PCI for Stable CAD

General description of procedure, equipment, technique

Coronary artery disease (CAD) is the leading cause of death in both men and women. Stable CAD is generally used to define patients with coronary atherosclerotic disease that are either asymptomatic or have nonaccelerating symptoms. It represents a large population of patients with CAD and has enormous epidemiologic and health economic relevance.

Percutaneous coronary intervention (PCI) is a technique for revascularization for high-grade coronary artery stenosis. The procedure is performed in a cardiac catheterization laboratory with fluoroscopy guidance and minimally invasive techniques, with use of catheters and wires to visualize and cross coronary stenosis, and revascularization of the stenosis by balloon angioplasty and/or placement of coronary stents (bare metal or drug-eluting).

Defining the role of PCI in management of patients with stable CAD has been a matter of continued controversy. As health care costs in our society rise, the decision to pursue expensive therapies such as PCI have come under close scrutiny.

This is in light of the fact that although PCI clearly has been shown to improve survival and reduce risk of nonfatal myocardial infarction in patients with acute coronary syndromes, similar results have not been replicated in patients with stable CAD. First line therapy for management of stable CAD includes lifestyle modification, dietary changes, exercise, smoking cessation, and aggressive medical therapy for control of lipids, hypertension, and diabetes.

Multiple large randomized controlled studies have been performed to understand the optimal approach to management of stable CAD. One of the most pivotal trials in this field was the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, which indicated that optimal medical therapy (OMT) was comparable to a combination of OMT+PCI in initial treatment of these patients.

However, most of these studies, including COURAGE enrolled a highly selected cohort of patients and thus, the applicability and generalizability of these findings to individual patients in daily clinical practice is a challenge. As we discuss further, a subgroup of patients with stable CAD may benefit from revascularization of hemodynamically significant coronary artery lesions and experience improvement in symptoms and quality of life.

Indications and patient selection

1. Persistent lifestyle-disabling anginal symptoms despite maximal medical therapy

2. Substantial ischemia on cardiac stress testing, such as significant ST segment changes, hypotensive response during early stages of the Bruce protocol, or presence of greater than 10% reversible ischemic myocardium on nuclear stress perfusion imaging.

3. Refractory anginal symptoms despite medical therapy and positive fractional flow reserve (FFR) testing (< or = 0.80) during cardiac catheterization

The COURAGE trial has been one of the largest trials to date that compared OMT to a combination of OMT+PCI in 2,287 patients with stable CAD. Although, it showed that PCI did not lead to a reduction in the risk of death or myocardial infarction when added to optimal medical therapy (19% in PCI group and 18.5% in OMT group at 4.6 years of follow-up), a statistically significant improvement was noted in anginal symptoms in patients undergoing PCI, the rates of which, however, were equalized within 5 years.

Another randomized study that shed light on the role of PCI in stable CAD was the FAME 2 trial. It studied 1,220 patients, out of whom 888 patients with >50% coronary artery stenosis were randomized to medical therapy versus PCI with drug-eluting stents if they had an FFR of <0.80.

The primary end point was a composite of death, myocardial infarction, or urgent revascularization. Recruitment was halted prematurely after enrollment of 1,220 patients (888 who underwent randomization and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary end-point event: 4.3% in the PCI group and 12.7% in the medical therapy group (hazard ratio with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P <.001).

The study concluded that in patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization.

Contraindications

Contraindications for PCI in stable CAD:

• Patients not currently on maximal medical therapy for CAD (less than two antianginal medications), unless intolerant
• Risk of PCI exceeds the benefit:Presence of chronic kidney disease and risk of renal failure/contrast nephropathy following intravenous contrast administrationHistory of bleeding diathesis, especially the history of recent major bleeding or intracranial hemorrhageCoronary arteries technically unsuitable or hazardous for PCI
• Patients with nonsignificant CAD in whom PCI would not be considered appropriate or indicated
• Low risk ischemia on noninvasive stress testing
• Left main disease or severe multivessel disease (with SYNTAX score of greater than 22)
• Severe noncardiovascular comorbidity limiting survival
• Inability to continue dual antiplatelet therapy for the recommended duration following PCI
• Unable to provide informed consent

Details of how the procedure is performed

Percutaneous coronary intervention involves revascularization of hemodynamically significant coronary artery stenosis. In the 1970s under the leadership of Andreas Gruntzig, a pioneer in this field, PCI started off as a procedure involving dilatation of high grade stenosis in coronary arteries with a balloon catheter. Over the last 3 decades, there has been tremendous progress in technology and pharmacotherapy in this field. In the current era, coronary stents are commonly used for revascularization of high-grade coronary artery stenosis.

