The PROMISE Trial, like any aptly named study chose an acronym meant to inspire. In this case, the hope for a better tomorrow. And though the authors of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain trial were not clear on the specific details their promise entailed, I fear the results of this trial will leave us feeling betrayed and forsworn.
The authors of the PROMISE Trial presented the findings from their massive undertaking at the 2015 ACC scientific assembly. The results were published simultaneously in the NEJM. Douglas et al randomized 10,003 patients to either standard non-invasive functional testing, as determined by the treating physician, or CTCA. Patients were recruited from outpatient facilities across North America when presenting with new onset chest pain in which the treating physician was suspicious of cardiac origin and had already ruled out ACS. Patients were excluded if they presented with unstable vitals, EKG changes, or positive biomarkers. Given the pragmatic nature of the trial, all other treatment decisions were left to the prerogative of the treating physician (1).
The authors found no difference in their primary outcome, the composite endpoint of death, MI, hospitalization for UA, or major procedural complications over the followup period (at least 12 months with average follow up of 24 months), between the CTCA and traditional testing groups (3.3% vs 3.0%). In fact other than a small decrease in the amount of negative invasive catheterization seen in the CTCA arm (3.4% vs 4.3%), the authors were unable to find any statistically significant differences in the multitude of secondary endpoints measured. As far as safety outcomes, the authors did cite some relevant concerns. Most notably those randomized to receive CTCA as their screening test underwent significantly more downstream testing and interventions. 12.2% of those randomized to the CTCA arm compared to 8.1% in the standard testing arm underwent invasive catheterization, 6.2% compared to 3.2% underwent subsequent revascularization including a 1.5% vs 0.76% rate of coronary artery bypass grafting (CABG) (1).
Now some might argue that the PROMISE trial was not performed on Emergency Department patients and thus its application to our low risk chest pain population is questionable. In some senses this may be true. Patients evaluated in the Emergency Department for chest pain are inherently at higher risk than their counterparts seen in primary care offices. Conversely the PROMISE Trial evaluated a cohort of chest pain in whom the treating physician suspected the symptoms were likely of cardiac origin. Before being enrolled in the trial all of these patients were ruled out for ACS with negative EKGs and biomarkers. Additionally the treating physician felt further provocative testing was necessary. This is not unlike the cohort of patients we include in our low-risk chest pain population in the Emergency Department. Furthermore we have four trials with over 3,000 Emergency Department patients evaluating the efficacy of CTCA, which demonstrate almost identical results to the PROMISE Trial (2,3,4,5). Each of these studies determined that CTCA adds no additional prognostic value to our standard risk stratification strategies and likely leads to increased invasive procedures. In a meta-analysis of these four trials published in JACC in 2013, Hulten et al found a significant increase in the number of invasive angiographies, PCIs and revascularizations performed in the patients randomized to the CTCA arm (6). PROMISE demonstrated the exact same tendencies of CTCA in a much larger cohort (1).
Why did PROMISE fail to find a difference? What are we to infer about the acuity and severity of a disease state that does not benefit from a timely and accurate diagnosis? We know CTCA is far more accurate than our more traditional forms of provocative testing. And yet, why in this massive trial did it fail to find any difference in clinically relevant outcomes? Might it be that a time-sensitive anatomical definition of CAD is unnecessary?
The first reason why PROMISE failed to show a difference is that the population enrolled in the trial was at such low risk for the disease state in question, they are likely to do well whatever diagnostic testing strategy they undergo. Only 3.1% of the group had any event during the follow-up period. Only 1.5% died and only 0.7% had a MI (1). With such a low event rate, even if CTCA is an effective means of identifying and preventing MI and cardiac death, a statistically significant benefit is unlikely to be found even with a sample size as large as 10,000 patients.
The second reason why the PROMISE Trial is likely to have failed, is simply because we are functioning under the misconception that when we diagnose these patients with obstructive CAD, an invasive strategy is superior to optimal medical management. Though we know that reperfusion therapy has objective benefits in patients actively experiencing a myocardial infarction, these same benefits have failed to translate to the more stable lesions of CAD. Multiple large RCTs have failed to find a benefit of PCI over optimal medical management in patients with stable obstructive CAD (7,8). Stergiopoulos et al have now published a number of meta-analyses examining these trials, which have also failed to uncover benefits that may have been missed in the weaker powered individual trials (9,10).
The PROMISE trial was not the only trial presented at the ACC Scientific Assembly examining the pragmatic use of CTCA for the diagnostic work up of chest pain. The SCOT-HEART trial was yet another massive undertaking, the results published online in The Lancet in concert with the oral presentation. In this trial, investigators enrolled 4,146 patients referred to chest pain clinics across Scotland, to either a standard work up or a standard work up plus the addition of CTCA. Although by sheer quantity it does not possess the statistical s of the PROMISE trial, it does present us with some insights, which the PROMISE trial proved incapable of providing(11).
