Continuing Education Activity

Multivessel disease is defined as significant stenosis (>70%) in two or more major coronary arteries of 2.5 mm diameter or more. This activity helps in understanding the pathophysiology of multivessel coronary artery disease and indications for surgery versus percutaneous interventions. It highlights the role of the interprofessional team.

Objectives:

• Describe the pathophysiology of multivessel coronary artery disease.
• Outline the process of evaluation of a patient with multivessel disease.
• Review the studies that evaluate a surgical versus interventional approach to multivessel disease.
• Summarize interprofessional team strategies for improving care coordination and outcomes in patients with multivessel disease.

Introduction

A coronary artery is a well-developed trilaminar structure. The innermost layer is termed the tunica intima, which is lined with endothelial cells that make contact with the circulating arterial blood.[1] The endothelial cells have a tightly regulated vascular homeostasis mechanism, failure of which leads to atherosclerotic disease process.[1] Multivessel disease is defined as significant stenosis (>70%) in two or more major coronary arteries of 2.5 mm diameter or more.[2] About 40% to 50% of patients presenting with ST-elevation myocardial infarction (STEMI) have multivessel coronary disease.[3][4]

Coronary artery bypass grafting (CABG) has been primarily used for revascularization of complex coronary artery disease (CAD) since 1968.[5] When percutaneous intervention (PCI) was introduced in 1977, it was initially considered a treatment option for patients with single-vessel disease.[5] Advancements in cardiothoracic surgical techniques with the utilization of smaller incisions, arterial conduits, off-pump CABG, and improved postoperative care have led to a reduction in morbidity and mortality and is the preferred revascularization method for multivessel disease.[6] Recent technological and technical advancement in PCI techniques has broadened the treatment scope to now include patients with multivessel disease.[5] Regardless of which modality is chosen, an interprofessional approach should be undertaken and account for various factors, including patient preference, surgical risk, and operator skill.

Etiology

Common risk factors for atherosclerosis and CAD include the following:[1]

• Hypertension
• Hyperlipidemia
• Diabetes mellitus
• Cigarette smoking
• Age 
• Menopause
• Hyperhomocysteinemia
• Family history of CAD
• Mutations in endothelial nitric oxide synthase

In the setting of myocardial infarction, coronary constriction plays a major role in addition to plaque rupture leading to platelet aggregation and thrombus formation.[1] Women have a worse prognosis from CAD, compared to males, despite a relatively lower pretest likelihood of CAD.[7]

Epidemiology

In industrialized countries, CAD is the most common cause of mortality.[8] CAD affects about 16.8 million Americans, with 8 million of those having had a previous myocardial infarction (MI).[9] In 2005, CAD led to 607,00 patient deaths; and predicted to reach 23.4 million by 2030.[9] CAD poses tremendous economic pressure on healthcare resources, not only because of the associated financial burden but also a significant loss of productivity among affected patients.[7] The estimated direct and indirect economic burden of CAD in the United States is $165.4 billion.[9]

Pathophysiology

The composition of atherosclerotic plaques has been studied in deceased patients after suffering from myocardial infarction. Plaques are composed of a thin fibrous cap, large necrotic core, smooth muscle cells, leukocytes, and foamy cells.[1] Plaque rupture and exposure of circulating thrombotic factors to exposed endothelial cells result in thrombus formation, which adheres to the luminal surface of the artery and results in acute occlusion of the vessel. It is composed of unstable platelet aggregates, erythrocytes, and leukocytes, all entrapped by a complex fibrin network.[10] Plaque rupture can be multifactorial with potential triggers, including the following: increase in intraluminal pressure, coronary vasospasm, tachycardia, elevated systolic blood pressure, increased viscosity, increase sympathetic activity, hypercoagulability, impaired fibrinolysis.[1] Atherosclerotic plaques are prone to rupture due to structural inflammation leading to the development of a necrotic core with a thin fibrous cap for protection.[1]

History and Physical

Presentation of multivessel disease is variable and dependent on the severity of the underlying disease, presence of comorbid conditions which may alter the typical presentation, and acuity of disease. Patients with stable multivessel disease may present with exertional chest pain or shortness of breath with radiation to the left arm and neck. The chest pain is termed "typical" chest pain when three of the following are present and "atypical" when two of the following are present: chest pain worsened by emotional or physical stress, chest pain relieved by rest and nitroglycerin, substernal chest pain, pressure or discomfort. Patients may also have associated nausea, diaphoresis, and lightheadedness. Patients of older age, particularly women and those with diabetes, may present atypically with frequent complaints of epigastric discomfort and associated nausea and vomiting. Acute thrombosis will typically present with crushing substernal chest pain not relieved by rest and temporarily relieved by nitroglycerin. Acute myocardial infarction should be ruled out in all patients presenting with chest pain, considering that the diagnosis represents a time-sensitive, potentially life-saving medical emergency.[11]

Evaluation

The pretest probability of a patient having CAD is dependent on age, gender, and whether the patient has typical angina, atypical angina, or nonanginal chest pain. 

