The benefit of percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) is undisputed. Clinical trials like DANAMI-2 (DANish Acute Myocardial Infarction 2),1-3 PRAGUE-2 (Primary Angioplasty in AMI Patients from General Community Hospitals Transported to PTCA Units vs Emergency Thrombolysis),4,5 STAT (Stenting Versus Thrombolysis in Acute Myocardial Infarction),6 AIR PAMI (Air Primary Angioplasty in Myocardial Infarction),7 Stent Versus Thrombolysis for Occluded Coronary Arteries in Patients With Acute Myocardial Infarction (STOPAMI)-1,8 and STOPAMI-29 have demonstrated better outcomes with primary PCI over fibrinolysis. Other clinical trials10-14 have demonstrated superiority of PCI over sole medical therapy for non-ST elevation myocardial infarction (NSTEMI) and unstable angina.
In contrast, there is ambiguity surrounding the benefit of elective PCI in stable coronary disease. The available evidence suggests no prognostic advantage over optimum medical therapy but deeper data scrutiny indicates that this remains uncertain. COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation),15 BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes),16 and ISCHEMIA (Initial Invasive or Conservative Strategy for Stable Coronary Disease)17 are the main trials that examined this issue, all concluding against the prognostic usefulness of elective PCI. We argue that those studies contained inherent flaws that impacted on their results, thereby rendering their final conclusions unreliable. We suggest an alternative design for a new trial so the question can be answered decisively, once and for all.
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This study compared PCI plus optimal medical therapy with optimal medical therapy alone. There were 2,287 patients enrolled: 1,149 patients were equally randomised to receive PCI or medical therapy, testing all-cause mortality and myocardial infarction (MI) over a median of 4.6 years. The cumulative primary-event rates were not significantly different between the two groups (p=0.62). The same was the case for the composite of death, MI, and stroke (p=0.62); acute coronary syndrome (ACS) hospitalisation (p=0.56), or MI (p=0.33). The trial concluded that elective PCI confers no prognostic benefit over medical therapy alone. However, we observed the following facts:
- Although 36,000 patients were screened, only 3,071 (8.6%) met the eligibility criteria and 2,287 (6.3%) were randomised. This indicates selective inclusion, which constrains the generalisation of the findings.
- 15.7% of the PCI arm were either not treated or did not complete follow-up. Conversely, 97 (8.5%) of the medical therapy arm were lost to follow-up. Furthermore, while the medical therapy group started the trial with little or no angina symptoms (80% were almost angina free), 32% of them ended up having PCI during the follow-up period for worsening angina symptoms, which negates the investigators’ claim that angina control was similar in the two trial arms. We also note that the trial design pre-specified that no more than 10% of the medically treated patients would cross over to PCI in the first four years.18
- COURAGE is an outlier in concluding that PCI is similar to optimum medical therapy in controlling stable angina. Other trials have demonstrated the opposite.19-24 This is probably because most participants had little or no angina to begin with.
- All-cause mortality as a primary end point was another methodology flaw, for PCI would not be expected to reduce non-cardiac mortality in comparison with medical therapy. During follow-up, 85 patients died in the PCI group compared with 95 patients in the medical therapy group (total of 180 patients). Of this total, only 48 deaths (26.7%) were later confirmed to be cardiac. It is unclear how many of those cardiac deaths belonged to the PCI group.
This trial compared coronary revascularisation with sole medical therapy in patients with type 2 diabetes and stable coronary disease: 2,368 patients were randomised. Primary end points were all-cause mortality and a composite of death, MI, or stroke. Randomisation was further stratified according to the choice of revascularisation, either PCI or coronary artery bypass grafting (CABG). Patients were excluded if they required immediate revascularisation or had left main coronary disease, class III or IV heart failure, or if they had PCI or CABG within the previous 12 months. Patients in the revascularisation group underwent the procedure within four weeks after randomisation, whereas patients in the medical-therapy group were to undergo revascularisation only if they experienced progression of angina or suffer an ACS event.
At five years, rates of survival and freedom from major cardiovascular events did not differ significantly between the two arms (p=0.97 and 0.70, respectively). There was no significant difference in primary end points between the PCI subgroup and the medical-therapy group, while there was a significant difference in favour of the CABG subgroup over medical therapy (p=0.002). Therefore, the investigators concluded that PCI had no prognostic benefit over medical therapy in diabetic coronary disease patients. However, we have observed the following facts:
- Of the 1,176 participants randomised for revascularisation, the decision to perform either PCI or CABG was determined by the cardiologists’ discretion and not by further randomisation. Thus, compared with the PCI arm, the CABG arm contained a much higher risk group (59.7% vs. 37.2% myocardial jeopardy, 52% vs. 20% three-vessel coronary disease, 19% vs. 10% proximal left anterior descending [LAD] disease, and 0.84 vs. 0.48 mean number of chronic total occlusions).
