Presenting diagnosis: Stable angina - 47% | Unstable angina - 43% | Acute MI - 9%
Randomized treatment groups
  • Group 1 (438 patients) - PCI with everolimus-eluting stent
  • Group 2 (442 patients) - CABG
  • During PCI, attempts were made to treat all lesions with everolimus-eluting stents. Patients received an average of 3.4 stents.
  • Dual antiplatelet therapy was prescribed for 1 year after PCI
Primary outcome: Composite of death, myocardial infarction, or target-vessel revascularization
Results

Duration: After a median of 4.6 years, the study was stopped early due to poor enrollment
Outcome PCI CABG Comparisons
Primary outcome (at 2 years) 11% 7.9% diff 3.1%, 95%CI [−0.8 to 6.9]
Primary outcome (at 4.6 years) 15.3% 10.6% HR, 1.47, 95%CI [1.01 - 2.13], p=0.04
Overall mortality (at 4.6 years) 6.6% 5% HR 1.34, 95%CI [0.77 – 2.34], p=0.30
Myocardial infarction (at 4.6 years) 4.8% 2.7% HR 1.76, 95%CI [0.87 – 3.58], p=0.11
Stroke (at 4.6 years) 2.5% 2.9% HR 0.86, 95%CI [0.39 – 1.93], p=0.72
Major bleeding (at 4.6 years) 6.8% 29.9% HR 0.20, 95%CI [0.14 – 0.30], p<0.001

Findings: Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG.
PRECOMBAT Trial - CABG vs PCI in Left Main Disease, NEJM (2015) [PubMed abstract]
  • The PRECOMBAT trial enrolled 600 patients with left main disease
Main inclusion criteria
  • > 50% stenosis of left main coronary artery
  • Diagnosed with stable angina, unstable angina, silent ischemia, or NSTEMI
  • Candidate for PCI or CABG
Main exclusion criteria
  • PCI within 1 year
  • Previous CABG
  • EF < 30%
  • Serum creatinine > 2 mg/dl
  • Bleeding disorder
Baseline characteristics
  • Average age 62 years
  • Previous PCI - 13%
  • Previous myocardial infarction - 5.5%
  • Average SYNTAX score - 25
  • Diseased vessels: LMD only - 10% | LMD + 1 vessel - 17% | LMD + 2 vessels - 32% | LMD + 3 vessels - 41%
Randomized treatment groups
  • Group 1 (300 patients) - PCI with sirolimus-eluting stent
  • Group 2 (300 patients) - CABG
  • All patients had unprotected left main disease defined as no collateral vessel or previous graft providing distal perfusion around the left main occlusion
  • Patients in Group 1 had follow-up angiography at 8 - 10 months after PCI
Primary outcome: Composite of major adverse cardiac or cerebrovascular events, including death from any cause, myocardial infarction, stroke, and ischemia-driven target-vessel revascularization during the 12-month period after randomization
Results

Duration: Median of 24 months
Outcome PCI CABG Comparisons
Primary outcome (at 12 months) 8.7% 6.7% diff 2%, 95%CI [-1.6 to 5.6]
Primary outcome (at 24 months) 12.2% 8.1% HR 1.50, 95%CI [0.90 - 2.52], p=0.12
Overall mortality (at 24 months) 2.4% 3.4% HR 0.69, 95%CI [0.26 - 1.82], p=0.45
Myocardial infarction (at 24 months) 1.7% 1.0% HR 1.66, 95%CI [0.40 - 6.96], p=0.49
Stroke (at 24 months) 0.4% 0.7% HR 0.49, 95%CI [0.04 - 5.40], p=0.56
Revascularization (at 24 months) 9% 4.2% HR 2.18, 95%CI [1.10 - 4.32], p=0.02

Findings: In this randomized trial involving patients with unprotected left main coronary artery stenosis, PCI with sirolimus-eluting stents was shown to be noninferior to CABG with respect to major adverse cardiac or cerebrovascular events. However, the noninferiority margin was wide, and the results cannot be considered clinically directive.
EXCEL Trial - CABG vs PCI in Left Main Disease, NEJM (2016) [PubMed abstract]
  • The EXCEL trial enrolled 1905 patients with left main disease
Main inclusion criteria
  • ≥ 70% stenosis of left main coronary artery or 50 - 69% stenosis causing hemodynamic instability
  • Low-to-intermediate anatomical complexity of CAD (SYNTAX score ≤ 32)
Main exclusion criteria
  • Prior PCI of left main artery or other PCI within 1 year
  • Prior CABG
  • Recent MI with CK-MB still elevated
Baseline characteristics
  • Average age 66 years
  • Diabetics - 29%
  • Previous PCI - 17%
  • Previous myocardial infarction - 17%
  • CHF - 7%
  • Recent MI within 7 days - 15%
  • Unstable angina - 24%
  • Stable angina - 53%
  • Average SYNTAX score - 21
Randomized treatment groups
  • Group 1 (948 patients) - PCI with everolimus-eluting stent
  • Group 2 (957 patients) - CABG
  • In the PCI group, dual antiplatelet therapy was continued for a minimum of one year
Primary outcome: Rate of a composite of death from any cause, stroke, or myocardial infarction at 3 years
Results

Duration: 3 years
Outcome PCI CABG Comparisons
Primary outcome 15.4% 14.7% HR 1.0, 95%CI [0.79 - 1.26], p=0.98
Primary outcome at 30 days 4.9% 7.9% HR 0.61, 95%CI [0.42 - 0.88],p=0.008
Overall mortality 8.2% 5.9% HR, 1.34, 95%CI [0.94 - 1.91], p=0.11
Myocardial infarction 8% 8.3% HR, 0.93, 95%CI [0.67 - 1.28], p=0.64
Stroke 2.3% 2.9% HR, 0.77, 95%CI [0.43 - 1.37], p=0.37
Revascularization 12.6% 7.5% HR, 1.72, 95%CI [1.27 - 2.33], p<0.001
  • In subgroup analysis, there was no significant difference in the primary outcome among patients with multivessel disease

Findings: In patients with left main coronary artery disease and low or intermediate SYNTAX scores by site assessment, PCI with everolimus-eluting stents was noninferior to CABG with respect to the rate of the composite end point of death, stroke, or myocardial infarction at 3 years.
EXCEL Trial 5-year Results, NEJM (2019) [PubMed abstract]
  • A follow-up study to the EXCEL trial was published in 2019. It included results for all patients at 5 years.

