Our obsession with diagnostic certainty has led us down many false paths and blind alleyways in the history of medicine. This statement has never been more true than when spoken in regards to cardiovascular health. The small successes that we have obtained when treating the highest acuity patients have been enthusiastically and incorrectly applied across the entire spectrum of coronary artery disease. Focusing too much on the anatomical definition of this disease state has limited our true understanding of the pathological process causing heart disease and in turn limiting our comprehension of how best to intervene. Despite a large body of evidence contradicting the theory, we have held fast to the “clogged pipe” model.
PCI found its initial success in the treatment of ST elevation myocardial infarctions, the most clinically obvious pathological end result of cardiovascular disease. In such cases we discovered that this invasive procedure was only slightly better than our systemic attempts to open the stenotic vessel using aspirin and thrombolytic therapy (1). In fact most data comparing PCI to thrombolytics in patients suffering from acute ST elevation MIs revealed that you had to treat close to 50 people with cardiac catheterization for one to benefit (1). Considering that thrombolytic therapy is only moderately better than aspirin alone, maybe the pedestal we have currently reserved for PCI in the management of ACS is not deserved (2).
The COURAGE trial, appropriately named for challenging the doctrine that coronary artery disease is best managed through invasive techniques, compared the efficacy of PCI vs “optimal” medical management in patients with stable coronary artery disease (3). The authors randomized patients with EKG evidence of ischemia at rest or ischemia induced by some form of provocative testing, with at least one culprit lesion of 70% occlusion or greater, to either PCI or medical management. Essentially the very patients we hope to identify through admission and provocative testing. No difference was found in the rates of death or MI during the follow up period (median 4.6 years) in the patients who received PCI vs those who underwent medical management (3).
These findings are consistent throughout the literature examining PCI vs medical management in patients with stable coronary artery disease. In a meta-analysis by Stergiopoulos et al of all 13 trials examining this question no difference could be found between medical management or aggressive interventional procedure (4). Even patients that are enzyme positive but otherwise clinically stable, no definitive benefits have been demonstrated with aggressive utilization of PCI. In fact when urgent PCI is empirically mandated, there is an increase in early mortality (5). In Emergency Department patients who have been ruled out for acute disease by EKG and enzymes, further evaluations for anatomic disease not only identify diminishingly small amounts of true positives but the interventions proposed do not result in clinically meaningful improvements in outcomes. Clearly we have overreached our meager successes and applied a crash procedure to a far different pathology than where it originally found it’s success.
This obvious lack of efficacy has not gone unnoticed. Many have suggested the need for a more refined method of identifying high risks lesions that would benefit from an invasive approach. Fractional Flow Reserve (FFR) is a technique that has been proposed as the answer to clarify which lesions would benefit from stent placement. This invasive technique is performed in concert with standard PCI and allows the interventionalist to assess the flow of blood before and after the stenotic lesion. These values are turned into a ratio in the hopes of numerically quantifying coronary flow. Anything under 0.80 is determined to be an ischemic stenosis and as such would benefit from the placement of a stent. Despite its physiologic plausibility, trials examining its efficacy have been less than stellar. The initial two studies, DEFER and FAME, comparing FFR-guided PCI to traditional PCI demonstrated a decreased rate of myocardial infarctions at 2 year follow-up (6,7). Initially these results seem to be in favor of FFR guided PCI but upon closer inspection the data reveals that the difference in the groups primarily consisted of a decrease in procedure related events. Suggesting that the only benefit FFR provides is to inhibit the ocular-stenotic reflex, quite prevalent in the modern Interventional Cardiologist (8). Neither of these studies address the important question, how does FFR-guided PCI compare to conservative medical management alone?
