Early Intervention for All Patients

Tom Maloney MS, RCIS, FSICP
Tom Maloney MS, RCIS, FSICP
I have been given the task of defending the position of early invasive therapy against that of early conservative therapy. My goal is to take the clinical trial data and incorporate it into our everyday practice. I believe that the concept of early intervention is well-tried and proven in the clinical trial arena. I will discuss the management of acute coronary syndromes (ACS), otherwise known as unstable angina and non-ST-elevation myocardial infarction (MI). Let’s start with the patient admitted to the emergency department, where intensive anti-ischemic agents are administered: nitrates, beta-blockers, antiplatelet agents, and anti-coagulants. If this type of patient experiences recurrent ischemia despite aggressive medical therapy, he will be sent to the cath lab (often at 3:00 am). The controversy behind this debate centers on the 83% of the patient population who become symptom-free on this medical regimen. Do we: a) Take the conservative route, whereby if they break through medical therapy, patients are then taken to the cath lab (called the selective invasive approach)? or; b) Do we take all of the patients to the cath lab and perform percutaneous coronary intervention (PCI) if needed? Finding Supportive Data for Early Intervention I consulted the AHA/ACC Acute Coronary Syndromes Guidelines, which I assumed would provide the answers to help my argument for early intervention. Obviously, the early invasive strategy is included in these guidelines for patients with hemodynamic instability, sustained ventricular tachycardia, or recurrent ischemia, all examples warranting an early invasive approach. However, again, what about the 83% of the patient population who don’t meet these criteria? In the absence of these high-risk factors, the AHA/ACC guidelines state that either early conservative or early invasive therapy would be appropriate. I found four clinical trials that compared early conservative therapy against early invasive therapy. 1. Figure 2 shows the incidence of death and myocardial infarction. The red bar graph represents the patient group that underwent early invasive treatment; the blue bar graph represents the group that received early conservative therapy. A p-value of Visting the Scene. I decided to look at the actual therapy and what happens when it is applied. Figure 3 demonstrates the time dependency of medical therapy in acute myocardial infarction. When reperfusion therapy is initiated early on, 100% benefit is achieved, showing the importance of getting acute MI patients to the hospital quickly. As time goes on, the slope descends all the way to 0% benefit for early conservative therapy at 12 hours. We can conclude that medical therapy is effective but importantly, time-dependent. Figure 4 was also presented by Sue Apple and shows the death and MI rates in the IIb/IIIa inhibitor trial PURSUIT. It also shows that if patients receive therapy early (After Drug Therapy. What happens when patients are on drug therapy and then it is stopped? The answer is that many of them will experience rebound ischemia. Figure 5 shows patients who are on heparin and have a very low incidence of myocardial infarction (8“18%). When the early conservative pharmacologic therapy is stopped for these patients, however, event rates skyrocket rather precipitously to four times greater for myocardial infarction. While patients are on medical therapy, they do well, but as soon as that therapy is stopped, they tend to do poorly. In order to medically manage the problem of rebound ischemia, the patient would essentially need to have an I.V. in his hand at all times, including when he leaves the hospital. At home, he would need the wound care assistance of visiting nurses as well as an I.V. pole which, incidentally, costs about $120. So if I were the patient, I would probably question the benefits of persistent medical therapy. Early Invasive Therapy: Patient Subgroups I would now like to discuss early invasive therapy the stenting approach beloved by balloonatics. 0-12 hours or > 12 hours. Let’s look at the results of NRMI-2: Primary PCI Time-to-Treatment vs. Mortality (Figure 6). The white line on Figure 4 represents neutral benefit; anything crossing that line is not significantly different. The yellow box represents the majority of the patient population; the yellow line is the confidence interval, which represents where all patient subjects’ results fall. You will note that the time period to treatment with balloon or stent, whether 0“12 hours or > 12 hours, is non-significant because the confidence interval cross the line of neutral benefit. Therefore, it does not matter when the patient receives invasive therapy it matters that they receive invasive therapy. What about patients who have not been managed for > 12 hours? Dr. William French and colleagues state that if patients have not been medically managed with fibrinolytics, they will derive little benefit, possibly even harm, beyond the 12-hour time period. They also state that when the invasive approach (Figure 7, shown in red) is compared with the conservative approach (shown in yellow), the invasive approach is favored. There is a greater reduction in recurrent ischemia, an equal reduction in reduced MI rates, and a significantly greater reduction in death rates. The Elderly. Another very high-risk subset of patients is the elderly population. The TIME trial looked at 305 patients > 75 years of age who had chronic angina and were currently