Duration: 5 years
Outcome PCI CABG Comparisons
Primary outcome 22% 19.2% diff 2.8%, 95%CI [-0.9 to 6.5], p=0.13
Overall mortality 13% 9.9% diff 3.1%, 95%CI [0.2 to 6.1]
Myocardial Infarction 10.6% 9.1% diff 1.4%, 95%CI [-1.3 to 4.2]
Stroke 2.9% 3.7% diff -0.8%, 95%CI [-2.4 to 0.9]
Revascularization 16.9% 10% diff 6.9%, 95%CI [3.7 to 10]

Findings: In patients with left main coronary artery disease of low or intermediate anatomical complexity, there was no significant difference between PCI and CABG with respect to the rate of the composite outcome of death, stroke, or myocardial infarction at 5 years.
NOBLE Trial - CABG vs PCI in Left Main Disease, Lancet (2016) [PubMed abstract]
  • The NOBLE trial enrolled 1201 patients with left main disease
Main inclusion criteria
  • Stenosis ≥ 50% or fractional flow reserve ≤ 0.80 in the left main coronary artery ostium, mid-shaft, or bifurcation with no more than 3 additional noncomplex lesions
Main exclusion criteria
  • ST-elevation infarction within 24 hours
Baseline characteristics
  • Average age 66 years
  • Diabetics - 15%
  • Previous PCI - 20%
  • Previous CABG - 1%
  • NYHA III or IV - 21%
  • Average SYNTAX score - 22
  • Stable angina - 82% | Acute coronary syndrome - 18%
Randomized treatment groups
  • Group 1 (592 patients) - PCI with drug-eluting stent
  • Group 2 (592 patients) - CABG
  • Biolimus-eluting stents were recommended
  • In the PCI group, all patients received dual antiplatelet therapy for one year
Primary outcome: Composite of death from any cause, non-procedural myocardial infarction, repeat revascularization, or stroke (Kaplan-Meier 5-year estimates)
Results

Duration: Median of 3 years
Outcome (5-year estimate) PCI CABG Comparisons
Primary outcome 28% 18% HR 1.51, 95%CI [1.13 - 2.0], p=0.0044
Overall mortality 11% 9% HR 1.08, 95%CI [0.67 - 1.74], p=0.84
Non-procedural myocardial infarction 6% 2% HR 2.87, 95%CI [1.40 - 5.89], p=0.0040
Stroke 5% 2% HR 2.20, 95%CI [0.91 - 5.36], p=0.08
Revascularization 15% 10% HR 1.50, 95%CI [1.04 - 2.17], p=0.0304

Findings: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease
AHA recommendations
  • The AHA issued its most recent guidelines for the treatment of stable CAD in 2012
  • Typical of other AHA guidelines, the recommendations are presented in an elaborate and confusing 12-tier system
  • We've provided a brief summary of the strongest recommendations below
  • The complete recommendations are available here - AHA CAD Guidelines
Recommendations to improve survival
  • Single or multivessel disease (1,2, or 3-vessel disease)
    • CABG is preferred in patients with 3-vessel disease
    • CABG or PCI is appropriate in patients with ventricular arrhythmia presumed to be caused by significant 1-vessel disease
  • Left main disease
    • CABG is the preferred treatment for Left main disease
Recommendations to improve symptoms (angina)
  • Single or multivessel disease (1,2, or 3-vessel disease)
    • CABG or PCI is beneficial in patients with 1 or more vessel disease whose symptoms are not controlled with MT
Summary
  • The treatment of CAD is constantly evolving as new drugs and procedures are introduced
  • Results from the trials detailed above are summarized below
Medical therapy
  • All patients with CAD should receive guideline-recommended medical therapy with aggressive risk factor management
  • The trials comparing medical therapy to PCI or CABG are plagued by high crossover rates that bias a study toward the null. In the STICH trial which only enrolled patients with an EF ≤ 35%, CABG was clearly superior to MT. This study was performed before the heart failure drug Entresto® was available; Entresto® would likely improve MT outcomes.
  • Medical therapy alone has not been studied in left main disease
PCI vs CABG
  • In trials involving multivessel disease, CABG generally outperformed PCI
  • In trials that looked specifically at left main disease, PCI and CABG were equivalent in two trials and CABG was superior in a third. In all three trials, revascularization during follow-up was significantly more frequent in the PCI groups.



Overview
  • Older patients (> 80 years) are mostly underrepresented in CAD trials. These patients typically have more comorbidities than younger patients which can make determining the most beneficial route of treatment difficult.
  • The After Eighty Study was designed to help guide decision-making in elderly patients with NSTEMI or unstable angina. It compared conservative therapy to an early invasive strategy in patients ≥ 80 years old.
After Eighty Study - Conservative Strategy vs Immediate Invasive Strategy in Patients ≥ 80 years old, Lancet (2016) [PubMed abstract]
  • The After Eighty Study enrolled 457 patients with NSTEMI or unstable angina who were ≥ 80 years old
Main inclusion criteria
  • ≥ 80 years old
  • Presenting to the hospital with NSTEMI or unstable angina with or without EKG changes or cardiac enzyme elevations
Main exclusion criteria
  • Clinically unstable with continuing chest pain
  • Short life expectancy (< 12 months)
  • Significant dementia
Baseline characteristics
  • Average age 85 years
  • Previous MI ∼ 43%
  • Previous PCI - 22%
  • Previous CABG ∼ 17%
  • A fib - 22%
  • Elevated troponin on admission - 93%
  • Average GFR - 53 ml/min
  • EF < 30% - 4% | EF 30% to 50% - 29% | EF > 50% ∼ 50%
Randomized treatment groups
  • Group 1 (229 patients) - Invasive strategy (immediate angiography with subsequent PCI, CABG, or medical therapy as indicated)
  • Group 2 (228 patients) - Conservative strategy
  • In Group 1, 47% of patients received PCI and 3% had CABG surgery
  • Conservative therapy was primarily aspirin (93%), statin (84%), P2Y12 inhibitor (77%), beta blocker (85%), ACE/ARB (54%), and nitrates (48%)
Primary outcome: Composite of myocardial infarction, need for urgent revascularization, stroke, and death. Need for urgent revascularization was defined as increasing angina despite optimal medical treatment with or without EKG changes.
Results