Introducing FAME-2. Like COURAGE before it, FAME-2 sought to answer the question whether FFR adds anything to medical management alone. The preliminary data was published in 2012 after the trials was halted prematurely (9), but the official 2-year follow-up results were recently published in the NEJM (10). Authors randomized patients with angiographic stentable lesions, with either classic anginal symptoms or positive findings on provocative testing after a negative ED workup, to either standard medical management or FFR-guided PCI. The authors utilized a composite endpoint of cardiovascular death, MI, or urgent revascularization. The trial was stopped early after enrolling only half its intended sample size, 1220 patients, due to an unacceptable number of events that occurred in the medical management group. Taken at face value this seems like an overwhelming approval of FFRs clinical utility. Long awaited proof that downstream testing after a negative ED workup results in clinically important benefits. A justification for the substantially large quantity of low-risk patients we admit to the hospital each day. Despite these seemingly positive results this trial does not justify our risk adverse strategy. Though there was a 11.4% absolute difference in the rate of primary events (8.1% vs. 19.5%) that occurred between the groups, this margin consisted entirely of an increased frequency of urgent revascularizations. There was no difference in the number of deaths or MIs that occurred between the groups. The majority of these excess revascularizations were due to persistent symptoms, demonstrating this claimed efficacy was primarily due to our biases rather than any overwhelming benefit of FFR-guided PCI.
Clearly FFR does not provide us with the clarity we seek. Even the theoretical ground FFR stands upon is thin as the ischemic threshold we currently use was derived by comparing FFR values to a gold standard of non-invasive perfusion imaging, a test with questionable clinical value (11). FFR may very well still play a role in the management of coronary artery disease, but its relevance in the management of ACS is insignificant.
How this changes the long-term management of coronary artery disease is unclear, but what is becoming increasingly apparent is an anatomic definition of coronary disease, following a negative Emergency Department work up for the diagnosis of ACS, provides no further clinical benefit. A number of trials have demonstrated that the addition of angiography or CT angiography add nothing to further risk stratify these patients (12-16). The rate of true positive disease in this cohort is diminishingly low (17). Even when the rare patient is found to truly have anatomically defined disease, direct invasive interventions add little clinical benefit over aggressive medical therapy. Anatomic investigation may very well remain an important component in the management of cardiovascular disease. Not to identify those patients that would truly benefit from cardiac catheterization, but to distinguish which patients require aggressive medical management. Surely this is not a priority in the Emergency Department evaluation of ACS.
More than ever we require a practical outlook when it comes to resource application in Emergency Medicine. Trying harder and doing more rarely lead to improved patient oriented outcomes. In the case of Emergency Department management of ACS it is imperative we admit that our current strategy has failed. We are striving to identify an exceedingly rare population in the hopes of offering an intervention which provides insignificant patient oriented benefits. Despite our technical mastery, technological advances, and intellectual mashinations, PCI remains a crash procedure that has only demonstrated proven benefit in the sickest cohorts of CAD. Outside the confines of ST- elevation MI we have yet to identify a population who consistently benefit from this invasive approach to management. Continually insisting on titling against the massive windmill that is Heart Diseae with a lance poorly equipped for this purpose, has led us too far down the path of madness. Surely its time to turn around and start the long walk back to sanity…
- Cucherat M, Bonnefoy E, Tremray G. Primary angioplasty ver-sus intravenous thrombolysis for acute myocardial infarction. Cochrane Database Syst Rev. 2000;2:CD001560.
- ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349-60.
- 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.
- 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
- 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.
- Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105-2111
- Tonino PA, De bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-24.
- Bradley SM, Spertus JA, Kennedy KF, et al. Patient selection for diagnostic coronary angiography and hospital-level percutaneous coronary intervention appropriateness: insights from the national cardiovascular data registry. JAMA Intern Med. 2014;174(10):1630-9.
- De bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991-1001.
- De bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014;371(13):1208-17.
- Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703-1708
- deFilippi CR, Rosanio S, Tocchi M, et al. Randomized comparison of a strategy of predischarge coronary angiography versus exercise testing in low-risk patients in a chest pain unit: in-hospital and long-term outcomes. J. Am. Coll. Cardiol. 2001;37(8):2042-2049
- 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(8):863-71
- Goldstein JA, Chinnaiyan KM, Abidov A, et al. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol. 2011;58(14):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(4):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(15):1393-403
- Hermann LK, Newman DH, Pleasant WA, et al. Yield of routine provocative cardiac testing among patients in an emergency department-based chest pain unit. JAMA Intern Med. 2013;173(12):1128-33.
University of Maryland
Resuscitation Fellowship Graduate
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