- ACRONYMS AND DEFINITIONS
- ABI - Ankle-brachial index. SBP in ankle/SBP in arm. ABI < 0.90 is associated with CVD.
- ACS - Acute coronary syndrome defined as myocardial infarction or unstable angina
- AHA - American Heart Association
- ASA - Acetylsalicylic acid, abbreviation for aspirin
- CABG - Coronary artery bypass grafting
- CAC - Coronary artery calcium scoring
- CAD - Coronary artery disease
- CCTA - Coronary CT angiography
- CKD - Chronic kidney disease
- CP - Chest pain
- CVD - Cardiovascular disease
- DAPT - Dual antiplatelet therapy
- DBP - Diastolic blood pressure
- DM - Diabetes mellitus
- DOAC - Direct-acting oral anticoagulant (factor Xa inhibitor or dabigatran)
- EF - Ejection fraction
- ESC - European Society of Cardiology
- EST - Exercise stress testing
- HFrEF - Heart failure with reduced ejection fraction
- LMD - Left main disease
- MPI - Myocardial perfusion imaging (general term for studies that evaluate coronary blood flow using noninvasive radiological techniques)
- MT - Medical therapy (antiplatelet therapy, statins, aggressive blood pressure and diabetes treatment)
- MVD - Multivessel disease
- NCGC - National Clinical Guideline Center for Acute and Chronic Conditions
- NSTEMI - Non-ST Elevation Myocardial Infarction
- PCI - Percutaneous coronary intervention (heart cath and associated procedures - stents, etc.)
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- STEMI - ST-elevation myocardial infarction
- USPSTF - United States Preventive Services Task Force
- EPIDEMIOLOGY
- Heart disease is the number one cause of death in the United States for men and women, and coronary artery disease (CAD) is the most common cause of heart disease. In the U.S. alone, CAD accounts for 109 billion dollars in healthcare spending each year.
- Every year about 785,000 Americans have their first heart attack, while another 470,000 have a recurrent heart attack. The average age for a first heart attack is 65.8 years for men and 70.4 years for women. [1,2]
- PHYSIOLOGY
- Coronary artery disease is a condition where the arteries that supply blood to the heart muscle become narrowed
- Narrowed arteries may not be able to supply enough blood to the heart muscle under certain conditions (ex. exertion)
- When heart muscle does not receive enough blood flow, symptoms of chest pain (angina) may occur
- If insufficient blood flow persists, heart muscle may die
- Narrowed arteries may also become occluded when plaques from upstream arterial disease (atherosclerosis) break off and become lodged in the narrowing
- When this occurs, chest pain and death may occur suddenly without warning
- VESSEL-DISEASE CATEGORIES
- Main arteries
- There are four main coronary arteries that are evaluated during a heart cath:
- Left Anterior Descending (LAD)
- The circumflex artery
- Right coronary artery (RCA)
- Left main artery
- Significant stenosis
- Significant stenosis is defined differently depending on the artery:
- LAD, circumflex, and RCA - stenosis of ≥ 70% of the diameter of the artery is considered significant
- Left main Artery - stenosis of ≥ 50% of the diameter of the artery is considered significant
- Vessel disease
- 1-vessel disease - one artery has significant stenosis
- 2-vessel disease - two arteries have significant stenosis
- 3-vessel disease - three arteries have significant stenosis
- Left main disease - Left main artery has significant stenosis
- Left main equivalent disease - combined stenosis of ≥ 70% in the proximal LAD and ≥ 70% in the proximal circumflex
- Unprotected left main disease - term that means there is no perfusion supplied distal to the left main occlusion from a collateral artery or an intact CABG graft
- Prognosis
- The degree of disease can help predict survival
- The CASS study was a study that followed the survival of a large group of patients who had undergone coronary angiography
- Patients were stratified into four groups based on their angiography findings: zero-vessel disease, 1-vessel disease, 2-vessel disease, or 3-vessel disease
- It's important to note that the CASS study was performed in the 1970s and 80s when statins, aspirin, ace inhibitors, and other meds were not routinely used to treat CAD and heart failure. Today, survival for patients treated with optimal medical therapy would undoubtedly be much better.
- For patients who did not undergo CABG, survival rates were as follows:
- Zero-vessel disease - 88% (12-year survival)
- 1-vessel disease - 74% (12-year survival)
- 2-vessel disease - 59% (12-year survival)
- 3-vessel disease - 40% (12-year survival) [14]
- Left main disease - 27% (15-year survival) [15]
- Left main equivalent disease - 31% (15-year survival) [16]
- RISK FACTORS
- Known risk factors for CAD
- Diabetes
- High blood pressure
- High cholesterol
- Family history of early-onset CAD (defined as CAD in a first-degree male relative < 55 years old, or CAD in a first-degree female relative < 65 years old)
- Smoking
- In one study, quitting smoking lowered CVD risk within 5 years of quitting. CVD risk returned to that of someone who never smoked at 10 - 15 years after quitting. [PMID 31429895]
- Physical inactivity
- Obesity (see weight loss)
- Male sex
- History of stroke or peripheral artery disease
- Age (men > 45 years old, women > 55 years) [3]
- Short stature [38]
- Possible risk factors for CAD
- Elevated homocysteine levels
- Elevated fibrinogen levels
- Elevated C-reactive protein [3]
- Calcium supplement intake (supplement dose does not appear to be a factor) [4]
- Breast arterial calcification seen on a mammogram [5]
- Radiation treatment for breast cancer (left-sided breast cancer may have higher risk than right) [6, 27]
- Severe Psoriasis [7]
- Risk calculators
- A number of risk calculators are available to estimate a person's risk of heart attack. Most calculators quantify a 10-year risk of stroke or heart attack.
- The Framingham risk calculator has been around for a number of years and is widely used. The Framingham calculator is not applicable to patients with diabetes. In 2013, the AHA introduced another calculator, and it can be used with diabetics.
- Some studies have found that risk calculators often overestimate risk. A study published in the Annals of Internal Medicine found that 4 different risk calculators (AHA calculator and 3 Framingham-based calculators) overestimated cardiovascular events by 37 - 154% in men, and 8 - 67% in women. [PMID 25686167]
- SCREENING FOR CAD
- Guidelines on screening patients for CAD risk factors can be found on these pages
- American College of Physicians (ACP) recommendations
- In 2015, the ACP recommended that healthcare providers not screen asymptomatic patients who are at low-risk for CAD events
- Low-risk is defined as having a 10-year risk of heart attack of < 10% (see risk calculators above)
- Screening tests they recommend against include resting and exercise ECG, stress echocardiography, and stress myocardial perfusion scanning [34]
- STUDY: A study (N=46,611 | median follow-up 5.6 years) published in 2022 found that screening men aged 65 to 74 with CT calcium scoring and ABI had no effect on overall mortality compared to no screening. [PMID 36027560]
- AHA recommendations
- The AHA published guidelines on CAD screening in asymptomatic adults in 2010. The recommendations are presented in the table below, and most are considered "soft," meaning they are based on little or no evidence.
