Chronic stable angina percutaneous coronary intervention versus medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S.

Overview

An increased risk of mortality and morbidity is associated with untreated coronary artery disease. The main aim of therapy in patients with chronic stable angina is to alleviate symptoms, delay the progression of atherosclerosis, reduce the incidence of adverse coronary events and improve prognosis. This may be achieved with either initial medical therapy or with initial revascularization that includes percutaneous coronary intervention or coronary artery bypass grafting. Medical therapy alleviates symptom and improves prognosis; however, on the contrary, revascularization procedures provide symptomatic relief but generally does not improve mortality.

PCI vs Medical Therapy

Limitations of Older Trials

There are some reservations to the application of results from older trials to the current clinical practice. Listed below are a few of the important limitations.

• The patient population evaluated in older trials was confined to patients with preserved left ventricular function and focal coronary artery disease. It is therefore, difficult to generalize the same results in patients with diffuse coronary artery disease and/or patients with left ventricular dysfunction.

• The majority of the patients evaluated in earlier trials underwent coronary angioplasty alone without stenting and even in a few trials prior to COURAGE that compared the benefit of PCI with concurrent bare-metal stenting; involved patients who did not receive the current optimal medical regimen and lifestyle intervention. The rate of progression of native coronary artery disease adversely affects the clinical outcome. Regardless of the treatment strategy employed, all patients with coronary artery disease should receive aggressive risk factor modification which includes low dose aspirin, blood pressure control, lipid control, tobacco cessation, weight loss, regular exercise and glycemic control.

Clinical Trial Data: PCI vs Medical Therapy

Based on the six-major randomized clinical trials such as ACME trial (1992 & 1997), RITA-2 trial (1997), AVERT trial (1999), and MASS-II trial (2004) the success rates for PCI varied between 80% and 100% and the associated complication rates varied between 0.01% and 2.8% for MI and between 1.5% and 2.8% for the need of immediate CABG.

The patient population evaluated in these trials had a preserved left ventricular function with an EF range that varied between 65% and 76%. The medical therapy in all trials included the administration of anti-platelet agents, beta-blockers, nitrates, calcium channel blockers and only the AVERT trial used an initial aggressive lipid-lowering therapy.

PCI has not been found to reduce the risk of death, myocardial infarction or other major cardiovascular events when used along with medical therapy as part of initial management in patients with stable coronary artery disease.

More recent literature provides comparison between the use of stents and medical management; however, there are a few data examining the extensive use of drug eluting stents and current extensive anti-thrombotic regimens (clopidogrel and GP IIb/IIIa inhibitors). In the most recent COURAGE trial, drug-eluting stents were used in only 15 percent of patients. However, the COURAGE trial has the data most applicable to the current practice. You can read more detail about the COURAGE trial, here.

Randomized Controlled Trials

• In the ACME trial (1992), approximately 107 patients with stable single-vessel CAD with mean ejection fraction of 65%, non-Q wave MI within 3-months, ischemia evidenced by ST segment depression greater than 3mm on exercise stress test and no history of previous PCI, were assessed to compare the effects of PCI with medical therapy on angina and exercise tolerance in patients with single-vessel CAD. Successful dilatation was achieved in 82%. The study demonstrated that PCI significantly reduced the incidence of anginal symptoms compared to medical therapy (50% angina free in PCI group versus 24% in medically treated group) at one month and a sustained significant benefit was observed at 6 month follow-up (64% angina free in PCI group versus 46% in medically treated group; p=less than 0.01). Patients treated with PCI were associated with better exercise duration of 2.1 minutes which was significantly greater than the 0.5 minute experienced in the medically treated group (p=less than 0.0001). However, complications related to PCI was the incidence of MI (1.0%), non-Q wave MI (3.0%) and need for CABG (2.0%). Thus, the study concluded that PCI offered earlier and more complete relief of angina than medical therapy and was associated with a better exercise tolerance.

• In a sub-study (1998) that assessed the long-term effectiveness of PCI for single-vessel CAD, during a mean follow-up of 2.4 year for interview and 3.0 year for exercise testing after randomization, reported a significant angina-free period observed with the PCI group in comparison to the medically treated group (62% versus 47%; p=less than 0.05). Furthermore, exercise duration as measured by treadmill testing was prolonged by 1.33 minutes over baseline in the PCI group, whereas it decreased by 0.28 minutes in the medical group (p=less than 0.04). Thus, the study demonstrated sustained benefits with PCI similar to the ACME trial; hence, making it an attractive therapeutic option.

• In the ACME trial (1997), approximately 328 patients with chronic stable angina with mean ejection fraction of 66%, presence of MI within the last 3-months, ischemia evidenced by ST segment depression greater than 3mm on exercise stress test and no history of prior PCI, were assessed to compare the effects of PCI with medical therapy on angina and exercise tolerance in patients with double-vessel CAD. Successful dilatation was achieved in 69%. At 6-month follow-up, PCI-treated and medically treated patients with double-vessel disease demonstrated comparable improvement in exercise duration (+1.2 versus +1.3 min, respectively; P=0.89), freedom from angina (53% versus 36%, respectively; P=0.09) and improvement of overall quality of life score (+1.3 versus +4.4, respectively; P=0.32). Trends present at 6 months persisted at late 2-3 year follow-up. Patients undergoing double-vessel dilation had less complete initial revascularization (45% versus 83%), greater average stenosis of worst lesions at 6-months (74% versus 56%) and demonstrated less improved myocardial perfusion imaging (59% versus 75%). Thus, contrasting the greater advantages that favored PCI by these criteria in patients with single-vessel disease (P=0.0001 to 0.02).