Duration: Median of 1.53 years
Outcome Invasive strategy Conservative Comparisons
Primary outcome 41% 61% RR 0.48, 95%CI [0.37 - 0.63], p=0.0001
Myocardial infarction 17% 30% RR 0.50, 95%CI [0.33 - 0.75], p=0.0003
Need for urgent revascularization 2% 11% RR 0.19, 95%CI [0.05 - 0.52], p=0.0001
Stroke 3% 6% RR 0.61, 95%CI [0.22 - 1.60], p=0.26
Overall mortality 25% 27% RR 0.87, 95%CI [0.59 - 1.27], p=0.53
  • Adverse events were similar between the groups

Findings: In patients aged 80 years or more with NSTEMI or unstable angina, an invasive strategy is superior to a conservative strategy in the reduction of composite events. Efficacy of the invasive strategy was diluted with increasing age (after adjustment for creatinine and effect modification). The two strategies did not differ in terms of bleeding complications.
Summary
  • The After Eighty Study found that a strategy of early invasive therapy was superior to conservative therapy in patients ≥ 80 years old with NSTEMI or unstable angina
  • Although early invasive treatment did not improve overall mortality, it did cut the risk of myocardial infarction in half. The need for urgent revascularization was also significantly reduced, but this was a soft endpoint that was likely susceptible to bias in this open-label study.
  • In conclusion, elderly patients with NSTEMI or unstable angina who do not have significant comorbidities will likely benefit from PCI



Overview
  • When a patient suffers a heart attack and undergoes angiography, past guidelines recommended that the cardiologist only perform angioplasty (PCI) on the artery that is suspected to have caused the ischemia (culprit-lesion). Several studies have now looked at outcomes when other stenosed arteries (nonculprit lesions) are also treated at or around the same time, an approach referred to as "preventive PCI."
  • In the CULPRIT-SHOCK study, preventive PCI was compared to culprit-lesion-only PCI in patients with cardiogenic shock. In the PRAMI and COMPLETE studies, preventive PCI was compared to culprit-lesion-only PCI in stable patients. All three studies are detailed below.
CULPRIT-SHOCK Study - Culprit-lesion-only PCI vs Preventive PCI in Cardiogenic Shock, NEJM (2017) [PubMed abstract]
  • The CULPRIT-SHOCK Study enrolled 706 patients with myocardial infarction and cardiogenic shock
Main inclusion criteria
  • Acute myocardial infarction with cardiogenic shock defined as SBP < 90 mmHg, pulmonary congestion, and signs of impaired organ perfusion
  • Planned early PCI
  • At least two major vessels with > 70% stenosis
  • An identifiable culprit lesion
Main exclusion criteria
  • Resuscitation for > 30 minutes
  • Indication for CABG
  • Onset of shock > 12 hours before randomization
Baseline characteristics
  • Median age 70 years
  • Previous MI - 16%
  • Previous PCI - 19%
  • Previous CABG - 5%
  • STEMI - 62%
  • Two affected vessels - 36%
  • Three affected vessels - 63%
Randomized treatment groups
  • Group 1 (344 patients) - Culprit-lesion-only PCI
  • Group 2 (342 patients) - Preventive PCI (culprit + nonculprit vessels)
  • In the preventive PCI group, PCI of all major coronary arteries with more than 70% stenosis of the diameter was to be performed
Primary outcome: Composite of death from any cause or severe renal failure leading to renal-replacement therapy within 30 days after randomization
Results

Duration: 30 days
Outcome Culprit-lesion only Preventive Comparisons
Primary outcome 45.9% 55.4% HR 0.83, 95%CI [0.71 - 0.96], p=0.01
Overall mortality 43.3% 51.6% HR 0.84, 95%CI [0.72 - 0.98], p=0.03
Renal replacement therapy 11.6% 16.4% HR 0.71, 95%CI [0.49 - 1.03], p=0.07
Staged PCI of nonculprit lesion 17.4% 2.3% p<0.001
Repeat revascularization 21.5% 3.8% HR 7.43, 95%CI [3.61 - 15.31], p<0.001
  • In Group 1, 12.5% of patients received PCI of nonculprit lesions during the initial PCI
  • In Group 2, 9.4% of patients received culprit-lesion-only PCI during the initial PCI

Findings: Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI.
CULPRIT-SHOCK Study - One-Year Outcomes, NEJM (2018) [PubMed abstract]
  • A follow-up study to the CULPRIT-SHOCK study was published in 2018. It included results from 684 of the original 706 patients.

Duration: 1 year
Outcome Culprit-lesion only Preventive Comparisons
Overall mortality 50% 56.9% HR 0.88, 95%CI [0.76 - 1.01]
Recurrent myocardial infarction 1.7% 2.1% HR 0.85, 95%CI [0.29 - 2.50]
Renal replacement therapy 11.6% 16.4% HR 0.71, 95%CI [0.49 - 1.03]
Any repeat revascularization 32.3% 9.4% HR 3.44, 95%CI [2.39 - 4.95]

Findings: Among patients with acute myocardial infarction and cardiogenic shock, the risk of death or renal-replacement therapy at 30 days was lower with culprit-lesion-only PCI than with immediate multivessel PCI, and mortality did not differ significantly between the two groups at 1 year of follow-up.
PRAMI Study - Preventive PCI vs Infarct-vessel-only PCI, NEJM (2013) [PubMed abstract]
  • In the PRAMI study, patients with STEMI were randomized in the cath lab to preventive PCI (infarct and noninfarct arteries) or infarct-vessel-only PCI. In all patients, infarct arteries were successfully treated before randomization.
Main inclusion criteria
  • Acute STEMI
  • Successful treatment of the infarct artery
  • Stenosis of 50% or more in one or more coronary arteries other than the infarct artery and the stenosis was deemed to be treatable by PCI
Main exclusion criteria
  • Previous CABG
  • Noninfarct artery stenosis (50% or more) of left main artery or the ostia of both the LAD and circumflex artery
  • Cardiogenic shock
Baseline characteristics
  • Average age 62 years
  • Infarct location: Anterior - 35% | Inferior - 60% | Lateral - 5%
  • Arteries with stenosis: Two - 64% | Three - 36%
Randomized treatment groups
  • Group 1 (234 patients) - Preventive PCI (infarct + noninfarct vessels)
  • Group 2 (231 patients) - Infarct-vessel-only PCI
  • The average number of noninfarct arteries that were stented in Group 1 was 1.36
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or refractory angina (refractory angina had to be supported by objective findings)
Results