- STUDY: A study (N=46,611 | median follow-up 5.6 years) published in 2022 found that screening men aged 65 to 74 with CT calcium scoring and ABI had no effect on overall mortality compared to no screening. [PMID 36027560]
AHA 2010 CAD Screening Recommendations |
---|
Step 1 - Categorize person into one of three groups:
|
Step 2 - screening tests and recommendations from the AHA
|
Tests that are not recommended
|
- EVALUATING CHEST PAIN IN A CLINIC SETTING
- Overview
- Chest pain is a common complaint in patients of all ages, and most cases have a benign cause. However, serious life-threatening etiologies exist, and most providers err on the side of caution when evaluating chest pain.
- The recommendations presented below are for assessing stable chest pain in a clinic setting in patients without known CAD. They are derived from AHA and ESC guidelines and are helpful in determining which patients should receive further testing. Given the litigious and consequential nature of missing cardiac ischemia, many providers refer all patients with chest pain for further evaluation. These practical and easy-to-follow steps provide an evidence- and guideline-based tool that can help alleviate the anxiety and excessive testing associated with these patients.
- Step 1 - Categorize chest pain into one of the following:
- Typical angina
- Atypical angina
- Non-anginal pain
- Typical angina has the following three qualities:
- 1. Described as a "constricting," "squeezing," "heavy," or "tight" pain in the front of the chest, neck, shoulders, jaw, or arms
- 2. Pain occurs with physical exertion
- 3. Pain is relieved with rest or nitroglycerin within 5 minutes [8,9,51]
- Typical angina - all three of the above features are present
- Atypical angina - two of the above symptoms are present
- Non-anginal chest pain - one or none of the three symptoms are present [9,51]
- Other features consistent with obstructive CAD:
- Pain described as dull, aching, pressure, or gripping
- Pain that is central, left-sided, or retrosternal
- Features that are inconsistent with obstructive CAD:
- Pain described as sharp, stabbing, tearing, ripping, or burning
- Pain that is right-sided, shifting, or positional
- Pain that is unrelated to activity and/or occurs at rest
- Pain that is exacerbated by deep breaths or coughing [8,9,51,52]
- Step 2 - Obtain a resting ECG
- Most patients with chest pain should have a resting ECG
- ECG may not be necessary in young patients (< 30 years old) with atypical symptoms or when there is an obvious noncardiac cause
- Changes on resting ECG associated with a higher risk of CAD include:
- Left bundle branch block
- ST-T wave changes
- Pathologic Q waves
- Step 3 - Assess the pretest probability of obstructive CAD
- The table below gives the pretest probability of obstructive CAD based on age, sex, and chest pain type. A separate category for dyspnea is also included. Table data is derived from 3 large studies that encompassed 15,815 patients with chest pain. Using the table, patients are divided into the following categories:
- Very low-risk - pretest probability ≤ 5%
- Low-risk - pretest probability of 6 - 15%. For patients with a pretest probability of < 15%, the annual rate of cardiovascular death or MI is < 1%.
- Intermediate-high risk - pretest probability ≥ 15%
Pretest probability of obstructive CAD | ||||||||
---|---|---|---|---|---|---|---|---|
Typical | Atypical | Non-anginal | Dyspnea | |||||
Age | Men | Women | Men | Women | Men | Women | Men | Women |
30 - 39 | 3% | 5% | 4% | 3% | 1% | 1% | 0% | 3% |
40 - 49 | 22% | 10% | 10% | 6% | 3% | 2% | 12% | 3% |
50 - 59 | 32% | 13% | 17% | 6% | 11% | 3% | 20% | 9% |
60 - 69 | 44% | 16% | 26% | 11% | 22% | 6% | 27% | 14% |
70+ | 52% | 27% | 34% | 19% | 24% | 10% | 32% | 12% |
- Step 4 - Order diagnostic tests if indicated
- Once the pretest probability has been determined, testing can be performed based on the recommendations below
Very low-risk patients (pretest probability ≤ 5%)
|
Low-risk patients (pretest probability of 6 - 15%)
|
Intermediate-high risk patients (pretest probability > 15%)
|
- Differential
- The differential for chest pain is broad, and studies have found that no specific cause is identified in over half of patients, regardless of age. The table below lists some select causes of chest pain and their associated features.
Causes of chest pain and their associated symptoms |
---|
Cardiac |
Aortic dissection
|
Heart valve disease
|
Pericarditis
|
Myocarditis
|
Pulmonary |
Pulmonary embolism
|
Pneumonia
|
Pneumothorax
|
Gastrointestinal |
Esophagitis
|
Peptic ulcers
|
Gallbladder disease
|
Esophageal tear/rupture
|
Other |
Panic attack
|
Costochondritis
|
- DIAGNOSTIC TESTS
- Overview
- A variety of diagnostic tests are available to diagnose CAD
- A summary of the available tests and their diagnostic accuracy is detailed below
- Exercise stress testing (EST)
- Procedure
- During EST, a person walks/runs on a treadmill while their ECG is continuously monitored
- In a Bruce protocol (most widely used), there are 7 stages of exercise, and each stage is 3 minutes long. Each successive stage increases in speed and incline.
- The goal of the test is for the patient to reach 85% of their maximum predicted heart rate (Maximum predicted heart rate = 220 (210 for women) - age). Completion of 9 - 12 minutes or exercise may also be adequate. [10]
- After completion of exercise, the ECG is monitored for up to 15 minutes
- Contraindications
- Resting ECG abnormalities
- Left Ventricular Hypertrophy - may make test uninterpretable
- Left Bundle Branch Block
- Wolff-Parkinson-White pattern
- Digoxin therapy (may produce false positive)
- Resting ST-segment depression ≥ 0.5mm [8,10]
- Unstable angina
- Uncontrolled heart failure
- Uncontrolled hypertension (SBP > 20 mmHg, DBP > 110 mmHg)
- Unable to achieve ≥ 5 METs
- Severe aortic stenosis [10]
- Accuracy
- Sensitivity: 78%
- Specificity: 70%
- Both are lower in women [8,10]
- Preparation
- Beta blockers should be stopped 24 - 48 hours before the test
- Digoxin should be stopped 1 week before the test
- Certain calcium channel blockers (diltiazem and verapamil) may also need to be stopped prior to the test
- Positive test
- A positive test is defined by the following:
- ST segment depression of ≥ 1 mm at 80 ms after the J point
- ST segment down-sloping at 80 ms after the J point
- ST segment elevation in a non-Q wave lead [8]
- Normal ECG changes with exercise
- P wave increases in height
- R wave decreases in height
- J point becomes depressed
- ST segment becomes sharply upsloping
- Q-T interval shortens
- T wave decreases in height [10]
- Reasons to stop the test
- Severe ST depression ( > 3 mm )
- ST elevation > 1 mm in non-Q wave lead
- Ventricular ectopy (Frequent Premature Ventricular Contractions (PVCs), V tach)
- Supraventricular arrhythmia (atrial fibrillation, supraventricular tachycardia)
- Development of new bundle branch block
- Development of new heart block (second and third degree)
- Fall in systolic blood pressure of > 20 mmHg
- Extreme rise in blood pressure - SBP > 300 mmHg, DBP > 130 mmHg
- Patient fatigue, chest pain, dizziness, etc. [10]
- Myocardial perfusion imaging (MPI)
- Exercise stress - patient's heart rate is increased through exercise as opposed to pharmacological stress where drugs are used to increase the heart rate
- Gated SPECT - imaging technique that combines information from SPECT images and ECG readings to evaluate left ventricular function during a SPECT scan. Ejection fraction, stroke volume, and wall motion abnormalities can be evaluated using gated SPECT.