The unique design of the SCOT-HEART trial insured all patients received a full standardized evaluation, often including (85% of the time) an exercise stress test. It was only after the treating physician assessed the patient, reported his or her baseline estimate of the likelihood of CAD and determined what further testing and treatment strategies he or she would recommend, that the patients were randomized to either receive CTCA or standard care. Like PROMISE, this was a pragmatic trial design and other than the use of CT angiography clinicians were given free rein to treat each patient as they deemed appropriate. At 6 weeks the physicians were then asked again to assess the likelihood of CAD(11).
What the authors revealed was that the use of CTCA significantly improved the clinicians confidence in their diagnosis of both CAD and angina of cardiac origin (the trial’s primary endpoint). They also found a statistically significant increase in the number of patients diagnosed with CAD in the group randomized to receive CTCA (23% vs 11%). Additionally patients in the CTCA arm were more frequently shifted towards more aggressive and invasive modes of management when compared to the standard care arm. Specifically more patients in the CTCA group saw an increase in number of medical therapies prescribed and invasive catheterizations performed (11).
In summary, patients randomized to CTCA were more often given the diagnosis of CAD and were more likely to be treated with medical therapies and invasive procedures than the patients in the standard care group. But did all of these investigations and interventions lead to better outcomes? Simply put no. The rate of cardiovascular death and myocardial infarction during the follow up period (1.7 years) was 1.3 vs 2.0, a 0.7% non-statistical difference. The overall mortality was 0.8% vs 1.0%, respectively. Even the decrease in the quality and severity of the patients’ symptoms (the reason the patients presented to the clinic in the first place) at 6-weeks, was identical (11).
The PROMISE trial demonstrated the use of CTCA promotes increased downstream testing and intervention. The SCOT-HEART trial validated these findings. The SCOT-HEART trial also demonstrated CTCA provides a significant degree of diagnostic certainty to the treating physician, leading to more aggressive medical management. And yet knowing a lot and doing a lot failed equate to a reduction in mortality or myocardial infarctions. These are coronary mirages, promising the weary clinicians water when in reality they are just leading them deeper into the barren desert.
Despite its size and decisively negative results, perhaps the most important study arm in the PROMISE Trial did not exist, an arm in which patients were randomized to not receive any form of provocative testing, but rather treated medically as per the judgment of their physician. Both the PROMISE and SCOT-HEART trials demonstrated that a cohort of outpatient chest pain patients are at such low risk for adverse events, they are likely to do equally as well with whatever provocative test is used, or more importantly without any at all. Surely it is time to examine such a hypothesis, to add a third arm to the PROMISE cohort. The ISCHEMIA Trial is currently enrolling patients to compare medical management vs invasive strategies in the setting of a positive provocative test. Unfortunately this trial’s applicability is limited by the fact that authors insist all patients undergo a CTCA before enrollment to rule out the presence of left main arterial disease. And though this may be a step in the right direction, we still can’t escape our need for anatomical certainty in the face of diminishing clinical utility. Surely it is time we define the value of both provocative and anatomical testing in the low risk chest pain population, truly a Promise worth keeping.
- Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372(14):1291-300.
- Goldstein JA, Chinnaiyan KM, Abidov A, et al. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Tri- age of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol 2011;58:1414–22.
- Hoffmann U, Truong QA, Schoenfeld DA, et al. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med 2012;367:299–308.
- Litt HI, Gatsonis C, Snyder B, et al. CT Angiography for safe discharge of patients with possible acute coronary syndromes. N Engl J Med 2012;366:1393–403.
- Goldstein JA, Gallagher MJ, O'Neill WW, Ross MA, O'Neil BJ, Raff GL. A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol 2007;49:863–71.
- Hulten E, Pickett C, Bittencourt MS, et al. Outcomes after coronary computed tomography angiography in the emergency department: a systematic review and meta-analysis of randomized, controlled trials. J Am Coll Cardiol. 2013;61:(8)880-92.
- 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(15):1503-16.
- Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005;293(23):2908-17.
- Stergiopoulos K, Brown DL. Initial Coronary Stent Implantation With Medical Therapy vs Medical Therapy Alone for Stable Coronary Artery Disease: Meta- analysis of Randomized Controlled Trials. Archives of Internal Medicine 2012 Feb;172(4):312
- Stergiopoulos K, Boden WE, Hartigan P, et al. Percutaneous Coronary Intervention Outcomes in Patients With Stable Obstructive Coronary Artery Disease and Myocardial Ischemia: A Collaborative Meta-analysis of Contemporary Randomized Clinical Trials. JAMA Intern Med. 2014;174(2):232-240.
- The SCOT-HEART investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel group multicenter trial. Lancet. 2015; (published online March 15.)