on a long-term regimen of two or greater anti-anginal medications. The results show that despite their high-risk profile, an early invasive assessment and possible PCI provided the greatest benefit. Taking a Step Back. We don’t just see the elderly or patients arriving after 12 hours from onset. Rather, we see the entire spectrum of patients. The Swedish MIR and MITRA registry data started with 22,000 patients and narrowed the study down to assess 10,000 patients (patients with contraindications for thrombolysis were excluded.) Patient populations were then divided into those who received early intervention and those who received early conservative therapy. The numbers are much greater for thrombolysis treatment because in Europe, a greater percentage of patients are treated conservatively with medical therapy due to a lack of cath labs (thrombolytics, n = 8579 vs. primary angioplasty, n = 1327). What happened in these registries regarding all of the different patient characteristics we’ve been discussing? Figure 8 shows that for all the different patient subgroups, PTCA is better by approximately 46%. Stenting. Stenting, as you know, now accounts for the vast majority of interventional procedures. In the STAT trial (Figure 9), the stenting group (blue line) shows that 80% of patients were event-free (no death or MI) after stenting, versus 40% of patients who received tPA instead. Important for hospital administrators in particular is the length of stay bar graph in Figure 9, which demonstrates a three-day length-of-stay difference favoring the early invasive approach a considerable cost savings for the hospital. Some conclusions can be made at this point: Late mortality appears to be independent of time in PCI because it does not matter when the patient has the procedure, as long as he has the procedure. Multiple subgroups favor the invasive strategy with a shorter length of stay as one of the advantages. There are also the secondary factors favoring PCI: - Prevention of LV dilatation; - Prevention of arrhythmias; - Provides a good source of collateral flow. Remember the trial data I showed earlier? One win, one loss, two ties. How can that be explained? The trials I cited, TIMI 3B, VANQWISH, MATE, and FRISC-2, were conducted several years ago, when stents and IIb/IIIa inhibitors were not readily available and time to cath was longer. A Modern-Day Answer: TACTICS-TIMI 18 At this point in 2002, American centers have performed a total of 700,000 PCI procedures. 80% involve stent implantation; 60% of those stented receive IIb/IIIa inhibitors; 17% of the patients arriving in the cath lab are on IIb/IIIa inhibitors. The TACTICS-TIMI 18 trial represents the modern-day answer to early invasive versus early conservative therapy. Every patient came in with ACS; every patient in this trial received aspirin, heparin, and a IIb/IIIa inhibitor. Half of the patients had early conservative therapy and half underwent early invasive therapy. At six months, the results (Figure 11) showed that 22% fewer patients suffered death, MI, and rehospitalization for ACS. Again, hospital administrators will be happy to note that regardless of the approach, it was a financial wash (Figure 12). The early invasive approach, in fact, appears to be cost-neutral, despite the use of expensive stents, balloons, catheters and wires. This is because the early conservative group that received no intervention returned later within that six-month period to undergo intervention. Facilitated PCI: An Answer? What, then, does the future hold? The AHA/ACC guidelines may now need revision to reflect the findings from the TACTICS-TIMI 18 trial. However, in Sue Apple’s presentation, Medical Management is the Only Rational Approach, she presents overwhelmingly convincing data favoring medical therapy up front for the ACS patient population. Yet balloon angioplasty, as I have shown, also provides substantial benefit early on. What would happen if we combined these two therapies in a concept called facilitated PCI, instead of pitting them against each other? A period of up-front medical therapy prior to invasive therapy may provide the greatest benefit in ACS and acute MI. This combination strategy may not favor one individual strategy, but instead a combination strategy. Figure 13, a hypothetical model, represents patients with acute MI who receive thrombolytic therapy. 1. For those patients who receive thrombolytic therapy (in red), 50% will have a good, brisk TIMI 3 flow rate (a measurement of the percentage of flow through a coronary artery) at 90 minutes. 2. If a IIb/IIIa inhibitor is combined with a thrombolytic, there will be a 77% TIMI 3 flow rate. 3. If the patients undergo balloon angioplasty, they will achieve a 93% TIMI 3 flow rate at 90 minutes. However, there is a gray zone. What would happen if we combined the effectiveness of early medical therapy with balloons at a later point? This entire gray zone could be eliminated by taking out the time deficit for PCI to be performed. This hypothesis is not proven, but is now actively being studied to determine if it will indeed become the gold standard of treatment. The recently published RIKS-HIA registry involves 61 Swedish hospitals, very few of which have stent capability. This registry, which is very similar to the NRMI-type database, studied a cohort of 22,000 acute MI patients from 1995 to 1998. It looked at the conservative and the invasive therapy arms. The data come as no surprise: the early invasive approach is shown to be superior to conservative therapy. The p-value is