- Myocardial Perfusion Imaging (MPI) - general term for studies that evaluate coronary blood flow using noninvasive radiologic techniques
- Pharmacological stress - patient's heart rate is increased with medications
- Radioisotope - an unstable compound that emits radiation. The emitted radiation can then be detected by external equipment.
- Scintigraphy - term used to describe the process where radioisotopes are taken internally and then detected externally with radiologic equipment
- SPECT imaging - stands for single photon emission computed tomography. SPECT is the most common method used to detect radioactive isotopes during MPI studies.
- Technetium-99m - Technetium-99m is the radioisotope most commonly administered during MPI
- Procedure
- In MPI, the patient's heart is stressed either through exercise (treadmill) or with medications (adenosine, dobutamine, dipyridamole)
- A radioisotope (Technetium-99m) is injected during peak stress
- Fifteen minutes to two hours later, SPECT images are obtained
- Resting images that require a second injection of radioisotope are also performed
- Protocols for obtaining rest/stress images differ, with some requiring one day and others two
- Accuracy
- Sensitivity: with exercise stress 82 - 88%, with pharmacological stress 88 - 91%
- Specificity: with exercise stress 70 - 88%, with pharmacological stress 75 - 90% [8]
- Precautions/limitations
- For exercise stress, beta blockers and certain calcium channel blockers (diltiazem and verapamil) may need to be stopped prior to the study being done
- In patients with severe or uncontrolled COPD or asthma, dobutamine may be the preferred agent because it does not induce bronchospasm
- Caffeine may interfere with the effects of dipyridamole and adenosine. Caffeine should be stopped 24 - 48 hrs before a study with these agents.
- Adenosine should not be given to patients with second or third degree AV block
- Images may be suboptimal in obese patients and patients with large breasts
- Patients are exposed to radiation during study
-
Terminology
- Stress echocardiography (Stress ECHO)
- Terminology
- Exercise stress - patient's heart rate is increased with exercise on a treadmill
- Pharmacological stress - patient's heart rate is increased with medications
- Procedure
- Patient's heart is stressed through exercise or with medications (dobutamine)
- Cardiac echocardiography is performed during or immediately after stress
- Positive test
- New or worsening wall motion abnormalities and/or changes in global left ventricular function during or immediately after stress
- Accuracy
- Sensitivity: with exercise stress 70 - 85%, with pharmacological stress 85 - 90%
- Specificity: with exercise stress 77 - 89%, with pharmacological stress 79 - 90% [8]
- Precautions
- Reduced image quality may be seen in obese patients and patients with significant lung disease (COPD and emphysema)
- Coronary CT angiography (CCTA)
- Procedure
- Patient is placed in CT scanner
- Heart rate is slowed if necessary with a beta blocker to a target of < 65 beats per minute
- IV contrast is injected and CT images of the coronary arteries and heart are obtained
- Some machines are capable of calculating fractional flow reserve across lesions using computer modeling
- Accuracy
- Sensitivity: 93 - 97%
- Specificity: 80 - 90% [8]
- There can be high variability in the accuracy of the test depending on machine used, testing center, and interpreter experience [11]
- Precautions/limitations
- Accuracy may be reduced in obese patients and patients with extensive coronary calcification
- Patients must be able to hold breath for 20 seconds and lie completely still
- Lesions detected on CCTA may not cause clinically significant ischemia [8]
- Exposure to IV contrast and radiation
- Studies
- DISCHARGE Trial
- The DISCHARGE Trial published in 2022 compared CCTA to invasive coronary angiography as an initial diagnostic strategy in patients with an intermediate pretest probability of obstructive CAD. The primary outcome was major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) over 3.5 years. At the end of the study, the primary outcome occurred in 2.1% of the CT group and 3% of the angiography group (p=0.10). [PMID 35240010]
- SCOT-HEART study
- The SCOT-HEART study published in 2018 compared standard care to standard care + CTA in patients referred to a cardiologist for chest pain
- The primary outcome was death from coronary heart disease or nonfatal myocardial infarction at 5 years
- The 5-year rate of the primary endpoint was lower in the CTA group than in the standard-care group (2.3% vs 3.9%; HR 0.59, 95%CI [0.41 to 0.84] p=0.004)
- The main weakness of the study is that the outcome measures were based on ICD-10 codes collected from a database [PMID 30145934 ]
- PROMISE study
- The PROMISE study published in 2015 compared initial evaluation with CCTA to functional testing (EST, exercise or pharmacologic nuclear stress testing, and stress echocardiography) in symptomatic patients (N=10,003) with suspected CAD
- The primary outcome of the study was death, heart attack, hospitalization for unstable angina, or major procedural complication. The median follow-up period was 25 months.
- There was no significant difference in the primary outcome between patients randomized to CCTA or functional testing (CCTA 3.3%, functional testing 3%, HR 1.04, p=0.75)
- CCTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%,p=0.02), although more patients in the CCTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%) [PMID 25773919 ]
- CCTA vs MPI study
- A study published in the Annals of Internal Medicine in 2015 compared initial evaluation with CCTA to MPI in 400 patients with acute chest pain
- The primary outcome of the study was cardiac catheterization not leading to revascularization within 1 year (false positive)
- There was no significant difference in the primary outcome between patients randomized to CCTA or MPI (CCTA 7.5%, MPI 10%, HR 0.77, 95%CI [0.40 to 1.49] p=0.44) [PMID 26052677]
- Coronary artery calcium (CAC) scoring
- Procedure
- Atherosclerotic plaques calcify over time, making calcification, which is easily detected on a CT scan, a marker of coronary artery disease. Coronary artery calcium scoring, commonly abbreviated CAC, is a procedure where a CT scan quantifies the amount of calcium in coronary arteries. The results are then converted into a score using a standardized system, with higher values indicating more atherosclerosis .
- CAC scores
- Low risk: < 100
- Intermediate risk: 100 - 399
- High risk: ≥ 400
- Precautions/limitations
- Low CAC scores (< 100) are most useful because they are associated with a very low risk of significant CAD. Scores greater than 100 are not as helpful because the presence of coronary calcium is a weak predictor of obstructive CAD.
- In asymptomatic patients, it is unclear how to proceed with intermediate-to-high CAC scores [8,12,51]
- Accuracy (symptomatic patients)
- Score of 0: less than 5% chance of obstructive CAD and a less than 1% annual risk of death or non-fatal MI
- Score < 100: less than 2% chance of having an abnormal myocardial perfusion scan, and a less than 3% chance of having significant obstruction on a heart cath
- Score ≥ 100: accuracy of CAC is limited with high sensitivity and marginal to low specificity (many false positives) [12,51]
- Accuracy (asymptomatic patients)
- The table below shows the estimated annual risk of CAD death or MI based on CAC scores in asymptomatic patients at intermediate risk (Framingham risk of 10 - 20% over ten years) for a heart attack
CAC score in asymptomatic intermediate-risk individuals | Annual risk of heart disease death or MI |
---|---|
0 - 99 | 0.4% |
100 - 399 | 1.3% |
≥ 400 | 2.4% |
- MESA study
- CAC scores can be combined with other risk factors to improve heart attack risk estimates
- A popular risk calculator for heart disease is the Framingham risk calculator, which estimates a person's 10-year risk of heart attack based on seven common risk factors. The MESA study evaluated the utility of adding a CAC score to the Framingham risk calculation. MESA found that adding CAC scores to risk factors in the Framingham tool improved the 5-year risk estimation of a heart attack compared to the Framingham risk factors alone. For people who went on to have a coronary event during follow-up (median 5.8 years), adding CAC scores to the risk prediction model correctly reclassified 23% of patients. For patients who did not have a coronary event during follow-up, adding CAC scores to the model correctly reclassified 2% of patients. [PMID 20424251]
- The NHLBI has a website with a calculator that incorporates the CAC score with Framingham risk factors to estimate a person's 10-year heart attack risk based on data from the MESA study. See MESA CAC risk calculator.