Duration: Average of 23 months
Outcome Preventive Infarct-vessel-only Comparisons
Primary outcome 9% 22.9% HR 0.35, 95%CI [0.21 - 0.58], p<0.001
Death from cardiac causes 1.7% 4.3% HR 0.34, 95%CI [0.11 - 1.08], p=0.07
Nonfatal myocardial infarction 3% 8.7% HR 0.32, 95%CI [0.13 - 0.75], p=0.009
Repeat revascularization 6.8% 19.9% HR 0.30, 95%CI [0.17 - 0.56], p<0.001

Findings: In patients with STEMI and multivessel coronary artery disease undergoing infarct-artery PCI, preventive PCI in noninfarct coronary arteries with major stenoses significantly reduced the risk of adverse cardiovascular events, as compared with PCI limited to the infarct artery.
COMPLETE Trial - Culprit-lesion PCI vs Preventive PCI in STEMI with Multivessel disease, NEJM (2019) [PubMed abstract]
  • The COMPLETE trial enrolled 4,041 patients who presented to the hospital with STEMI and multivessel CAD
Main inclusion criteria
  • Presented to hospital with STEMI
  • Multivessel CAD
Main exclusion criteria
  • Previous CABG
  • Planned surgical revascularization
Baseline characteristics
  • Average age 62 years
  • Previous MI - 7.4%
  • Previous PCI - 7%
Randomized treatment groups
  • Group 1 (2016 patients): Preventive PCI
  • Group 2 (2025 patients): Culprit-lesion-only PCI
  • Patients were randomized within 72 hours after culprit-lesion-only PCI. Patients randomized to preventive PCI then underwent a second PCI for nonculprit lesions no later than 45 days after randomization. All nonculprit lesions that met the definition of significant stenosis were treated.
  • Guideline-based medical therapy was recommended in both groups. Dual antiplatelet therapy was recommended for 1 year.
Primary outcomes:
  • First: Composite of death from cardiovascular causes or new myocardial infarction
  • Second: Composite of death from cardiovascular causes, new myocardial infarction, or ischemia-driven revascularization
Results

Duration: Median of 3 years
Outcome Preventive Culprit-lesion-only Comparisons
CVD death or MI 7.8% 10.5% HR 0.74, 95%CI [0.60 - 0.91], p=0.004
CVD death, MI, or revascularization 8.9% 16.7% HR 0.51, 95%CI [0.43 - 0.61], p<0.001
Death from CVD 2.9% 3.2% HR 0.93, 95%CI [0.65 - 1.32]
Myocardial Infarction 5.4% 7.9% HR 0.68, 95%CI [0.53 - 0.86]
Revascularization 1.4% 7.9% HR 0.18, 95%CI [0.12 - 0.26]
Overall mortality 4.8% 5.2% HR 0.91, 95%CI [0.69 - 1.20]
  • In the preventive group, the median time from randomization to nonculprit-lesion PCI was 1 day
  • Within 45 days of randomization, 4.7% of patients in the culprit-lesion-only group received preventive PCI, and 3.9% of patients in the preventive group received culprit-lesion-only PCI.

Findings: Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization
AHA 2015 recommendations
  • PCI of a noninfarct artery may be considered in selected patients with STEMI and multivessel disease who are hemodynamically stable, either at the time of primary PCI or as a planned staged procedure [41]
Summary
  • Preventive PCI appears to be beneficial in stable patients. In the CULPRIT-SHOCK study that only enrolled patients with acute MI who were unstable, preventive PCI was not beneficial.



Overview
  • Thrombectomy is a procedure where the occluding thrombus (clot) in the coronary artery is manually removed during PCI. Removing the thrombus before stenting may thereoretcilly prevent distal embolization and improve blood flow
  • The TAPAS trial [PMID 18256391] published in 2008 showed improvement in markers of perfusion when thrombectomy was added to PCI. After TAPAS, a number of guidelines began to recommend routine thrombectomy in patients with STEMI.
  • In 2015, the TOTAL trial was published that compared PCI alone to PCI with manual thrombectomy in 10,732 patients. Results from 1-year of follow-up were also published, and both are detailed below.
TOTAL Trial - Thrombectomy + PCI vs PCI alone in Patients with STEMI Undergoing PCI, NEJM (2015) [PubMed abstract]
  • The TOTAL trial enrolled 10,732 patients with STEMI undergoing primary PCI
Main inclusion criteria
  • STEMI
  • ≤ 12 hours since symptoms onset
Main exclusion criteria
  • Previous CABG
  • Received fibrinolytic therapy
Baseline characteristics
  • Average age 61 years
  • Previous MI - 9%
  • Previous PCI - 8.3%
  • MI location: Anterior - 39% | Inferior - 54% | Lateral or other - 5%
Randomized treatment groups
  • Group 1 (5033 patients) - Thrombus aspiration (thrombectomy) followed by PCI
  • Group 2 (5030 patients) - PCI alone
  • In Group 2, bailout thrombectomy was allowed if initial PCI did not work
  • Of the 10,732 enrolled patients, only 10,063 patients actually underwent PCI and were included in the final analysis
Primary outcomes
  • Efficacy: Death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or new or worsening NYHA class IV heart failure within 180 days
  • Safety: Stroke within 30 days
Results

Duration: 180 days
Outcome Thrombectomy + PCI PCI Comparisons
Primary outcome (efficacy) 6.9% 7% HR 0.99, 95%CI [0.85 to 1.15], p=0.86
Stroke within 30 days 0.7% 0.3% HR 2.06, 95%CI [1.13 to 3.75] p=0.02
Cardiovascular death within 180 days 3.1% 3.5% HR 0.90, 95%CI [0.73 to 1.12] p=0.34
  • In Group 2, 8.5% of patients ended up having thrombectomy performed

Findings: In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days.
TOTAL Trial One-year Follow-up Results (Lancet 2015) [PubMed abstract]
  • A one-year follow-up study to the TOTAL trial was published in 2015. It included results from 10,064 of the original patients.

