Review of the RITA-2 trial

Coronary angioplasty versus medical therapy for coronary artery disease

Lancet 1997;350(9076):461-468

Background: In the ACME trial, percutaneous transluminal coronary angioplasty (PTCA) improved symptoms in patients with single-vessel stable coronary artery disease, but it did not lead to reduction in myocardial infarction or mortality, which were not primary endpoints and the study was under powered for these endpoints. The available data on the efficacy of PTCA for reducing hard endpoints were limited. Moreover, the findings from surgery trials had been inconsistent, as discussed in prior reviews.

The second Randomized Intervention Treatment of Angina (RITA-2) trial sought to test the hypothesis that coronary angioplasty compared to medical therapy improves outcomes in patients with coronary artery disease.

Patients: Eligible patients were recruited from the United Kingdom and Ireland. Patients had to have significant stenosis amenable to dilation, in at least one major coronary artery. A significant coronary lesion was defined as a 50% or greater diameter stenosis in at least two radiographic projections or at least 70% diameter stenosis in one projection.

Patients were not required to have current symptoms. Patients with multivessel coronary disease, occluded coronaries or who had abnormal left ventricular function were allowed to be enrolled, as well as patients with unstable angina if the most recent episode was at least 7 days before randomization. Patients were excluded if they had left main disease, prior revascularization procedure or recent myocardial infarction.

Baseline characteristics: There were about 70,000 patients who underwent coronary angiogram during the recruitment phase. Around, 2,750 patients were eligible and among them 1,018 were randomized – 504 randomized to the PTCA arm and 514 to the medical therapy arm. The main reasons for not randomizing eligible patients were clinician’s decision or patient’s refusal.

The average age of enrolled patients was 58 years and 82% were men. Approximately 47% had prior myocardial infarction and 9% took medications for diabetes.

Approximately 20% reported no angina at the time of randomization. Single-vessel coronary artery disease was present in 60% of the patients, 2-vessel in 33% and 3-vessel in 7%.

Approximately 87% were taking aspirin, 13% were taking lipid lower drugs, 67% were taking beta-blockers, 50% were taking calcium channel blockers, and 44% were taking long acting nitrates.

Procedures: Patients were randomized to coronary angioplasty or medical therapy. Randomization was stratified by center, extent of coronary disease and the presence of recent unstable angina. PTCA was to be performed within 3 months of randomization. In patients with multivessel disease, not all lesions had to be dilated. Multivessel dilatation could be staged over more than one procedure. Conventional balloon dilatation was the intended strategy, but stents were permissible if the initial angioplasty result was unsatisfactory.

Aspirin was recommended in all patients. Lipid lowering drugs were prescribed at the discretion of the treating physician.

Patients were followed at 3 months, 6 months, then yearly.

Endpoints: The primary endpoint was a composite of all-cause death or non-fatal myocardial infarction at 5-years. Secondary endpoints included unstable angina, heart failure, arrhythmias, angina based on the Canadian Cardiovascular Society classification, anti-anginal drug use, and exercise duration on a symptom-limited treadmill test.

Analysis was performed based on the intention-to-treat principle. The sample size to achieve 80% power at an alpha level of 0.05 was 1,400. This was based on the assumption that the event rate of the primary outcome is 15% at 5-years in the medical arm, and that PTCA would reduce the primary outcome by 33%. The study enrolled less patients than planned due to slow recruitment.

Results: The median follow up time was 2.7 years. Among the 504 patients randomized to PTCA, the procedure was performed in 417 (93%) patients. Among the 514 patients randomized to medical therapy, 118 (23%) underwent PTCA or coronary bypass surgery.

PTCA increased the risk of the primary composite outcome (6.3% vs 3.3%, RR: 1.92, 95% CI: 1.08 – 3.41; p= 0.02). This difference was primarily driven by more non-fatal myocardial infarction with PTCA (4.2% vs 1.9%; p value not provided). All-cause death was not significantly different between both groups (2.2% with PTCA vs 1.4% with medical therapy; p= 0.32).

No significant differences noted in unstable angina (9.9% with PTCA vs 9.1% with medical therapy; p value not provided), heart failure (1.6% with PTCA vs 2.9% with medical therapy; p= 0.15) or arrhythmias (3.0% with PTCA vs 1.4% with medical therapy; p= 0.08).

Symptoms improved significantly in both treatment groups. The improvement in symptoms was greater with PTCA at 3 months (16.5% more patients with grade 2+ angina in the medical arm; p< 0.0001) but the difference was smaller at 2 years (7.6% more patients with grade 2+ angina in the medical arm; p= 0.02). These differences disappeared at 3 years. More patients in the PTCA arm were not taking anti-anginal medications at 3 years (36.2% vs 13.8%). PTCA led to greater improvement in exercise time compared to medical therapy but the differences were small (mean difference favoring PTCA was 35s at 3 months and 25s at 1 year).

No subgroup analysis was provided for the primary outcome.

Conclusion: In patients with coronary artery disease without recent myocardial infarction, PTCA compared to medical therapy worsened the primary outcome of all-cause death or non-fatal myocardial infraction with a number needed to harm of approximately 33 patients over 2.7 years follow up. This difference was largely due to more non-fatal myocardial infarction in the PTCA arm. PTCA led to greater improvement in symptoms at 3 months but there were no significant differences at 3 years.

Read the results above and compare our conclusion with the authors’ conclusion: [In patients with coronary artery disease considered suitable for either PTCA or medical care, early intervention with PTCA was associated with greater symptomatic improvement, especially in patients with more severe angina. When managing individuals with angina, clinicians must balance these benefits against the small excess hazard associated with PTCA due to procedure-related complications].

Medical and percutaneous interventions for coronary artery disease have advanced since the publication of this trial. However, reviewing older trials remains crucial to understand the evolution of the cardiology field and why certain interventions are no longer used. Studying the history of these treatments is important because it sheds light on how current practices have been shaped.

This trial serves as a reminder that a bias toward interventions exists in medicine; the authors’ conclusion downplayed the harms associated with PTCA while emphasizing its potential benefits for symptom relief, even though this was not the primary outcome and is highly subject to bias based on the study design. The trial also has reporting bias; subgroup analysis was not provided for the primary outcome but rather for the secondary endpoints of symptom relief and exercise tolerance. Additionally, the effects of PTCA on symptom relief and exercise tolerance were reported at various time points that seem to have been chosen to emphasize the protentional benefits of PTCA.