High pretest probability is defined as over 75% or over 90% pretest probability of CAD. Medical therapy for CAD should be initiated. If there is no response to therapy, lifestyle limiting symptoms, or progression to unstable angina, then coronary angiography should be performed. 

Intermediate pretest probability is defined as between 10% and 25% to 75% and 90%, respectively, pretest probability of CAD. It must be determined if the patient has baseline EKG abnormalities, which would preclude the interpretation of the EKG and whether the patient has the capacity to exercise. If able to exercise without baseline EKG changes, then the patient can undergo treadmill exercise stress testing. If unable to exercise and baseline EKG abnormalities are present, then they should undergo pharmacological stress echocardiography. If the patient has baseline EKG changes and is able to exercise, then stress nuclear or treadmill stress echocardiography can be performed. If any test returns markedly positive, then the next step would be to perform coronary angiography.[8]

Low pretest probability is defined as a lower than 25% or 10% pretest probability of CAD. No additional testing is required.

The use of perfusion imaging modalities in women is challenging and has a high rate of false-positive and false-negative results, likely due to breast attenuation and partial volume effect due to relatively smaller ventricles.[7] Carotid ultrasound can also be used to evaluate atherosclerosis.[12] 

Treatment / Management

In cases of non-ST-elevation myocardial infarction (NSTEMI) or unstable angina, recent studies have failed to show any significant difference in treatment with revascularization versus optimal medical therapy.[8] In stable CAD, the principal goal of revascularization is symptomatic management, improved quality of life, and improved exercise tolerance.[8] Patients with multivessel disease require optimal medical therapy consisting of intensive lifestyle modification and medical therapy. Lifestyle modification begins with the elimination of tobacco use, reduction to alcohol use to less than two drinks for men and one for women, exercise, reduced salt intake, and weight loss. Medical therapy begins with aspirin, which is indicated for secondary prophylaxis for acute coronary syndromes or cerebrovascular events, including transient ischemic attacks or strokes. Beta-blockers and calcium channel blockers in the setting of CAD are useful for symptomatic management of typical angina. Statin therapy for lipid management has been shown to be an effective primary and secondary preventive medication with improvement in mortality.[8] Management of underlying diabetes with tight glycemic control and hypertension are other modifiable risk factors.

The FAME1 trial found patients with multivessel disease who underwent routine measurement of fractional flow reserve (FFR) during PCI were found to have reduced primary endpoint rates of death, MI, and repeat revascularization at 1 year when compared to PCI guided by conventional angiography.[8] This trial found the 1-year rate for death and MI was 11.1% in the angiography group and 7.3% in the FFR group.[8] The preventive angioplasty in myocardial infarction (PRAMI) trial assessed 465 patients with multivessel disease for preventive PCI versus no preventive PCI.[13] The primary outcome of this trial was a composite risk of nonfatal MI, cardiovascular mortality, or refractory angina with a mean follow-up of 23 months.[13] The primary outcome was observed in 21 of 234 patients who received preventive PCI compared to 53 of 231 patients who did not receive preventive PCI.[13] Subsequently, practice guidelines were updated when similar results were produced by complete versus lesion only primary PCI (CvLPRIT) trial.[13]

A pooled analysis of 7812 patients from ten randomized trials was performed where patients were assigned to one of two arms: PCI with balloon angioplasty and or bare-metal stent (BMS) placement versus CABG.[14] They concluded that the 5-year mortality among patients who underwent PCI and or BMS was 10% compared to 8.4% for those who underwent CABG (p=0.12).[14] Multiple other trials that compared PCI with drug-eluting stents and CABG found similar mortality results.[14] Another extensive study pooled 11518 patient data from 11 trials, where patients were randomly assigned to either CABG or PCI. The subset of patients in whom drug-eluting stents were used in the PCI group, the 5-year all-cause mortality was 12.4% in the PCI group and 10.0% among the patients with CABG (p=0.0017).[14] In an associated subgroup analysis among the patients with diabetes, the 5-year all-cause mortality was 15.7% in the PCI group and 10.7% in the CABG group  (p=0.0001).[14] 

The SYNTAX trial compared patients who underwent CABG versus PCI  in patients with left main coronary disease or three-vessel disease.[5] They studied the major adverse cardiac and cerebrovascular events for their primary endpoint and found that PCI did not meet the non-inferiority goal compared to CABG.[5] Patients in the PCI group had a significantly higher rate of revascularization compared to those with CABG.[5] Based on the 5-year data from the SYNTAX trial, surgery is considered the standard of care in patients with complex multivessel disease, while PCI is reasonable in patients with low to intermediate SYNTAX scores.[5] Furthermore, an analysis of ten randomized trials, performed by Hlatky et al., found similar conclusions.[15]