Duration: 1 year
Outcome Thrombectomy + PCI PCI Comparisons
Primary outcome 8% 8% HR 1.0, 95%CI [0.87 to 1.15], p=0.99
Stroke within 1 year 1.2% 0.7% HR 1.66, 95%CI [1.10 to 2.51] p=0.015
Cardiovascular death within 1 year 4% 4% HR 0.93, 95%CI [0.76 to 1.14] p=0.48

Findings: Routine thrombus aspiration during PCI for STEMI did not reduce longer-term clinical outcomes and might be associated with an increase in stroke. As a result, thrombus aspiration can no longer be recommended as a routine strategy in STEMI.
AHA 2015 recommendations
  • The usefulness of selective and bailout aspiration thrombectomy in patients undergoing primary PCI is not well established
  • Routine aspiration thrombectomy before primary PCI is not useful [41]
Summary
  • After the TOTAL trial was published, recommendations changed and routine thrombectomy was no longer recommended



Overview
  • First and foremost for preventing CAD, risk factors (e.g. hypertension, dyslipidemia, diabetes) should be managed appropriately
  • A major question is whether or not daily low-dose aspirin is effective for the primary prevention of CAD. Aspirin may lower the risk of CVD events, but it also increases the risk of bleeding events.
  • Five large randomized controlled trials that compared aspirin to placebo or control in various populations are detailed below. None of the trials found a net benefit of aspirin.
ARRIVE Trial - Aspirin vs Placebo for Primary Prevention of CVD in High-risk Patients, Lancet (2018) [PubMed abstract]
  • The ARRIVE trial enrolled 12,546 patients with an average 10-year CVD risk of 10 - 20%
Main inclusion criteria
  • 10-year risk of CVD of 10 - 20% based on various risk calculators
Main exclusion criteria
  • History of CVD
  • Diabetes
  • High risk of GI bleeding
Baseline characteristics
  • Average age - 64 years
  • Average BMI - 28
  • Average 10-year risk - 17% (AHA calculator)
  • Median SBP - 145 mmHg
Randomized treatment groups
  • Group 1 (6270 patients) - Enteric-coated aspirin 100 mg once daily
  • Group 2 (6276 patients) - Placebo
Primary outcome: Composite outcome consisting of time to first occurrence of confirmed myocardial infarction, stroke, cardiovascular death, unstable angina, or transient ischaemic attack
Results

Duration: Median of 5 years
Outcome ASA Placebo Comparisons
Primary outcome 4.29% 4.48% RR 0.96, 95%CI [0.81 - 1.13], p=0.60
Overall mortality 2.55% 2.57% RR 0.99, 95%CI [0.80 - 1.24], p=0.95
GI bleeding event 0.97% 0.46% RR 2.11, 95%CI [1.36 - 3.28], p=0.0007

Findings: The event rate was much lower than expected, which is probably reflective of contemporary risk management strategies, making the study more representative of a low-risk population. The role of aspirin in primary prevention among patients at moderate risk could therefore not be addressed. Nonetheless, the findings with respect to aspirin’s effects are consistent with those observed in the previously published low-risk primary prevention studies.
ASPREE Study - Aspirin vs Placebo for the Primary Prevention of Disability, CVD, and Mortality in Healthy Elderly Patients, NEJM (2018) [PubMed abstract]
  • The ASPREE study enrolled 19,114 healthy elderly patients without CVD
Main inclusion criteria
  • Age ≥ 70 years or ≥ 65 years if black or Hispanic and living in the US
Main exclusion criteria
  • Diagnosis of CVD
  • Atrial fibrillation
  • Dementia
  • Physical disability
  • Current use of anticoagulant or antiplatelet medication
Baseline characteristics
  • Median age - 74 years
  • Diabetes - 11%
  • Hypertension - 75%
  • Dyslipidemia - 66%
  • Current smoker - 4%
  • Taking statin at study entry - 34%
Randomized treatment groups
  • Group 1 (9525 patients) - Enteric-coated aspirin 100 mg once daily
  • Group 2 (9589 patients) - Placebo
  • Trial results were published as 3 different studies. Results from all 3 trials are combined below.
Primary outcome: Composite of death, dementia, or persistent physical disability
Results

Duration: After a median follow-up of 4.7 years, the trial was stopped early due to a lack of efficacy
Outcome ASA Placebo Comparisons
Primary outcome (%/year) 2.15% 2.12% HR 1.01, 95%CI [0.92 - 1.11], p=0.79
Cardiovascular disease (%/year) 1.07% 1.13% HR 0.95, 95%CI [0.83 - 1.08]
All-cause mortality (%/year) 1.27% 1.11% HR 1.14, 95%CI [1.01 - 1.29]
Major bleeding (%/year) 0.86% 0.62% HR 1.38, 95%CI [1.18 - 1.62], p=<0.001

Findings: Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo.
ASCEND Study - Aspirin vs Placebo for Primary Prevention of CVD in Diabetics, NEJM (2018) [PubMed abstract]
  • The ASCEND study enrolled 15,480 patients with diabetes and no history of CVD
Main inclusion criteria
  • Diabetes
  • Age ≥ 40 years
Main exclusion criteria
  • Diagnosis of CVD
  • Clear indication for aspirin
Baseline characteristics
  • Average age - 63 years
  • Average BMI - 31
  • Aspirin use before randomization - 35%
  • Median duration of DM - 7 years
  • Average SBP - 136 mmHg
  • Taking statin - 75%
Randomized treatment groups
  • Group 1 (7740 patients) - Aspirin 100 mg once daily
  • Group 2 (7740 patients) - Placebo
  • The trial had another factor where fish oil 1 gram was compared to placebo for the same outcomes. That arm of the trial found no significant effect of fish oil.
Primary outcomes
  • Efficacy: First serious vascular event, which was defined as a composite of nonfatal myocardial infarction, nonfatal stroke (excluding confirmed intracranial hemorrhage) or transient ischemic attack, or death from any vascular cause (excluding confirmed intracranial hemorrhage)
  • Safety: First occurrence of any major bleeding event, which was defined as a composite of any confirmed intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or any other serious bleeding (i.e., a bleeding event that resulted in hospitalization or transfusion or that was fatal)
Results

Duration: Average of 4.7 years
Outcome ASA Placebo Comparisons
Primary outcome (efficacy) 8.5% 9.6% RR 0.88, 95%CI [0.79 - 0.97], p=0.01
Primary outcome (safety) 4.1% 3.2% RR 1.29, 95%CI [1.09 - 1.52], p=0.003
Overall mortality 9.7% 10.2% RR 0.94, 95%CI [0.84 - 1.04]
  • A prespecified secondary outcome that looked at the incidence of different cancers found that aspirin had no significant effect on the occurrence of any cancer including gastrointestinal cancers