- Professional guidelines
- The USPSTF does not recommend CAC screening in asymptomatic individuals
- The AHA states that CAC screening is reasonable in patients with intermediate risk (defined as a Framingham risk score of 10 - 20%), and may be reasonable in patients at low-intermediate risk (6 - 10%). CAC screening is not useful in patients at low risk (< 6%), and in patients at high risk.
- The AHA 2018 lipid treatment guidelines offer some guidance on using CAC scores in decisions regarding statin therapy (see CAC scoring in lipid therapy management)
- Summary
- Most providers by now have had an asymptomatic patient bring in a CAC study and ask them what to do with the results. Unfortunately, there are no good studies at this time to guide decision-making.
- Given the available evidence, the following guidance seems reasonable:
- CAC score < 100: no intervention needed
- CAC score 101 - 399: patients with risk factors for heart disease should have them managed aggressively
- CAC score ≥ 400: heart disease risk factors should be managed aggressively. It is reasonable to consider some type of stress testing, although objective evidence that this improves outcomes does not exist.
- Cardiac magnetic resonance imaging (CMRI)
- Procedure
- An MRI machine is used to evaluate heart motion and anatomy
- Contrast can be given to the patient to evaluate coronary blood flow and artery disease
- Accuracy
- Sensitivity: 87 - 88%
- Specificity: 56 - 70% [8]
- Precautions/limitations
- Not widely available
- High variability in accuracy due to lack of experience and nonuniformity of techniques
- Studies
- A study that compared CMRI to angiography with fractional flow reserve found that CMRI led to a lower rate of revascularization and was noninferior for a composite outcome of death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. [PMID 31216398]
- Myocardial positron emission tomography (PET) scans
- Procedure
- During myocardial PET scanning, a radioactive compound called a tracer is injected into the patient during pharmacological stress. As the tracer decays, photons are detected by the PET scanner, and an image of the heart is formed. Common tracers used in myocardial PET imaging include Oxygen-15-labeled water(H₂¹⁵O), 13 N-labeled ammonia (¹³NH₃), and ⁸²rubidium (⁸²Rb). In recent years, PET scanners have been combined with CT scanners to create a hybrid device that provides more accurate and comprehensive anatomical and functional information.
- Tracers decay rapidly, so patients are injected while they are lying in the scanner, and cardiac stressing is done with pharmacological agents (e.g. adenosine)
- Accuracy
- Sensitivity: 84 - 93%
- Specificity: 81 - 88%
- Advantages
- Image quality is superior to SPECT and obesity does not affect quality
- Radiation exposure is lower than SPECT
- PET scans have higher resolution so smaller perfusion defects can be detected
- Perfusion can be quantified (ml/min/gram of tissue)
- Precautions/limitations
- Onsite cyclotron or generator is required to make the tracers
- Expensive and not widely available
- Current tracers decay rapidly so exercise stressing is not plausible [45,46]
- Coronary angiography (heart cath)
- Terminology
- Coronary angiography - coronary angiography is a procedure where a cardiologist inserts a catheter into the femoral or radial artery. The catheter is advanced to the heart, where it is used to inject contrast into the coronary arteries, allowing their anatomy to be observed on X-rays. Other techniques that allow for intravascular assessment of arterial stenosis, including ultrasonography and optical coherence tomography, have also been developed.
- Angioplasty - angioplasty is a procedure where a narrowed coronary artery is opened with an inflatable balloon, and a stent is placed to keep it open
- Coronary artery bypass grafting (CABG) - surgery where vessels grafted from other parts of the body, typically the leg and chest wall, are used to bypass narrowed arteries in the heart
- Percutaneous Coronary Intervention (PCI) - term for heart catheterization with angioplasty
- Percutaneous transluminal coronary angioplasty (PTCA) - term for heart catheterization with angioplasty
- Procedure
- Patient is taken to a cath lab where coronary angiography is performed, and stenotic vessels are treated with PCI
- Accuracy
- Coronary angiography allows for direct visualization of arterial anatomy and is considered the gold standard for assessing coronary artery disease
- Precautions/limitations
- It is not uncommon for interpretations of stenosis to vary between observers
- Significant stenosis seen on heart cath may not cause clinically significant ischemia (decreased blood flow)
- Angiography cannot determine which plaques are likely to break off and cause an infarction
- Patient is exposed to radiation and contrast [8]
- Studies
- A study published in 2023 found that intravascular imaging-guided PCI was superior to angiography-guided PCI in patients with complex coronary-artery lesions. [PMID 36876735]
- ACUTE HEART ATTACK
- Acute heart attacks are typically divided into two categories:
- Non-ST Elevation Myocardial Infarction (NSTEMI)
- ST Elevation Myocardial Infarction (STEMI)
- Non-ST elevation myocardial infarction (NSTEMI)
- Pathology
- NSTEMI is thought to be caused by the disruption or erosion of atherosclerotic plaques in the coronary blood vessels. The defect initiates a pathological process that leads to decreased blood flow (ischemia). This is in contrast to STEMI, where blood flow is entirely occluded (infarction).
- Treatment
- Antiplatelet therapy
- Unless contraindicated, all patients with suspected heart attack should receive a dose of nonenteric-coated aspirin (162 - 325 mg). The aspirin may be chewed or swallowed.
- See AHA dual antiplatelet therapy (DAPT) recommendations for more on antiplatelet therapy in acute heart attack
- Coronary angiography followed by PCI/CABG as indicated
- Early angiography with intent to perform revascularization should be performed in patients with refractory angina, hemodynamic instability, or electrical instability
- Early angiography with intent to perform revascularization should be performed in patients with an elevated risk for clinical events
- Elevated risk for clinical events is defined as
- Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy
- Elevated cardiac biomarkers (TnT or TnI)
- New or presumably new ST-segment depression
- Signs or symptoms of heart failure or new or worsening mitral regurgitation
- High-risk findings from noninvasive testing
- Hemodynamic instability
- Sustained ventricular tachycardia
- PCI within 6 months
- Prior CABG
- High risk score (e.g., TIMI, GRACE)
- Reduced left ventricular function (LVEF less than 40%) [1, 30]
- Medical therapy (noninvasive)
- Medical therapy should be used in patients with extensive comorbidities (ex. liver or lung failure, cancer) where the risks of revascularization outweigh the benefits
- Medical therapy may be used in patients with a low risk of clinical events (ex. low TIMI, GRACE score) [1]
- Fibrinolysis
- Fibrinolysis is not effective in patients with NSTEMI and should not be used [1]
- ST-elevation myocardial infarction (STEMI)
- Pathology
- STEMI occurs when a thrombi lodges in a coronary artery and blood flow is totally occluded (infarction). This is in contrast to NSTEMI, where blood flow is only partially occluded (ischemia).