- The five-year mortality among patients assigned to medical therapy in the CABG stratum was higher (16.4%) than that among patients assigned to medical therapy in the PCI stratum (10.2%). Therefore, the PCI group was disadvantaged by being judged against a much lower risk medical therapy comparator, which explains the resultant failure of PCI to demonstrate prognostic value in such a low-risk event group.
- Over the five-year follow-up period, 42.1% of the medical therapy arm ended up receiving coronary revascularisation (either CABG or PCI) because of uncontrolled angina or ACS. As such, the trial seemed more of a comparison between prompt versus delayed revascularisation, at least for those 42.1% of patients.
The research question here was: “In stable patients with at least moderate ischemia on a stress test, is there a benefit to adding cardiac catheterisation and, if feasible, revascularisation to optimal medical therapy?”. There were 8,518 patients enrolled, but only 5,179 of them were randomised for either conservative (2,591 patients) or interventional (2,588 patients) treatment, namely PCI or CABG. The primary end point was time to cardiovascular (CV) death (defined as deaths attributed to either cardiac or vascular causes), MI, hospitalisation for unstable angina (UA), heart failure (HF) or resuscitated cardiac arrest (ReCA). In the revascularisation arm, 74% of the patients received PCI while the remaining 26% received CABG.
Some primary end points showed no statistical difference between medical therapy and revascularisation, including cumulative CV death, MI, UA, HF and ReCA (p=0.50), CV death alone (p=0.33), all-cause mortality (p=0.67), cumulative MI (p=0.38) and ReCA (p=0.98). On the other hand, hospitalisations for UA (p=0.02) and HF (p<0.01) were shown to be statistically different in favour of the revascularisation arm. The trial concluded that, in patients with stable angina, revascularisation provided no prognostic benefit over medical therapy. Notwithstanding this, closer data review reveals the following facts:
- The trial excluded high-risk patients, including those with significant left main disease and severe left ventricular systolic dysfunction, who would naturally be expected to benefit the most from revascularisation. As such, mostly the lower risk stable angina patients were included, whose expected five-year risk of morbidity and mortality with optimum medical therapy would be low to begin with, thus making it statistically harder for revascularisation therapy to demonstrate significant benefit in such a cohort.
- Cardiovascular death as a primary end point was a methodology flaw, for coronary revascularisation would NOT be expected to reduce vascular yet non-cardiac mortality (e.g. death from stroke or ischaemic bowel) in comparison with medical therapy. The trial did not measure cardiac death alone as an end point, so it remains unclear as to how many of those cardiovascular deaths in the PCI arm were actually cardiac in origin.
- While the cumulative MI incidence was shown to be similar in both groups, the trial used different troponin cut-off values for different types of MI. The troponin value for diagnosing post-PCI MI was set at >35 times the upper limit of normal (ULN), while for post-CABG MI it was set at >70 times ULN. This inequality disadvantaged the PCI group in comparison with the CABG group.
- The incidence of MI in the revascularisation arm was higher than that of the medical therapy arm in the first two years, which could be explained by asymptomatic post-procedural troponin release that reached the cut-off point for MI diagnosis, particularly in the PCI group, since their cut-off value was lower. In contrast, the subsequent two years witnessed a higher incidence of spontaneous MI in the medical therapy group, thereby indicating that revascularisation had helped provide some protection against spontaneous MI during that period of time. The two MI occurrences, pre- and post-two years, were offset against each other to produce the non-statistically significant cumulative MI incidence (p=0.38), which we argue is difficult to interpret and contextualise.
- In the medical therapy arm, 28% of the patients ended up receiving cardiac catheterisation and 23% actually received coronary revascularisation by four years, either to control incessant angina or to treat ACS.
The lesson from COURAGE, BARI 2D and ISCHEMIA is that optimal medical therapy should be provided to all patients with stable coronary disease while interventional treatment can be added if needed. Moreover, a significant percentage of stable coronary disease does not immediately progress into ACS and, therefore, it is safe to not perform PCI upfront, but defer it for when angina worsens or if ACS develops, hence, the importance of close follow-up of medically treated patients. Elective PCI seems to provide better control of angina symptoms compared with sole optimum medical therapy, and it also seems to reduce the future incidence of ACS. The mortality data from the three trials contained uncertainties, hence, rendering unreliable any conclusions drawn. The impact of elective PCI on ‘cardiac’ mortality remains controversial. We suggest a new three-armed clinical trial to randomise stable angina patients eligible for coronary angiography to receive optimum medical therapy alone or in combination with either PCI or CABG. The trial must include patients with higher risk cardiac profiles, like those with left main stenosis or poor left ventricular systolic function. The three arms must have comparable baseline characteristics and the primary end point should be ‘cardiac’ mortality only, NOT all-cause or cardiovascular mortality.