Findings: Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard.
JPPP Study - Aspirin vs Placebo for Primary Prevention of CVD in High Risk Patients, JAMA (2014) [PubMed abstract]
  • The JPPP study enrolled 14,464 Japanese patients at increased risk for vascular disease
Main inclusion criteria
  • Age 60 - 85 years
  • No history of CVD
  • Diagnosed with ≥ 1 of the following: hypertension, high cholesterol, or diabetes
Main exclusion criteria
  • Atrial fibrillation
  • Condition associated with bleeding (ex. peptic ulcer disease, clotting disorder)
  • Receiving antiplatelet agents, anticoagulants, or long-term NSAIDs
Baseline characteristics
  • Average age 70 years
  • Male sex - 42%
  • Hypertension - 85%
  • Dyslipidemia - 72%
  • Diabetes - 34%
  • Average BP - 137/78
  • Smoker - 13%
  • Average LDL - 119 mg/dl
Randomized treatment groups
  • Group 1 (7323 patients) - Enteric-coated aspirin 100 mg once daily
  • Group 2 (7335 patients) - No aspirin
  • Study was open-label
  • Nonstudy antiplatelet agents and anticoagulants were not allowed
Primary outcome: Composite of death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal myocardial infarction
Results

Duration: After a median of 5 years, the study was stopped early because of lack of efficacy with ASA
Outcome ASA No aspirin Comparisons
Primary outcome 2.77% 2.96% HR 0.94, 95%CI [0.77 - 1.15], p=0.54
Overall mortality 4.29% 4.11% HR 0.99, 95%CI [0.85 - 1.17], p=0.93
Nonfatal myocardial infarction 0.30% 0.58% HR 0.53, 95%CI [0.31 - 0.91], p=0.02
Nonfatal stroke 1.65% 1.64% HR 1.04, 95%CI [0.80 - 1.34], p=0.78
Serious extracranial bleeding 0.86% 0.51% HR 1.85, 95%CI [1.22 - 2.81], p=0.004
  • In the aspirin group, 76% of patients were still taking aspirin at 5 years. In the no aspirin group, 9.8% of patients were taking aspirin at 5 years.

Findings: Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors.
AAA Study - Aspirin vs Placebo for Primary Prevention of CVD in Patients with Low ABI, JAMA (2010) [PubMed abstract]
  • The AAA study enrolled 3350 Scottish patients with a low ABI (ankle-brachial-index)
Main inclusion criteria
  • Age 50 - 75 years
  • No history of vascular disease
  • ABI ≤ 0.95
Main exclusion criteria
  • Taking antiplatelet therapy or anticoagulants
  • Chronic liver or kidney disease
Baseline characteristics
  • Average age 62 years
  • Male sex - 29%
  • Average ABI - 0.86
  • Average BP - 148/84
  • Smoker - 33%
  • Diabetes - 44%
  • Average total cholesterol - 238 mg/dl
  • Taking lipid-lowering agent - 4.2%
Randomized treatment groups
  • Group 1 (1675 patients) - Enteric coated aspirin 100 mg once daily
  • Group 2 (1675 patients) - Placebo once daily
  • If patients started an antiplatelet medication for another reason, study treatment was stopped
Primary outcome: Composite of fatal or nonfatal coronary event, stroke, or revascularization (PCI or CABG)
Results

Duration: Average of 8.2 years
Outcome ASA Placebo Comparisons
Primary outcome 10.8% 10.5% HR 1.03, 95%CI [0.84 - 1.27]
Overall mortality 10.5% 11.1% HR 0.95, 95%CI [0.77 - 1.16]
Nonfatal myocardial infarction 3.7% 4.1% p>0.05
Nonfatal stroke 2.2% 2.3% p>0.05
Major hemorrhage 2% 1.2% HR 1.71, 95%CI [0.99 - 2.97]

Findings: Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events.
Professional recommendations
  • The AHA updated their aspirin recommendations in 2019 after the ARRIVE trial, ASCEND study, and ASPREE study were published
  • The USPSTF recommendations are from 2016, and they combine CVD prevention with colorectal cancer prevention
AHA recommendations
  • Low-dose aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk
  • Low-dose aspirin (75-100 mg orally daily) should not be administered on a routine basis for the primary prevention of ASCVD among adults > 70 years of age
  • Low-dose aspirin (75-100 mg orally daily) should not be administered for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding
  • The AHA does not specifically define "higher ASCVD risk" or "increased risk of bleeding" but states the following:
    • Elevated ASCVD risk - as calculated by risk estimators like the AHA risk calculator or based on the presence of specific ASCVD risk factors
    • Increased risk of bleeding - A nonexhaustive list of scenarios associated with increased risk of bleeding includes: a history of previous gastrointestinal bleeding or peptic ulcer disease or bleeding from other sites, age >70 years, thrombocytopenia, coagulopathy, CKD, and concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory drugs, steroids, direct oral anticoagulants, and warfarin [47]
USPSTF recommendations

  • Recommended dose is 81 mg once daily
  • *B - there is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial; C - there is at least moderate certainty that the net benefit is small; I - insufficient evidence to recommend for or against
  • Increased risk of bleeding defined as dose of aspirin used, history of GI ulcers or upper GI pain, bleeding disorders, renal failure, severe liver disease, and thrombocytopenia. Other factors that increase risk include concurrent anticoagulation therapy or NSAID use, uncontrolled hypertension, male sex, and older age.
  • Reference USPSTF website
Aspirin for the primary prevention of cardiovascular disease and colorectal cancer
Age Recommendation
50 - 59 years Low-dose aspirin is recommended in patients who meet the following criteria:
  • 10-year risk of CVD of ≥ 10% (based on AHA risk calculator)
  • Not at increased risk of bleeding
  • Life expectancy of at least 10 years
  • Willing to take low-dose aspirin for at least 10 years
  • Grade B*
60 - 69 years
  • Decision should be individualized
  • Criteria for 50 - 59 year olds should be met
  • Grade C*
< 50 years or ≥ 70 years
  • Insufficient evidence to make recommendation
  • Grade I*
Summary
  • Five large randomized controlled trials have now been published that found no clear benefit of aspirin for the primary prevention of CVD. Most of the trials only enrolled patients who were at high risk for CVD.
  • Aspirin has no proven net benefit in the primary prevention of CVD in any patient population