- Treatment
- Antiplatelet therapy
- Unless contraindicated, all patients with suspected heart attack should receive a dose of nonenteric-coated aspirin (162 - 325 mg). The aspirin may be chewed or swallowed.
- See AHA dual antiplatelet therapy (DAPT) recommendations for more on antiplatelet therapy in acute heart attack
- Coronary angiography followed by PCI/CABG as indicated
- All patients with STEMI and symptom onset within the last 12 hours should receive angiography followed by PCI/CABG as indicated
- The goal is for patients with STEMI to undergo angiography within 90 minutes of their first contact with medical personnel
- If a patient is taken to a hospital that does not have angiography/PCI capabilities, the goal is to transfer the patient to a hospital with PCI, and for the patient to undergo angiography/PCI within 120 minutes of first contact with medical personnel [31]
- Fibrinolysis
- If it is not possible for the patient to undergo angiography/PCI within 120 minutes of first contact with medical personnel, then fibrinolytic therapy should be administered [31]
- Ideally, fibrinolytic therapy should be administered within 30 minutes of arrival to a non-PCI-capable hospital
- Definitions
- Fibrinolysis - Fibrinolysis is the dissolution of blood clots with medications. rt-PA is the most common medication used to dissolve clots.
- Recombinant tissue plasminogen activator (rt-PA) - Tissue plasminogen activator (t-PA) is a naturally occurring protein that acts by enhancing the conversion of plasminogen to plasmin. Plasmin causes dissolution and lysis of blood clots. Recombinant tissue plasminogen activator (rt-PA) is a synthetic version of (t-PA). It is available in several medications (ex. Alteplase®, Reteplase®, Tenecteplase®). rt-PA is selective for plasminogen that is bound to fibrin, and therefore it is more selective for blood clots. First generation tissue plasminogen activators (ex. streptokinase, urokinase) are not selective for plasminogen bound to fibrin and may lead to higher bleeding rates.
- Absolute and relative contraindications for fibrinolytic therapy
- Absolute contraindications
- Any prior Intracranial hemorrhage
- Known structural cerebral vascular lesion (eg, arteriovenous malformation)
- Known malignant intracranial neoplasm (primary or metastatic)
- Ischemic stroke within 3 months (EXCEPT acute ischemic stroke within 4.5 hours)
- Suspected aortic dissection
- Active bleeding or bleeding diathesis (excluding menses)
- Significant closed-head or facial trauma within 3 months
- Intracranial or intraspinal surgery within 2 months
- Severe uncontrolled hypertension (unresponsive to emergency therapy)
- For streptokinase, prior treatment within the previous 6 months
- Relative contraindications
- History of chronic, severe, poorly controlled hypertension
- Significant hypertension on presentation (SBP > 180 mmHg or DBP > 110 mmHg)
- History of prior ischemic stroke > 3 months
- Dementia
- Known intracranial pathology not covered in absolute contraindications
- Traumatic or prolonged (> 10 minutes) CPR
- Major surgery (< 3 weeks)
- Recent (within 2 to 4 weeks) internal bleeding
- Noncompressible vascular punctures
- Pregnancy
- Active peptic ulcer
- Oral anticoagulant therapy [31]
- TREATMENT (PCI vs CABG vs MT)
- 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.
- The ISCHEMIA trial enrolled 5179 patients with moderate to severe ischemia on stress testing
Main inclusion criteria
- Moderate to severe reversible ischemia on imaging tests or severe ischemia on exercise tests without imaging
Main exclusion criteria
- EF < 35%
- NYHA stage III or IV heart failure
- Unprotected left main stenosis ≥ 50% on CCTA or previous cath
- GFR < 30 ml/min
- ACS within 2 months
- PCI within 12 months
Baseline characteristics
- Median age 64 years
- Male sex - 77%
- Median EF - 60%
- Diabetes - 42%
- Previous MI - 19%
- Previous PCI - 20%
- Previous CABG - 4%
- Angina symptoms at least monthly - 64%
Randomized treatment groups
- Group 1 (2588 patients): Invasive strategy defined as angiography and revascularization when feasible + medical therapy
- Group 2 (2591 patients): Conservative strategy defined as medical therapy alone with angiography reserved for failure of medical therapy
- Most enrolled trial patients underwent coronary computed tomographic (CT) angiography to rule out left main coronary disease and nonobstructive coronary disease
- Goals of medical therapy included the following: SBP < 130 mmHg; LDL < 70 mg/dl; daily aspirin; A1C < 8% in diabetics; maximally tolerated high-intensity statin; beta blocker + ACE/ARB in heart failure
Primary outcome: Composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest
Results
Duration: median of 3.2 years | |||
Outcome | Invasive | Conservative | Comparisons |
---|---|---|---|
Primary outcome (6 months) | 5.3% | 3.4% | diff 1.9% (0.8 to 3.0) |
Primary outcome (3 years) | 11.3% | 12.7% | diff -1.3% (-3.2 to 0.6) |
Primary outcome (5 years) | 16.4% | 18.2% | diff -1.8% (-4.7 to 1.0) |
Overall mortality (5 years) | 9% | 8.3% | diff 0.7 (-1.6 to 3.1) |
Myocardial infarction (5 years) | 10.3% | 11.9% | diff -1.6 (-3.9 to 0.7) |
|
Findings: Among patients with stable coronary disease and moderate or severe ischemia, we
did not find evidence that an initial invasive strategy, as compared with an initial
conservative strategy, reduced the risk of ischemic cardiovascular events or death
from any cause over a median of 3.2 years. The trial findings were sensitive to the
definition of myocardial infarction that was used.
- The ISCHEMIA-CKD trial enrolled 777 patients with advanced kidney disease and stable CAD
Main inclusion criteria
- GFR < 30 ml/min or on dialysis
- At least moderate ischemia on exercise or pharmacologic stress test
Main exclusion criteria
- EF < 35%
- NYHA stage III or IV heart failure
- Unprotected left main stenosis ≥ 50% on CCTA or previous cath
- ACS within 2 months
- PCI within 12 months
Baseline characteristics
- Median age 63 years
- Male sex - 69%
- Median EF - 58%
- Diabetes - 57%
- Dialysis - 53%
- Median GFR (not on dialysis) - 23 ml/min
- Previous MI - 17%
- Previous PCI - 19%
Randomized treatment groups
- Group 1 (388 patients): Invasive strategy defined as angiography and revascularization when feasible + medical therapy
- Group 2 (389 patients): Conservative strategy defined as medical therapy alone with angiography reserved for failure of medical therapy. Medical therapy failure was defined as acute coronary syndrome, heart failure, resuscitated cardiac arrest, or angina refractory to medical therapy.
- Goals of medical therapy included the following: BP < 130/80 mmHg; LDL < 70 mg/dl; daily aspirin; A1C < 8% in diabetics; maximally tolerated high-intensity statin; beta blocker in heart failure; ACE/ARB in all patients as tolerated
Primary outcome: Composite of death or nonfatal myocardial infarction
Results
Duration: Median of 2.2 years | |||
Outcome (3-year cumulative) | Invasive | Conservative | Comparisons |
---|---|---|---|
Primary outcome | 36.4% | 36.7% | p=0.95 |
Overall mortality | 27.2% | 27.8% | HR 1.02 (0.76 - 1.35) |
Any MI | 15% | 15.9% | HR 0.84 (0.57 - 1.25) |
|
Findings: Among patients with stable coronary disease, advanced chronic kidney disease, and
moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction.