Differential Diagnosis

Differential diagnosis of typical and atypical chest pain is broad and consists of the following:

Gastrointestinal

• Gastroesophageal reflux disease (GERD)
• Dyspepsia
• Dysphagia 
• Pancreatitis

Cardiac

• Acute myocardial infarction (STEMI/NSTEMI)
• Unstable angina
• Stable angina
• Acute pericarditis
• Aortic dissection
• Prinzmetal angina
• Drug use (cocaine, amphetamines)

Musculoskeletal

• Rib fracture
• Chronic pain syndromes
• Costochondritis
• Trauma

Pulmonary

• Pleurisy
• Acute pulmonary embolism
• Pneumonia
• Pulmonary contusion
• Pneumothorax

Prognosis

The SYNTAX trial compared patients who underwent CABG versus PCI with DES placement and followed up patients in 1 year, 3 years, 5 years, and 10-year intervals. At 10 years follow-up, patients with triple vessel disease who underwent PCI with DES placement had a hazard ratio for death of 1.41 (CI 95%: 1.1 - 1.8) compared to CABG.[16] This trial had several limitations, however, most notable of which was the utilization of first-generation paclitaxel eluting-stents and bare-metal stents. Newer generation everolimus stents have reduced risk of death, myocardial infarction, and stent thrombosis compared to earlier generations. An observational study in patients with multivessel disease compared patients who underwent PCI with everolimus stent placement versus CABG and found a similar risk of death at 2.9 years between the two groups with a hazard ratio of 1.04 for PCI with stent placement.[17] 

Complications

Complications of multivessel disease, including the following:

• Acute coronary syndrome (unstable angina, non-ST-segment elevation myocardial infarction, STEMI)
• In-stent restenosis
• In-stent thrombosis
• Stent embolization
• Side branch occlusion
• Stent fracture
• Graft failure
• Surgical complications (bleeding, wound dehiscence, infection, pulmonary complication, stroke, myocardial infarction, arrhythmia, acute kidney injury, transfusion-related reactions)
• PCI complications (bleeding, pseudoaneurysm, retroperitoneal hematoma, infection, arterial dissection, distal arterial embolization, coronary perforation, stroke, acute kidney injury, reperfusion injury)

Deterrence and Patient Education

• Smoking cessation
• Medication and exercise therapy compliance
• Regular outpatient follow up
• Cholesterol management with diet and statin therapy
• Glycemic control with HbA1c goal less than 7% (or more for significant comorbid conditions or hypoglycemia)
• Ambulatory blood pressure monitoring with systolic blood pressure goal under 130 mmHg and diastolic pressure goal under 80 mmHg
• Weight reduction
• Interprofessional involvement

Pearls and Other Issues

Multivessel coronary artery disease has a wide prevalence in the United States. About 40 to 50% of patients with STEMI have multivessel coronary artery disease.[3][4] There is an ongoing debate about the use of CABG versus PCI in patients with multivessel disease. Advancements in medical technologies and operative skills have led to the introduction of various treatment modalities—risk factor management is very crucial in coronary artery disease. Moreover, aggressive management of hypertension, hyperlipidemia, and diabetes, along with lifestyle modification, including smoking cessation, maintaining a healthy diet, and regular physical activity, have shown to reduce the incidence of multivessel disease.

Enhancing Healthcare Team Outcomes

Multivessel CAD carries significant morbidity and mortality risk and requires input from various medical and surgical specialists for individualized patient care. Internists and primary care physicians are valuable for primary disease prevention and identification of patients at risk of developing CAD. Risk factor modification through pharmacological and lifestyle modification has been shown to reduce the risk and progression of CAD significantly. Cardiologists and cardiothoracic surgeons should provide the patient with information regarding procedural risks, benefits, and need for further revascularization if needed. The decision for CABG versus PCI should account for multiple factors, including age, comorbidities, surgical risk, patient preference. This condition is best managed by an interprofessional team of primary care providers, emergency medicine, cardiology, cardiovascular surgery, specialty trained nurses, and pharmacists. [Level 5] Nurses are valuable for their familiarity with the patient and updates on how the patient's condition has progressed. Pharmacists are needed for patient and physician education on potential medication side effects and drug-to-drug interactions.

Currently, CABG remains the recommended treatment modality for patients with triple vessel disease due to reduced risk of mortality and repeat revascularization procedure. [Level 1] The increased risk of stroke with CABG does not outweigh the long-term benefit of the procedure.