Overview
  • Stable CAD
    • A number of trials that took place in the 1970s and 1980s found that aspirin reduced the risk of heart attacks and death in patients with cardiovascular disease. Daily low-dose aspirin is universally recommended in patients with established CAD who do not have a contraindication.
    • P2Y12 inhibitors have also been studied in stable CAD. Clopidogrel was compared to aspirin in the CAPRIE trial detailed below, and dual antiplatelet therapy with a P2Y12 inhibitor and aspirin has been evaluated in several large trials. In the CHARISMA trial, clopidogrel + aspirin was compared to aspirin alone, and in the PEGASUS-TIMI 54 trial and the THEMIS trial, the combination of ticagrelor and aspirin was compared to aspirin alone.
  • Acute coronary syndrome
    • After ACS, dual antiplatelet therapy (DAPT) is recommended for a period of time in most patients. See antiplatelet therapy in CAD for a review.
CAPRIE Trial - Clopidogrel vs Aspirin for Secondary Prevention of CVD, Lancet (1996) [PubMed abstract]
  • The CAPRIE trial enrolled 19,185 patients with a history of stroke, heart attack, or peripheral artery disease
Main inclusion criteria
  • One of the following: recent ischemic stroke (onset ≥ 1 week and ≤ 6 months), recent heart attack (onset ≤ 35 days), history of intermittent claudication (with ABI ≤ 0.85 or history of leg surgery for vascular disease)
Main exclusion criteria
  • Uncontrolled hypertension
  • History of bleeding or bleeding disorder
  • Carotid endarterectomy after qualifying stroke
Baseline characteristics
  • Average age ∼ 62 years
  • Patients with diabetes - 20%
  • Qualifying criteria: Stroke - 33.5% | Heart attack - 33% | Intermittent claudication - 33.5%
Randomized treatment groups
  • Group 1 (9599 patients) - Clopidogrel 75 mg once daily
  • Group 2 (9586 patients) - Aspirin 325 mg once daily
Primary outcome: Composite of stroke, heart attack, or vascular death
Results

Duration: Average of 1.91 years
Outcome Clopidogrel Aspirin Comparisons
Primary outcome (%/year) 5.32% 5.83% p=0.043
Overall mortality (%/year) 3.05% 3.11% p=0.71
GI bleeding 1.99% 2.66% p<0.05
Any bleeding disorder 9.27% 9.28% p>0.05

Findings: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.
CHARISMA trial - Clopidogrel + Aspirin vs Aspirin for the Prevention of CVD, NEJM (2006) [PubMed abstract]
  • The CHARISMA trial enrolled 15,603 patients with documented CVD or multiple risk factors for CVD
Main inclusion criteria
  • Age ≥ 45 years
  • Documented CVD (CAD, Stroke, TIA, PAD) or multiple risk factors for CVD (diabetes, dyslipidemia, hypertension, etc.)
Main exclusion criteria
  • Taking oral antithrombotics or NSAIDs on a long-term basis
Baseline characteristics
  • Median age 64 years
  • Documented CAD - 37%
  • History of stroke/TIA - 28%
  • Documented PAD - 18%
  • Qualifying criteria: CVD - 78% | Multiple risk factors - 21%
Randomized treatment groups
  • Group 1 (7802 patients) - Clopidogrel 75 mg once daily + Aspirin 75 - 162 mg once daily
  • Group 2 (7801 patients) - Placebo + Aspirin 75 - 162 mg once daily
Primary outcome: Composite of myocardial infarction, stroke, or death from cardiovascular causes
Results

Duration: Median of 28 months
Outcome Clopidogrel Placebo Comparisons
Primary outcome 6.8% 7.3% HR 0.93, 95%CI [0.83 - 1.05], p=0.22
Myocardial infarction (nonfatal) 1.9% 2.0% HR 0.94, 95%CI [0.75 - 1.18], p=0.59
Stroke (nonfatal) 1.9% 2.4% HR 0.79, 95%CI [0.64 - 0.98], p=0.03
Overall mortality 4.8% 4.8% HR 0.99, 95%CI [0.86 - 1.14], p=0.90
Severe bleeding 1.7% 1.3% HR 1.25, 95%CI [0.97 - 1.61], p=0.09
Moderate bleeding 2.1% 1.3% HR 1.62, 95%CI [1.27 - 2.08], p<0.001
Treatment discontinuation 20.4% 18.2% p<0.001

Findings: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes.
PEGASUS-TIMI 54 Trial - Ticagrelor + Aspirin vs Aspirin for Secondary Prevention of CVD, NEJM (2015) [PubMed abstract]
  • The PEGASUS-TIMI 54 trial enrolled 21,162 patients with a history of myocardial infarction 1 - 3 years earlier
Main inclusion criteria
  • Myocardial infarction 1 - 3 years before enrollment
  • One of the following: age ≥ 65 years, diabetes requiring medication, a second prior heart attack, multivessel CAD, or chronic renal failure (CrCl < 60 ml/min)
Main exclusion criteria
  • Planned use of other antiplatelet agent or anticoagulant
  • History of ischemic stroke or intracranial bleeding
  • GI bleed within previous 6 months
Baseline characteristics
  • Average age 65 years
  • Qualifying event: STEMI - 53% | NSTEMI - 40%
  • History of PCI - 83%
  • Multivessel disease - 60%
  • Median time since qualifying event - 1.7 years
Randomized treatment groups
  • Group 1 (7050 patients) - Ticagrelor 90 mg twice a day + Aspirin 75 - 150 mg once daily
  • Group 2 (7045 patients) - Ticagrelor 60 mg twice a day + Aspirin 75 - 150 mg once daily
  • Group 3 (7067 patients) - Placebo + Aspirin 75 - 150 mg once daily
Primary outcome: Composite of cardiovascular death, myocardial infarction, or stroke
Results

Duration: Median of 33 months
Outcome (3-year estimates) Ticagrelor 90 mg Ticagrelor 60 mg Placebo Comparisons
Primary outcome 7.85% 7.77% 9.04% 1 vs 3 p=0.008 | 2 vs 3 p=0.004
Any stroke 1.61% 1.47% 1.94% 1 vs 3 p=0.14 | 2 vs 3 p=0.03
Myocardial infarction 4.40% 4.53% 5.25% 1 vs 3 p=0.01 | 2 vs 3 p=0.03
Overall mortality 5.15% 4.69% 5.16% 1 vs 3 p=0.99 | 2 vs 3 p=0.14
Major TIMI bleeding events 2.6% 2.3% 1.06% p<0.001 for 1 or 2 vs 3
Bleeding requiring transfusion 2.43% 2.09% 0.72% p<0.001 for 1 or 2 vs 3
Stopped drug due to side effects 32% 29% 21% p<0.001 for 1 or 2 vs 3