- 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 (ECG 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 |
|
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.
- 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.
- 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 |
|
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.
- The REVIVED-BCIS2 trial enrolled 700 patients with EF ≤ 35%, extensive CAD amendable to PCI, and demonstrable myocardial viability
Main inclusion criteria
- EF ≤ 35%
- Extensive CAD amendable to PCI
- Demonstrable myocardial viability
Main exclusion criteria
- Acute MI within 4 weeks
- Decompensated heart failure
- Sustained V-tach/V-fib within 72 hours
- GFR < 25 ml/min
Baseline characteristics
- Average age 69 years
- Male sex - 88%
- Diabetes - 41%
- Previous MI - 53%
- Average EF - 27%
- NYHA class: I or II - 74% | III or IV - 26%
Randomized treatment groups
- Group 1 (347 patients): PCI + MT
- Group 2 (353 patients): MT
- Demonstrable myocardial viability was determined using dobutamine stress echo, cardiac MRI, single photon emission CT, or myocardial PET scan
- In the PCI group, revascularization was attempted on all diseased proximal coronary vessels subtending areas of viable myocardium
- Medical therapy refers to individually adjusted pharmacologic and device therapy for heart failure. Medical therapy for heart failure was initiated before enrollment and customized according to the patient’s individual needs throughout the trial by heart failure specialists at the recruiting centers. A medical-therapy committee reviewed guidelines periodically and refined recommendations to ensure that the pharmacologic and device therapy given to all patients in the trial remained contemporary.
Primary outcome: Composite outcome was death from any cause or hospitalization for heart failure over a minimum follow-up period of 24 months
Results
Duration: median of 41 months | |||
Outcome | PCI + MT | MT | Comparisons |
---|---|---|---|
Primary outcome | 37.2% | 38% | p=0.96 |
Overall mortality | 31.7% | 32.6% | HR 0.98 95%CI (0.75–1.27) |
Hospitalization for heart failure | 14.7% | 15.3% | HR 0.97 95%CI (0.66–1.43) |
Acute MI | 10.7% | 10.8% | HR 1.01 95%CI (0.64–1.60) |
Unplanned revascularization | 2.9% | 10.5% | HR 0.27 95%CI (0.13–0.53) |
Major bleeding at 1 yr | 3.1% | 0.6% | HR 4.95 95%CI (1.09–22.43) |
|
Findings: Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure.
- 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 |
|
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.
- 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 |
|
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.
- 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.
- A follow-up study to the SYNTAX trial was published in 2013. It included results for 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.
- Another follow-up study to the SYNTAX trial was published in 2019. It included overall mortality results for 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.
- 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.
- 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.
- STUDY
- Design: Randomized controlled trial (N=1500 | length = 1 year) in patients with three-vessel coronary artery disease not involving the left main coronary artery
- Treatment: FFR-guided PCI with zotarolimus-eluting stents vs CABG
- Primary outcome: Occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization
- Results:
- Primary outcome: PCI - 10.6%, CABG - 6.9% (HR 1.5, 95%CI [1.1 - 2.2])
- Overall mortality: PCI - 1.6%, CABG - 0.9% (HR 1.7, 95%CI [0.7 - 4.3])
- Findings: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year
- 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.
- A follow-up study to the PRECOMBAT trial was published in 2020. It included results for 576 of the original 600 patients at a median of 11.3 years.
Duration: Median 11.3 years | |||
Outcome | PCI | CABG | Comparisons |
---|---|---|---|
Primary outcome | 29.8% | 24.7% | HR 1.25, 95%CI [0.93 - 1.69] |
Overall mortality | 14.5% | 13.8% | HR 1.13, 95%CI [0.75 - 1.70] |
Myocardial infarction | 3.2% | 2.8% | HR 0.76, 95%CI [0.32 - 1.82] |
Stroke | 1.9% | 2.2% | HR 0.71, 95%CI [0.22 - 2.23] |
Revascularization | 21.3% | 10.6% | HR 2.04, 95%CI [1.33 - 3.11] |
Findings: Ten-year follow-up of the PRECOMBAT trial of patients with left main coronary artery disease randomized to PCI or CABG did not demonstrate significant difference in the incidence of major adverse cardiac or cerebrovascular events. Because the study was underpowered, the results should be considered hypothesis-generating, highlighting the need for further research.
- 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 |
|
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.
- 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.
- 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
- A follow-up study to the NOBLE trial was published in 2020. It included results for 1093 of the original 1201 patients at a median of 4.9 years.
Duration: Median 4.9 years | |||
Outcome | PCI | CABG | Comparisons |
---|---|---|---|
Primary outcome | 28% | 19% | HR 1.58, 95%CI [1.24 - 2.01], p=0.0002 |
Overall mortality | 9% | 9% | HR 1.08, 95%CI [0.74 - 1.59], p=0.68 |
Non-procedural myocardial infarction | 8% | 3% | HR 2.99, 95%CI [1.66 - 5.39], p=0.0002 |
Stroke | 4% | 2% | HR 1.75, 95%CI [0.86 - 3.55], p=0.11 |
Revascularization | 17% | 10% | HR 1.73, 95%CI [1.25 - 2.40], p=0.0009 |
Findings: In revascularization of left main coronary artery disease, PCI was associated with an inferior clinical
outcome at 5 years compared with CABG. Mortality was similar after the two procedures but patients treated with PCI
had higher rates of non-procedural myocardial infarction and repeat revascularization.
- AHA 2021 recommendations
- Recommendations for revascularization to improve survival in stable CAD compared with medical therapy
- Three vessel disease (with or without proximal LAD) and normal ejection fraction
- CABG may be reasonable to improve survival in patients with suitable anatomy
- The usefulness of PCI to improve survival is uncertain
- Left main disease
- CABG is recommended to improve survival
- In selected patients with stable CAD and significant left main stenosis for whom PCI can provide equivalent revascularization to that possible with CABG, PCI is reasonable to improve survival
- Patients with diabetes
- In patients with diabetes and multivessel CAD with involvement of the LAD, who are appropriate candidates for CABG, CABG (with a LIMA to the LAD) is recommended in preference to PCI to reduce mortality and repeat revascularizations
- In patients with diabetes, who have multivessel CAD amenable to PCI and an indication for revascularization and are poor candidates for surgery, PCI can be useful to reduce long-term ischemic outcomes
- In patients with diabetes, who have left main stenosis and low- or intermediate-complexity CAD in the rest of the coronary anatomy, PCI may be considered an alternative to CABG to reduce major adverse cardiovascular outcomes [50]
- 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 ISCHEMIA and ISCHEMIA-CKD trials published in 2020 are the most recent trials to compare MT to an invasive strategy. The trials are superior to previous trials because contemporary medical therapy was used and crossover rates (21%, ISCHEMIA | 19.6%, ISCHEMIA-CKD) were low for revascularization. Medical therapy was found to be noninferior to an invasive strategy in patients with stable CAD. Patients with left main disease and significant heart failure were excluded.
- 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.
- Patients with HFrEF
- In the REVIVED-BCIS2 Trial, PCI + MT did not improve outcomes over MT alone in patients with an EF ≤ 35% and proven myocardial viability. In the STICH trial, CABG + MT was superior to MT in a similar patient population. Entresto®, a drug that improves heart failure outcomes, was used by 35% of participants in the REVIVED-BCIS2 trial, but it was not available when STICH was performed. It's likely that Entresto® would have improved MT results in STICH.