Conflicts of interest
1. Andersen HR, Nielsen TT, Rasmussen K et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction (DANAMI-2 Investigators). N Engl J Med 2003;349:733–42. https://doi.org/10.1056/NEJMoa025142
2. Thune JJ, Hoefsten DE, Lindholm MG et al. Simple risk stratification at admission to identify patients with reduced mortality from primary angioplasty. Circulation 2005;112:2017–21. https://doi.org/10.1161/CIRCULATIONAHA.105.558676
3. Busk M, Maeng M, Rasmussen K et al. The Danish multicentre randomized study of fibrinolytic therapy vs. primary angioplasty in acute myocardial infarction (the DANAMI-2 trial): outcome after 3 years follow-up. Eur Heart J 2008;29:1259–66. https://doi.org/10.1093/eurheartj/ehm392
4. Widimský P, Budesínský T, Vorác D et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial – PRAGUE-2. Eur Heart J 2003;24:94–104. https://doi.org/10.1016/S0195-668X(02)00468-2
5. Widimský P, Bilkova D, Penicka M et al. Long-term outcomes of patients with acute myocardial infarction presenting to hospitals without catheterization laboratory and randomized to immediate thrombolysis or interhospital transport for primary percutaneous coronary intervention. Five years’ follow-up of the PRAGUE-2 trial. Eur Heart J 2007;28:679–84. https://doi.org/10.1093/eurheartj/ehl535
6. Le May MR, Labinaz M, Davies RF et al. Stenting versus thrombolysis in acute myocardial infarction trial (STAT). J Am Coll Cardiol 2001;37:985–91. https://doi.org/10.1016/S0735-1097(00)01213-4
7. Grines CL, Westerhausen DR Jr, Grines LL et al. Transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002;39:1713–19. https://doi.org/10.1016/S0735-1097(02)01870-3
8. Schömig A, Kastrati A, Dirschinger J et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. N Engl J Med 2000;343:385–91. https://doi.org/10.1056/NEJM200008103430602
9. Kastrati A, Mehilli J, Dirschinger J et al. Myocardial salvage after coronary stenting plus abciximab versus fibrinolysis plus abciximab in patients with acute myocardial infarction: a randomised trial. Lancet 2002;359:920–5. https://doi.org/10.1016/S0140-6736(02)08022-4
10. Sorajja P, Gersh BJ, Cox DA et al. Impact of delay to angioplasty in patients with acute coronary syndromes undergoing invasive management: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2010;55:1416–24. https://doi.org/10.1016/j.jacc.2009.11.063
11. Riezebos RK, Ronner E, Ter Bals E et al. Immediate versus deferred coronary angioplasty in non-ST-segment elevation acute coronary syndromes. Heart 2009;95:807–12. https://doi.org/10.1136/hrt.2008.154815
12. Montalescot G, Cayla G, Collet JP et al. Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial. JAMA 2009;302:947–54. https://doi.org/10.1001/jama.2009.1267
13. Navarese EP, Gurbel PA, Andreotti F et al. Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: a systematic review and meta-analysis. Ann Intern Med 2013;158:261–70. https://doi.org/10.7326/0003-4819-158-4-201302190-00006
14. O’Donoghue M, Boden WE, Braunwald E et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2008;300:71–80. https://doi.org/10.1001/jama.300.1.71
15. Boden WE, O’Rourke RA, Teo KK et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/NEJMoa070829
16. BARI 2D Study Group, Frye RL, August P et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. https://doi.org/10.1056/NEJMoa0805796
17. Maron DJ, Hochman JS, Reynolds HR et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395–1407. https://doi.org/10.1056/NEJMoa1915922
18. Boden WE, O’Rourke RA, Teo KK et al. Design and rationale of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial Veterans Affairs Cooperative Studies Program no. 424. Am Heart J 2006;151:1173–9. https://doi.org/10.1016/j.ahj.2005.08.015
19. Hueb W, Lopes NH, Gersh BJ et al. Five-year follow-up of the Medicine, Angioplasty, or Surgery Study (MASS II) – a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9. https://doi.org/10.1161/CIRCULATIONAHA.106.625475
20. Hueb WA, Bellotti G, de Oliveira SA et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses. J Am Coll Cardiol 1995;26:1600–05. https://doi.org/10.1016/0735-1097(95)00384-3
21. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992;326:10–16. https://doi.org/10.1056/NEJM199201023260102
22. Henderson RA, Pocock SJ, Clayton TC et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003;42:1161–70. https://doi.org/10.1016/S0735-1097(03)00951-3
23. Bavry AA, Kumbhani DJ, Rassi AN et al. Benefit of early invasive therapy in acute coronary syndromes – a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006;48:1319–25. https://doi.org/10.1016/j.jacc.2006.06.050
24. Pitt B, Waters D, Brown WV et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–6. https://doi.org/10.1056/NEJM199907083410202