Findings: In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding.
THEMIS trial - Ticagrelor + Aspirin vs Aspirin for the Secondary Prevention of CAD in Diabetics, NEJM (2019) [PubMed abstract]
  • The THEMIS trial enrolled 19,220 diabetics with stable CAD
Main inclusion criteria
  • Age ≥ 50 years
  • Type 2 diabetes
  • Stable CAD defined as history of PCI, CABG, or ≥ 50% stenosis of 1 coronary vessel
Main exclusion criteria
  • Previous MI
  • Previous stroke
  • Receiving DAPT
Baseline characteristics
  • Median age 66 years
  • History of PCI - 58%
  • History of CABG - 22%
  • History of CABG and PCI - 7%
  • Median A1C - 7.1%
Randomized treatment groups
  • Group 1 (9619 patients): Ticagrelor 60 mg twice daily + Aspirin 75 - 150 mg once daily
  • Group 2 (9601 patients): Placebo + Aspirin 75 - 150 mg once daily
  • At the start of the trial, the dose of ticagrelor was 90 mg twice daily. It was changed to 60 mg twice daily in all patients in May 2015 after the results of the PEGASUS-TIMI 54 trial were published.
Primary outcome: Composite of cardiovascular death, myocardial infarction, or stroke
Results

Duration: Median of 39.9 months
Outcome Ticagrelor Placebo Comparisons
Primary outcome 7.7% 8.5% HR 0.90, 95%CI [0.81 - 0.99], p=0.04
Cardiovascular death 3.8% 3.7% HR 1.02, 95%CI [0.88 - 1.18], p=0.79
Myocardial infarction 2.8% 3.4% HR 0.84, 95%CI [0.71 - 0.98]
Stroke 1.6% 2% HR 0.80, 95%CI [0.64 - 0.99]
Overall mortality 6% 6.2% HR 0.98, 95%CI [0.87 - 1.10]
Major bleeding 2.2% 1% HR 2.32, 95%CI [1.82 - 2.94], p<0.001
Intracranial hemorrhage 0.7% 0.5% HR 1.71, 95%CI [1.18 - 2.48], p=0.005
Death, MI, stroke, fatal bleed, intracranial hemorrhage 10.1% 10.8% HR 0.93, 95%CI [0.86 - 1.02]
Drug discontinuation 34.5% 25.4% p<0.05
  • A follow-up study looked at outcomes among the subgroup of patients (N=11,154) who had undergone previous PCI [PMID 31484629]

Findings: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin.
AHA recommendations
  • The AHA recommends that all patients with CAD take 75 - 162 mg of aspirin daily in the absence of contraindications
  • For patients who cannot take aspirin, clopidogrel (Plavix®) is considered an appropriate alternative
  • Clopidogrel + aspirin "might" be reasonable in certain high-risk patients with CAD [8]
Summary
  • Clopidogrel and aspirin appear to have similar efficacy in the secondary prevention of CVD. Patients with a contraindication to aspirin will benefit from clopidogrel.
  • In the dual antiplatelet therapy trials, the addition of clopidogrel or ticagrelor to aspirin lowered CVD risk in general but significantly increased the risk of bleeding. There was no significant effect on mortality in any of the trials.



Overview
  • Stable CAD
    • Patients with stable CAD sometimes have an indication for anticoagulation (e.g. A fib, DVT, PE). Whether these patients should receive antiplatelet therapy in addition to their anticoagulant therapy has long been a matter of debate. In 2019, a study was published that finally offered some guidance on the issue. The AFIRE study compared rivaroxaban + antiplatelet therapy to rivaroxaban alone in patients with stable CAD and A fib. It is detailed below.
  • Acute coronary syndrome
    • After ACS, antiplatelet therapy is recommended with anticoagulation for some patients. See triple therapy for a review.
AFIRE study - Rivaroxaban vs Rivaroxaban + Antiplatelet Therapy in Patients with A fib and Stable CAD [PubMed abstract]
  • The AFIRE study enrolled 2236 patients with A fib and stable CAD
Main inclusion criteria
  • A fib with a CHADS2 score ≥ 1
  • CAD defined as history of PCI with or without stenting at least 1 year before enrollment, history of angiographically-confirmed stenosis of ≥ 50% not requiring revascularization, or CABG at least 1 year before enrollment
Main exclusion criteria
  • History of stent thrombosis
  • Active cancer
  • Poorly-controlled hypertension (SBP ≥ 160)
Baseline characteristics
  • Average age 74 years
  • Previous stroke - 14%
  • Previous MI - 36%
  • Previous CABG - 11%
  • Previous PCI - 71%
  • Median CHADS2 score - 2
  • Stent type: DES - 68% | BMS - 24% | Both - 4%
  • A fib type: Paroxysmal - 53% | Persistent - 15% | Permanent - 31%
Randomized treatment groups
  • Group 1 (1107 patients): Rivaroxaban
  • Group 2 (1108 patients): Rivaroxaban + Antiplatelet therapy (aspirin or P2Y12 inhibitor)
  • Choice of antiplatelet therapy was left to the discretion of the treating provider. Approximately 70% of patients received aspirin and 25% received clopidogrel.
  • Rivaroxaban was dosed 10 mg once daily for CrCl 15 - 49 ml/min and 15 mg once daily if CrCl ≥ 50 ml/min
Primary outcomes
  • Efficacy: Composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause
  • Safety: Major bleeding
Results

Duration: After a median of 23 months, the trial was stopped due to higher death in the combination group
Outcome (%/year) Rivaroxaban Rivaroxaban + Antiplatelet Comparisons
Primary outcome (efficacy) 4.14% 5.75% HR 0.72, 95%CI [0.55 - 0.95]
Primary outcome (safety) 1.62% 2.76% HR 0.59, 95%CI [0.39 - 0.89], p=0.01
Overall mortality 1.85% 3.37% HR 0.55, 95%CI [0.38 - 0.81]
Hemorrhagic stroke 0.18% 0.60% HR 0.30, 95%CI [0.10 - 0.92]
Myocardial infarction 0.59% 0.37% HR 1.60, 95%CI [0.67 - 3.87]

Findings: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease.
Professional recommendations
  • The AHA guidelines do not specifically address the combination of anticoagulants and antiplatelet therapy in patients with stable CAD
  • The ACCP guidelines from 2012 recommend that only anticoagulation be used when patients are ≥ 12 months post-stent placement [48]
Summary
  • The AFIRE study is the first study to address this critical issue. It clearly found that antiplatelet therapy should not be used with anticoagulation in patients with stable CAD and A fib.
  • Guidelines on pulmonary embolism and deep vein thrombosis do not address the antiplatelet/anticoagulant combination issue, but it is likely that the results of the AFIRE study would apply to these patients also