- ELDERLY PATIENTS
- 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.
- 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 ECG 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 ECG 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 |
|
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
- PREVENTIVE 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.
- 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 |
|
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.
- 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.
- 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.
- 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 (culprit and nonculprit lesions)
- 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] |
|
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
- STUDY
- Design: Randomized, open-label trial (N=764 | length = 1 year) in patients with STEMI or NSTEMI acute coronary syndrome and multivessel disease with a clearly identifiable culprit lesion
- Treatment: Immediate culprit and nonculprit lesion PCI (Immediate group) vs Immediate culprit PCI and staged nonculprit PCI within 6 weeks (Staged group)
- Primary outcome: Composite of all-cause mortality, myocardial infarction, any unplanned ischemia-driven revascularisation, or cerebrovascular events at 1 year after the index procedure
- Results:
- Primary outcome: Immediate - 7.6%, Staged - 9.4% (p=0.0011 for noninferiority)
- Overall mortality: Immediate - 1.9%, Staged - 1.2% (p=0.30)
- Findings: In patients presenting with acute coronary syndrome and multivessel disease, immediate complete revascularization was non-inferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.
- AHA 2021 recommendations
- In selected hemodynamically stable patients with STEMI and multivessel disease, after successful primary PCI, staged PCI of a significant noninfarct artery stenosis is recommended to reduce the risk of death or MI
- In selected patients with STEMI with complex multivessel noninfarct artery disease, after successful primary PCI, elective CABG is reasonable to reduce the risk of cardiac events
- In selected hemodynamically stable patients with STEMI and low-complexity multivessel disease, PCI of a noninfarct artery stenosis may be considered at the time of primary PCI to reduce cardiac event rates.
- In patients with STEMI complicated by cardiogenic shock, routine PCI of a noninfarct artery at the time of primary PCI should not be performed because of the higher risk of death or renal failure [50]
- Summary
- Preventive PCI appears to be beneficial in stable patients. In the CULPRIT-SHOCK study that only enrolled unstable patients with acute MI, preventive PCI led to worse outcomes.
- THROMBECTOMY
- 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.
- 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 |
|
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.
- 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]
- PRIMARY PREVENTION WITH ASPIRIN
- Overview
- The most effective way to prevent CVD is to properly manage risk factors like hypertension, dyslipidemia, and diabetes. Antiplatelet therapy with aspirin can also lower the risk of CVD events, but at the same time, it increases the risk of significant bleeding. Whether the risk-benefit ratio of aspirin therapy is favorable in patients without documented CVD is a matter of controversy.
- 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.
- 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.
- 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.
- 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] |
|
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.
- 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 |
|
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.
- 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 were updated in 2021
- AHA 2019 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 2021 recommendations
- Adults 40 to 59 years with a 10-year CVD risk ≥ 10%: The decision to initiate low-dose aspirin use for the primary prevention of CVD should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. [Grade C] (AHA 10-year risk calculator)
- Adults ≥ 60 years The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults age 60 years or older. [Grade D]
- 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
- SECONDARY PREVENTION | Antiplatelet therapy
- Overview
- Stable CAD (> 12 months since ACS, PCI, or CABG)
- 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 and HOST-EXAM 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 and/or PCI
- After ACS, dual antiplatelet therapy (DAPT) is recommended for a period of time in most patients. See antiplatelet therapy in CAD for a review.
- 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 |
Vascular death (%/year) | 1.9% | 2.06% | p=0.29 |
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.
- The HOST-EXAM trial enrolled 5438 patients in South Korea who had undergone PCI with DES and successfully completed 6 - 18 months of DAPT
Main inclusion criteria
- PCI with DES
- Completed 6 - 18 months of DAPT without any ischemic or major bleeding events
Main exclusion criteria
- History of major bleeding
- Receiving anticoagulant therapy
- Concomitant CYP2C19 inhibitor
Baseline characteristics
- Average age 63 years
- Diabetes - 34%
- Previous MI - 16%
- Previous history of stroke - 4.6%
- Average number of stents - 1.5
- Median length of DAPT - 12.5 months
- CAD: 1-vessel - 50% | 2-vessel - 31% | 3-vessel - 18% | Left main - 5%
Randomized treatment groups
- Group 1 (2710 patients): Clopidogrel 75 mg once daily
- Group 2 (2728 patients): Aspirin 100 mg once daily
- Treatment was open label
- DAPT therapy was aspirin + clopidogrel in 81% of patients, aspirin + ticagrelor in 9.8% of patients, and aspirin + prasugrel in 8.2%
Primary outcome: Composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due
to acute coronary syndrome, and major bleeding complications during the 24-month follow-up period. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type bleeding of at least 3.
Results
Duration: 24 months | |||
Outcome | Clopidogrel | Aspirin | Comparisons |
---|---|---|---|
Primary outcome | 5.7% | 7.7% | p=0.003 |
All-cause death | 1.9% | 1.3% | p=0.101 |
Non-fatal MI | 0.7% | 1% | p=0.15 |
Stroke | 0.7% | 1.6% | p=0.002 |
Readmission for ACS | 2.5% | 4.1% | p=0.001 |
Major bleeding | 1.2% | 2% | p=0.035 |
Findings: Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance
period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause
death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding
type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention,
clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events.
- 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.
- 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.
- 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 |
|
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
- In the CAPRIE trial and HOST-EXAM trial, clopidogrel was slightly more effective than aspirin in preventing a composite of cardiovascular outcomes and bleeding events. Overall mortality was not significantly different in either trial. The CAPRIE trial was an international study and the HOST-EXAM trial was performed in South Korea where 50 - 60% of the population have a CYP2C19 loss-of-function allele (see clopidogrel and CYP2C19 poor metabolizers for more). The significance of this and how it relates to other patient populations is unknown.
- In the trials where aspirin was compared to dual antiplatelet therapy, the addition of clopidogrel or ticagrelor to aspirin lowered the overall risk of CVD events but increased the risk of bleeding. There was no significant effect on mortality in any of the trials.
- SECONDARY PREVENTION | Antiplatelet + Anticoagulant Therapy
- Overview
- Stable CAD (> 12 months since ACS, PCI, or CABG)
- Patients with stable CAD sometimes have an indication for anticoagulation (e.g. A fib, DVT, PE). Whether these patients should receive an antiplatelet agent 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 detailed below compared rivaroxaban alone to rivaroxaban + antiplatelet therapy in patients with stable CAD and A fib.
- Acute coronary syndrome and/or PCI
- Antithrombotic therapy recommendations for patients with ACS and/or PCI who also have A fib or VTE are reviewed here - triple therapy
- 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.
- ACC 2020 recommendations for antithrombotic therapy in patients with CAD and A fib or VTE
- Patients with A fib or VTE who are > 12 months since ACS, PCI, or CABG
- Patients should receive oral anticoagulant therapy only (DOAC is preferred). Antiplatelet therapy is not recommended.
- Patients with A fib or VTE who are < 12 months since ACS, PCI, or CABG
- Summary
- The AFIRE study found that adding antiplatelet therapy to an anticoagulant in patients with A fib and stable CAD led to worse outcomes. The ACC 2020 recommendations are in line with these findings.