The procedure consists of an initial coronary angiogram to evaluate the coronary artery anatomy and estimate the severity of stenosis. Vascular access for coronary angiography is usually either via the femoral or radial artery, although brachial artery access can also be used for selected cases.

Following coronary angiography, if a decision is made to proceed with PCI, the patients are anticoagulated with either intravenous heparin or bivalirudin infusion to decrease risk of periprocedural thrombosis. Generally, guidelines recommend proceeeding with PCI if the visual estimate of stenosis is clearly greater than 70%. However, if the stenosis appears to be between 50% and 70%, it is recommended to perform fractional flow reserve (FFR) testing to demonstrate hemodynamic significance of the stenosis before proceeding with revascularization.

The coronary artery is cannulated using a guiding catheter, and the stenosis is crossed with a 0.014 inch diameter coronary wire. Depending upon the severity of calcification present in the artery at the site of stenosis, the lesion is initially prepared for stenting by using a predilatation balloon catheter that is used to gently dilate the stenosis.

If the vessel appears to be heavily calcified, leading to difficult expansion of the balloon catheter, rotational atherectomy can be considered to facilitate adequate balloon expansion. Subsequently, a coronary stent is deployed across the stenosis and expanded with the help of the balloon catheter on which the stent is premounted.

The two most commonly used types of stents are bare-metal stents and drug-eluting stents. Drug-eluting stents have a polymer coating that is lined with a medication that tends to decrease risk of subsequent neointimal proliferation, thus decreasing the risk of restenosis. Following stent deployment, certain cases may require using another balloon catheter to postdilate the stent to achieve adequate apposition of the stent to the vessel wall. The most commonly used first-generation drug-eluting stents were Cypher (sirolimus coated) and Taxus (paclitaxel coated).

However, the second generation of drug-eluting stents are coated with either zotaralimus (Endeavor, Resolute) or everolimus (Xience, Promus). These stents are made of thinner struts and are more deliverable and have improved visibility on fluoroscopy. Newer coronary stents are being studied in randomized trials, some of which will have a bioabsorbable polymer coating or may be completely reabsorbed in the future.

Some additional tools used as an adjunct in decision making during PCI are FFR, intravascular ultrasound (IVUS), and optical coherence tomography (OCT). FFR is performed with the help of a specially designed 0.014-inch wire that has a pressure transducer before its tip.

The wire is placed across the site of stenosis in a coronary artery and helps in assessing pressure change across the stenosis. Maximal coronary vasodilatation is performed with the help of intravenous adenosine infusion to accurately assess the hemodynamic significance of the stenosis, and an FFR of less than or equal to 0.80 is generally accepted as significantly abnormal.

Intravascular ultrasound is also an important tool for imaging the coronary arteries to understand the characteristics of coronary plaque, estimating the severity of coronary stenosis, estimating the minimal luminal area (especially important for left main coronary stenosis), evaluation of coronary dissection, stent expansion and stent apposition.

Recently, OCT has been introduced as a modality for coronary artery imaging by placing a specially designed catheter in the coronary artery, which is advanced over a 0.014 coronary guidewire. OCT provides high resolution and excellent imaging of the coronary arteries and especially helps in imaging stent expansion, apposition, any stent fractures, presence of coronary dissection, and coronary plaque characteristics.

It is standard care to use dual antiplatelet therapy (DAPT) for all patients undergoing PCI, including the use of aspirin and another antiplatelet agent, which could include clopidogrel, prasugrel, or ticagrelor (though prasugrel and ticagrelor are not approved for use in stable patients). DAPT has been shown to reduce the risk of stent thrombosis after PCI.

Following completion of the procedure, the arterial access sheath is removed after the anticoagulation wears off and manual pressure is held to achieve adequate hemostasis, although some institutions prefer to use vascular closure devices for achieving hemostasis if the femoral artery anatomy is favorable. Most patients are recommended to maintain bed rest for 2 to 6 hours to decrease the risk of vascular complications following the procedure.

Interpretation of results

Revascularization with PCI is a strategy that complements medical therapy in selected patients with stable CAD. Efforts are needed to improve adherence to medical therapy, as per the COURAGE study standards.

In patients with refractory symptoms or significant ischemia on cardiac stress testing, PCI can help in improvement of anginal symptoms. FFR assessment should be increasingly used to aid in decision making regarding coronary revascularization in stable CAD.

By reducing angina and the need for urgent revascularization, FFR-guided PCI can lead to a better quality of life. The overall cost-effectiveness of the FFR-guided PCI approach over medical therapy was reported to be $53,000 per quality-adjusted life-year, which is comparable to some other widely accepted therapies. Data from some of the large observational studies performed recently with drug-eluting stents hint at possible survival benefit in patients with stable CAD following PCI; however, this finding has not been reported yet in any of the randomized controlled trials.