• The AVERT trial (1999), demonstrated that in patients with low-risk for coronary artery disease, an initial aggressive lipid-lowering therapy aimed at reversing plaque growth and promoting plaque stabilization, had significantly prolonged the time to first ischemic event (p=0.03) when compared to PCI and standard medical therapy. Hence, in low-risk patients with stable CAD, it is beneficial to start with medical therapy and reserve revascularization strategies for non-responders.

• Another randomized study (2004) that assessed PCI versus exercise training in patients with stable CAD, demonstrated a 12-month program of regular physical exercise resulted in a significant benefit in the event-free survival (88% versus 70% in the PCI group; p=0.023) and the improvement in exercise capacity was achieved at a much lower cost (to gain 1 CCS class, 6956 dollars was spent in the PCI group versus 3429 dollars in the training group; p= less than 0.001).

• Major trials such as the RITA-2 and MASS-II, which used PCI as a method of revascularization reported similar rates of mortality and MI incidence observed in both the PCI and medically treated groups. However, the incidence of angina during the initial few years were significantly reduced in the PCI groups.

• The RITA-2 trial (1997) compared the long-term effects of PCI and conventional medical therapy in patients with CAD, demonstrated an early intervention with PCI was associated with greater symptomatic improvement, particularly observed in patients with more severe angina. However, on the contrary, the primary composite end-points during a median 2.7 year follow-up was significantly higher in patients treated with PCI than in patients treated with medical therapy (6.3% in the PCI group versus 3.3% in the medically treated group; p=0.02).

• The quality of life did not improve significantly in the PCI group in comparison to the continued medical therapy group at 3-year follow-up. However, the substantial improvement in the physical functioning, vitality and general health observed with the PCI group at both 3-month and one-year follow-up was attributed to the alleviation of symptoms.

• At 7-year follow-up, similar rates of mortality and MI were observed in both the groups (14.5% in the PCI group versus 12.3% in the medically treated group; 95% CI -2.0% to +6.4%; p=0.21). However, there was sustained improvement in angina and exercise tolerance noted in the PCI group.

Meta-analysis

• A 2000 meta-analysis of six randomized controlled trials that assessed the benefit of PCI versus medical treatment for patients with non-acute coronary heart disease, reported that PCI may lead to a greater reduction in angina in patients with CAD in comparison to medical therapy; however, sufficient patients were not included to assess the effect of PCI on MI, death, or subsequent revascularization.

• A 2005 meta-analysis of 11 randomized studies involving 2950 patients with stable CAD reported no significant difference between the PCI and medical therapy strategies with regard to mortality, incidence of MI or subsequent revascularization. However, a possible survival benefit was seen with PCI only in trials that involved patients with recent myocardial infarction (RR 0.40; 95% CI 0.17 to 0.95). Except for PCI during follow-up, there was no significant between-study heterogeneity for any outcome.

• The results of the COURAGE trial were reflected in meta-analysis listed below.

• A 2009 meta-analysis, assessed 61 PCI randomized trials involving 25,338 patients to compare the effect of PCI/PTCA (with BMS or DES) versus medical therapy in the management of patients with non-acute CAD. In all direct or indirect comparisons, succeeding advancements in percutaneous coronary intervention did not produce detectable improvements in the rate of mortality or myocardial infarction incidence. The risk ratio for indirect comparisons between DES and medical therapy was 0.96 (95% CI 0.60-1.52) for death and 1.15 (0.73-1.82) for myocardial infarction. Thereby, the results from this meta-analysis strengthened the strategy of initial management with optimal medical therapy before resorting to revascularization with PCI.

• A 2010 meta-analysis of 14 randomized trials evaluated the evidence of angina-relief from PCI compared to medical therapy in patients with stable CAD. The study reported that more patients were angina free after PCI than compared to medical therapy alone (OR 1.69; 95% CI, 1.24 to 2.30). The incremental benefit of PCI observed in recent trials (OR 1.13; CI, 0.76 to 1.68 ) was substantially reduced in comparison to older trials performed before the year 2000 (OR 3.38; CI, 1.89 to 6.04).

• A 2012 meta-analysis of 8 randomized trials established no evidence of benefit of use of initial stent implantation for stable coronary artery disease compared with initial medical therapy for prevention of death, non fatal MI, unplanned revascularization, or angina. The respective event rates for death with stent implantation and medical therapy were 8.9% and 9.1% (OR, 0.98; 95% CI, 0.84-1.16); for nonfatal MI, 8.9% and 8.1% (OR, 1.12; 95% CI, 0.93-1.34); for unplanned revascularization, 21.4% and 30.7% (OR, 0.78; 95% CI, 0.57-1.06); and for persistent angina, 29% and 33% (OR, 0.80; 95% CI, 0.60-1.05).