- SECONDARY PREVENTION
- Statins
- All patients who have documented CAD should receive a high-intensity statin unless contraindicated
- See AHA cholesterol treatment recommendations for more
- Beta blockers
- The AHA 2012 CAD guidelines recommend that beta blockers be given for 3 years to all patients with a normal EF after a myocardial infarction or acute coronary syndrome
- Beta blockers should be used indefinitely in all patients with an EF ≤ 40% with heart failure and prior myocardial infarction. Carvedilol, metoprolol succinate, and bisoprolol are the only three beta blockers that should be used [8]
- See beta blockers for more
- ACE inhibitors and ARBs
- The AHA 2012 CAD guidelines recommend that the following patients with stable ischemic heart disease receive an ACE Inhibitor or ARB:
- Patients with an ejection fraction ≤ 40%
- Patients with hypertension
- Patients with chronic kidney disease
- Patients with diabetes [8]
- AHA RECOMMENDATIONS FOR CABG PATIENTS
- Overview
- In 2015, the AHA published recommendations specifically for CABG patients
- The recommendations are summarized below
- Antiplatelet therapy
- Aspirin should be administered preoperatively and within 6 hours after CABG in doses of 81 to 325 mg daily. It should then be continued indefinitely to reduce graft occlusion and adverse cardiac events. (Clopidogrel 75 mg once daily is a reasonable alternative in patients who cannot take aspirin)
- After off-pump CABG, dual antiplatelet should be administered for 1 year with combined aspirin (81 – 162 mg daily) and clopidogrel 75 mg daily to reduce graft occlusion
- Statin therapy
- All patients should receive a statin
- For patients < 75 years, high-intensity statin therapy (atorvastatin 40–80 mg, rosuvastatin 20–40 mg) should be administered
- Moderate-intensity statin may be appropriate in patients who cannot tolerate high-intensity statins, or in those at higher risk for drug interactions (ex. > 75 years old)
- Beta blockers
- All CABG patients should be prescribed perioperative beta blocker therapy to prevent postoperative atrial fibrillation, ideally starting before surgery, unless contraindicated (e.g. bradycardia, severe reactive airway disease)
- Patients with a history of heart attack should be prescribed a beta blocker
- Patients with heart failure or left ventricular dysfunction should be prescribed a beta blocker (bisoprolol, sustained-release metoprolol succinate, or carvedilol)
- ACE inhibitors/ARBs
- ACE inhibitors should be given to CABG patients with recent heart attack, heart failure, left ventricular dysfunction, diabetes, and/or chronic kidney disease
- ARBs may be used in patients who cannot tolerate ACE inhibitors
- Aldosterone antagonists
- Aldosterone antagonists are reasonable after CABG in patients with EF < 35% and who have NYHA class II - IV heart failure
- Blood pressure goals
- Blood pressure goal of < 140/85 mmHg is reasonable, although the ideal BP goal has not been determined in randomized controlled trials
- Implantable cardioverter-defibrillators (ICDs)
- ICD therapy for the prevention of sudden cardiac death should only be performed after 3 months of post-op medical therapy has been provided and persistent left ventricular dysfunction (EF < 35%) has been confirmed [39]
- ANGINA (CHEST PAIN) TREATMENT
- Overview
- The AHA recommends beta blockers as first-line treatment for angina in patients with CAD
- Calcium channel blockers and long-acting nitrates are recommended as second-line therapies in patients who cannot tolerate beta blockers and in those who are uncontrolled on beta blockers
- PCI
- A study published in the Lancet in 2018 compared PCI to sham PCI in patients with single vessel disease and stable angina. The study found no significant effect of PCI on difference in exercise time and angina symptoms when compared to the sham procedure. [PMID 29103656]
- Pharmacological treatments for angina are reviewed on these pages:
- FOLLOW-UP IN CAD
- Patients with CAD should have regular follow-up for risk factor evaluation and treatment, along with monitoring for new or worsening symptoms. Routine noninvasive testing (e.g. ECG, stress testing, ECHO, MPI) in stable patients has not been proven to be beneficial. A study in high-risk patients that compared routine functional testing (nuclear stress testing, EST, or stress echo) one year after PCI to standard care found no benefit of routine testing. [PMID 36036496]
- The AHA makes a soft recommendation that noninvasive testing may be helpful in patients with a prior history of silent ischemia or those at high risk for a recurrent event. The recommendation gives a time interval for testing of every 2 years or more. [8]
- BIBLIOGRAPHY
- 1 - PMID 21444888 - AHA GL on Unstable angina and NSTEMI
- 2 - PMID CDC website
- 3 - PMID 12485966 - ATP III
- 4 - PMID 21505219
- 5 - PMID 21252734
- 6 - PMID 21251585
- 7 - PMID 21787906
- 8 - PMID 23166211 - AHA GL on CAD
- 9 - PMID 22420013 - NCGC GL
- 10 - PMID 11991917
- 11 - PMID 21403014
- 12 - PMID 17220398 - AHA CAC GL
- 13 - PMID 20424251 - Mesa study
- 14 - PMID 7994804 - CASS study
- 15 - PMID 7729018 - CASS study left main dx
- 16 - PMID 7729019 - CASS study left main equivalent dx
- 17 - PMID 17387127 - Courage trial
- 18 - PMID 19502645 - BARI2 trial
- 19 - PMID 17339566 - MASS trial
- 20 - PMID 21463150 - STICH trial
- 21 - PMID 19228612 - SYNTAX trial
- 22 - PMID 23121323 - FREEDOM trial
- 23 - PMID 22231610 - AIM MA
- 24 - PMID 19482214 - Lancet MA
- 25 - PMID 8918275 - CAPRIE trial
- 26 - PMID 16531616 - CHARISMA trial
- 27 - PMID 23484825
- 28 - PMID 23439102
- 29 - PMID 20197530
- 30 - PMID 22800849
- 31 - PMID 23247304
- 32 - PMID 23991625
- 33 - PMID 25401325
- 34 - PMID 25775317
- 35 - PMID 25773919 PROMISE study
- 36 - PMID 25774645 BEST trial
- 37 - PMID 25853743 TOTAL trial
- 38 - PMID 25853659 Height and CAD
- 39 - PMID 25679302 Post-CABG GL
- 40 - PMID 26052677 CCTA vs MPI
- 41 - PMID 26490017 - AHA 2015 focused update
- 42 - PMID 26559572 - COURAGE follow-up
- 43 - PMID 21463149 - PRECOMBAT trial
- 44 - PMID 30145934 - Coronary CT Angiography and 5-Year Risk of Myocardial Infarction, NJEM (2018)
- 45 - PMID 28188475 - Myocardial perfusion imaging with PET, Int J Cardiovasc Imaging (2017)
- 46 - PMID 30145934 - American Society of Nuclear Cardiology and Society of Nuclear Medicine and Molecular Imaging Joint Position Statement on the Clinical Indications for Myocardial Perfusion PET, The Journal of Nuclear Medicine (2016)
- 47 - PMID 30894319 - 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease
- 48 - PMID 22315257 ACCP GL on thrombosis
- 49 - PMID 33250267 - 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease, JACC (2020)
- 50 - PMID 34882436 - 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Circulation (2022)
- 51 - PMID 31504439 - 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes, Eur Heart J (2020)
- 52 - PMID 34709879 - 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Circulation (2021)