Outcomes (applies only to therapeutic procedures)

PCI is an important tool for symptomatic improvement in patients with stable CAD who have refractory angina despite maximal medical therapy with substantial ischemia demonstrable on cardiac stress testing or hemodynamically significant coronary stenosis on FFR assessment. However, none of the randomized studies so far have shown any survival benefit or reduction in MI in patients with stable CAD undergoing PCI.

The COURAGE trial randomized 2,287 patients with stable CAD (single vessel or more, >70% coronary stenosis and ischemia on EKG or cardiac stress test, or >80% stenosis and persistent symptoms) to OMT versus a combination of OMT+PCI. The study showed that PCI did not offer any survival benefit or reduction in MI in these patients.

However, a statistically significant improvement was noted in anginal symptoms in patients undergoing PCI, although the rates equalized within 5 years. A nuclear substudy of COURAGE was also reported subsequently and showed that 314 patients who underwent serial nuclear perfusion imaging had a significant reduction in the amount of ischemia (>5% reduction in ischemic myocardium ) following PCI, P <.0001. Also, these patients had lower rates of death or MI, but this study was not powered adequately to detect this outcome.

There were also certain caveats to COURAGE. In this study, patients were randomized based upon angiographic findings and patients with high-risk coronary anatomy were excluded from the study, such as left main coronary artery disease, EF <30%, concomitant valvular heart disease likely to require surgery, significant systemic hypertension (BP> 200/100 mm Hg unresponsive to medical therapy), and patients with restenosis of a lesion previously treated with a stent.

In addition, 32% of patients in the medical therapy arm in COURAGE crossed over to the revascularization arm over the follow-up period of 4.6 years due to worsening of symptoms or development of acute coronary syndrome. Drug-eluting stents were also used only in a small minority of patients in this study (2.9%).

Another large study that compared OMT to revascularization (PCI or CABG) in recent times has been the BARI 2D study. A total of 2,368 patients with diabetes were randomized to initial PCI or CABG versus OMT. At 5 years of follow-up, there was no difference in the primary endpoint of mortality or secondary endpoint of death, MI, or stroke.

Thus this study found that OMT is as effective as initial revascularization in patients with diabetes. However, in the medical therapy group, 42% of patients crossed over to the revascularization arm.

Fractional flow reserve has become an important tool in decision making regarding PCI in patients with CAD. This is based upon the FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study published in 2009 that randomly assigned 1,005 patients with multivessel coronary artery disease to undergo PCI with implantation of drug-eluting stents guided by angiography alone or guided by FFR measurements in addition to angiography.

Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions, whereas those assigned to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was 0.80 or less. The primary endpoint was the rate of death, nonfatal myocardial infarction, or repeat revascularization at 1 year. The 1-year event rate was 18.3% (91 patients) in the angiography group and 13.2% (67 patients) in the FFR group (P = .02).

Subsequently, the FAME 2 study was conducted to specifically study patients with stable CAD. In patients for whom PCI was being considered, all stenoses were assessed by measuring FFR.

Patients in whom at least one stenosis was functionally significant (FFR < or = 0.80) were randomly assigned to FFR-guided PCI plus the best available medical therapy (PCI group) or the best available medical therapy alone (medical therapy group). Recruitment was halted prematurely after enrollment of 1,220 patients (888 who underwent randomization and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary end-point event: 4.3% in the PCI group and 12.7% in the medical therapy group (hazard ratio with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P <.001).

The difference was driven by a lower rate of urgent revascularization in the PCI group than in the medical therapy group (1.6% vs. 11.1%; hazard ratio, 0.13; 95% CI, 0.06 to 0.30; P <.001); in particular, in the PCI group, fewer urgent revascularizations were triggered by a myocardial infarction or evidence of ischemia on electrocardiography (hazard ratio, 0.13; 95% CI, 0.04 to 0.43; P <.001). Thus the study concluded that in patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization.

In summary, optimal medical therapy remains the cornerstone for treatment of patients with stable CAD. PCI has an important role in treating patients with angina refractory to medical therapy.

With ongoing advances in PCI technology and antiplatelet therapy, better tools are needed to assess patients with stable CAD who will benefit from PCI. Further randomized controlled studies, especially the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), which will study 8,000 patients with at least moderate ischemia on stress imaging, and randomize patients to revascularization plus optimal medical therapy (OMT) or OMT alone, will hopefully answer some of these important questions.

Alternative and/or additional procedures to consider

An alternative option to PCI, which may be considered for a selected group of patients with stable CAD is coronary artery bypass graft surgery (CABG). CABG is generally reserved for patients with advanced coronary disease (complex two-vessel or three-vessel CAD, including chronic total occlusions, bifurcation disease, etc.). Several important publications of randomized controlled trials have been reported recently comparing CABG to PCI, although most of these trials have included both patients with stable CAD and acute coronary syndromes.

One of the recent trials comparing PCI to CABG was the SYNTAX trial (Synergy between PCI with Taxus and Cardiac Surgery trial), which randomized 1800 patients with three vessel CAD or left main disease to PCI with Taxus Express DES or CABG. Recently reported 3-year follow-up from SYNTAX shows that major adverse cardiac and cerebrovascular events were elevated in the PCI group [MACCE: death, stroke, myocardial infarction (MI), or repeat revascularization; CABG 20.2% vs. PCI 28.0%, P <.001], repeat revascularization (10.7 vs. 19.7%, P <0.001), and MI (3.6 vs. 7.1%, P = .002). Thus the SYNTAX trial concluded that CABG was superior to PCI, especially in patients with complex two-vessel or three-vessel CAD (SYNTAX score of >22).

Another large study comparing PCI to CABG in the diabetic population has been the FREEDOM trial. It included 1,900 patients enrolled from 2005 through 2010 who had diabetes and multivessel CAD. The study showed that primary outcome, a composite of death, nonfatal MI, or nonfatal stroke occurred more frequently in the PCI group (P = .005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. Thus CABG was found to be superior to PCI in reducing the rates of death and myocardial infarction, although CABG had a significantly higher incidence of stroke (5.4% vs. 2.4%).

Complications and their management

Complications of PCI:

1. Vascular complications

2. Death

3. MI

4. Stroke

5. Coronary dissection

6. Coronary perforation

7. Contrast nephropathy

8. Contrast allergy

The most common complications associated with PCI are vascular access related complications, which include bleeding, hematoma formation, retroperitoneal hemorrhage, pseudoaneurysm, or arterio-venous fistula. Vascular complications at the femoral artery access site can occur in up to 6% of cases.

Radial access has been reported to be associated with lower rates of vascular complications. In a meta-analysis published in 2009, radial access significantly reduced the rate of major bleeding (0.5 vs. 2.3). However, in the recently reported randomized RIVAL trial, there was no significant difference in the rate of composite of death, MI, stroke, or noncoronary artery bypass graft related major bleeding (3.7% vs. 4.0%) with radial versus femoral access, though there were fewer vascular complications.

Multiple coronary artery related complications can be associated with PCI; however, their frequency has decreased in the era of stents, especially coronary artery dissections and perforations, which used to be more frequent with balloon angioplasty alone. Complications specific to stents are the risk of stent thrombosis leading to acute myocardial infarction, infection, and stent embolization. Although most patients with coronary artery perforation can be managed with covered stents, occasionally emergent surgery may be required.

Stroke is a rare complication of PCI and occurs in less than 0.5% of cases. However, in patients with severe atherosclerotic disease or who require manipulation in the aortic arch and its branches, the stroke risk may be increased.

Other complications of PCI can include risk of contrast allergy/anaphylaxis, contrast-induced nephropathy leading to renal failure or requiring hemodialysis, and risk of radiation induced injury.

What’s the evidence?

Boden, WE, O’Rourke, RA, Teo, KK. “Optimal medical therapy with or without PCI for stable coronary disease”. N Engl J Med. vol. 356. 2007. pp. 1503-16. (This paper presents the main results of the COURAGE trial.)

“A randomized trial of therapies for type 2 diabetes and coronary artery disease”. N Engl J Med. vol. 360. 2009. pp. 2503-15. (This paper presents the main results of the BARI 2D trial.)

Shaw, LJ, Berman, DS, Maron, DJ. “Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy”. Circulation. vol. 117. 2008. pp. 1283-91. (This paper presents the nuclear substudy from the COURAGE trial.)

Tonino, PAL, De Bruyne, B, Pijls, NHJ. “Fractional flow reserve versus angiography for guiding percutaneous coronary intervention”. N Engl J Med. vol. 360. 2009. pp. 213-24. (This paper presents the main results of the FAME trial.)

Kappetein, AP, Feldman, TE, Mack, MJ. “Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial”. Eur Heart J. vol. 32. 2011. pp. 2125-34. (This paper presents the 3-year follow-up of the SYNTAX trial.)

Farkouh, ME, Domanski, M, Sleeper, LA. “Strategies for multivessel revascularization in patients with diabetes”. N Engl J Med. vol. 367. 2012. pp. 2375-84. (This paper presents the main results of the FREEDOM trial.)

De Bruyne, B, Pijls, NHJ, Kalesan, B. “Fractional flow reserve–guided PCI versus medical therapy in stable coronary disease”. N Engl J Med. vol. 367. 2012. pp. 991-1001. (This paper presents the main results of the FAME 2 trial.)

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