Medical Management is the Only Rational Approach

Washington Hospital Center has an annual case volume of approximately 15,000, and between four and five thousand are interventional procedures. There isn’t a toy or device we don’t use! Thus, I could easily discuss interventional cardiology, but to my surprise, I was asked to debate the merits of early medical management versus early invasive therapy, which Tom Maloney defends in his presentation, Early Intervention for All Patients. This morning’s presentation on the pathophysiology of acute coronary syndromes (Editor’s Note: James J. Ferguson III, MD of Houston, presented on this topic at ASOCC) offered an excellent overview of the subject. Let’s take that topic back now, to the clinical side, and divide cases into non-ST segment elevation and ST-segment elevation categories. The vast majority of non-ST segment elevation patients will be diagnosed with unstable angina or non-Q-wave myocardial infarction (MI). Very few of these patients actually go on to develop Q-wave MI. About five or six years ago, we thought that as long as there wasn’t a Q-wave MI, the patient did not require aggressive treatment. We essentially divided these cases into the bad category or not-so-bad category. However, today we look at these cases differently. The not-so-bad unstable angina, non-ST segment elevation MI cases account for roughly 70% of the 1.92 million annual emergency room visits for acute coronary syndromes (ACS) an overwhelming problem. Furthermore, it has become painfully apparent over the past several years that all types of clinical symptoms classified as ACS are associated with an increased risk of MI and cardiac death. Whether the patient ends up with a diagnosis of unstable angina or Q-wave MI, the risk assessment and the chances of a poor outcome are very high early on, which is not surprising, given what we have learned about the unstable and vulnerable plaque. How are we to look at our patients? We must first perform a risk assessment using one of two methods. The first is Braunwald’s classification, which is included in the Guidelines for the Treatment of Unstable Angina. The second are the recently revised guidelines published online (not yet in print) by the American Heart Association and the American College of Cardiology. These AHA/ACC revised guidelines contain 96 pages devoted to the management of ACS and that’s just unstable angina and non-ST segment elevation! Braunwald’s guidelines, shown in Figure 1, divide risk into high-, intermediate-, and low-risk categories and look at the patient’s history, presentation, pain, clinical assessment, ECG reading, and enzymes. Low-risk patients typically have no prior history. They will have new onset Canadian Classification III or IV symptoms during the past two weeks, but no episodes of prolonged pain generally lasting more than 20 minutes. The low-risk patients present clinically in very stable condition: they have no findings; they are not elderly or diabetic; their ECG shows no evidence of ischemia; their enzymes are normal; and they will probably not need to go to the cath lab. The high-risk patient would likely need intervention with aggressive medical management, stabilization, and possible treatment in the cath lab. Important Risk Assessment Guidelines from TIMI 11-B Risk assessment guidelines for unstable angina and non-ST segment elevation patients were also published in 2000, following the TIMI 11-B trial. In this trial, researchers looked at the risk factors that can be quickly assessed when the patient presents to the emergency department a situation where a detailed history on the patient is not usually available. The TIMI 11-B risk assessment guidelines are also applicable to new patients who are immediately referred to the cath lab. TIMI 11-B researchers identified seven risk factors, each one an independent predictor of acute events (MI, need for urgent revascularization, or death) within the next fourteen days (Figure 2). The guidelines identify patients with three or more cardiac risk factors and >= 65 years of age. Initially, the researchers looked at prior stenosis > 50%, but as the guidelines have been applied over time in other studies, it was found that if the patient has had a prior MI or CABG, or appears to have heart disease, these can be counted as risk factors as well. Other risk factors include any ST deviation, anginal events at least two or more within the last 24 hours, history of aspirin use within the last seven days, or an increase in cardiac markers. The guidelines assign one point for each risk factor that is present, and a zero if it is not. The risk assessment score is obtained by simply adding the risk factor points. The chance of an adverse event increases as the TIMI risk score increases. Management Pathways Of course, nothing is complete in interventional cardiology without clinical trials, which I will attempt to cover briefly here. Let’s look at what the various clinical trials to date have shown regarding the medical management of these patients. Activated platelets are looking for their friends to join together and form platelet thrombus in the vulnerable plaque. We now know that platelets are activated in many ways. ASA and ADP. First, let’s look at oral antiplatelets: aspirin, which inhibits the arachidonic acid pathway; and ticlopidine and clopidogrel, which are adenosine diphosphate (ADP) inhibitors. Aspirin, of course, is our trusted friend. We know that it inhibits thromboxane A2 and that it is a very weak but effective inhibitor of platelet activity. Aspirin has been available now for approximately one hundred years and its antithrombotic properties have been known since the 1930s. No study has ever shown aspirin to not be beneficial and thus it remains the standard treatment. Aspirin dosing is still the subject of debate, but there is no debate over the fact that medical management should begin with aspirin. Today there is increased use of the adenosine diphosphate antagonists ticlopidine and clopidogrel. I include clopidogrel due to the fact that it has increasingly become the drug of choice for ACS management, primarily because of the side effects experienced with Ticlid. Clopidogrel, like Ticlid, is an adenosine diphosphate receptor blocker, inhibiting one mechanism of platelet activation. The recently completed CURE trial actually had the indication for clopidogrel changed. The researchers looked at over 12,000 patients who received aspirin or clopidogrel 300 mg, then 75 mg plus aspirin. The primary endpoints were cardiac death, myocardial infarction, or stroke. The endpoints were decreased by 20% in the patients who received clopidogrel plus aspirin. Interestingly, clopidogrel plus aspirin proved to be beneficial in all subgroups, whether these were patients with unstable angina, non-ST elevation, or acute MI. The combination of clopidogrel plus aspirin is now indicated for the treatment of unstable angina and is standard treatment at the Washington Hospital Center. Thus, aspirin can be used to block arachidonic acid, and ticlopidine or clopidogrel can be used as adenosine diphosphate receptor blockers, but what about some of the other pathways? Inhibiting Thrombin Activation. It has long been known that the thrombin pathway is activated in ACS. Today, thrombin activation can be blocked with unfractionated heparins, low-molecular weight heparins, or direct thrombin inhibitors. In Figure 3, you can see that thrombin possesses an active site and two other binding sites (exosites). To inhibit thrombin activation, the active site must be blocked. Heparin must first combine with an antithrombin (AT) complex in order to block thrombin generation. However, the heparin-antithrombin complex can only block inactivated thrombin; it cannot inhibit the active site once the thrombin has become activated. What do we mean by activated? Once thrombin is located in the clot, there is a change in the shape of the active site. Now the heparin antithrombin complex cannot bind to thrombin. To solve this problem, many years were devoted to looking for more effective thrombin inhibitors. The result was the development of direct thrombin inhibitors, the first of which were hirudin and Bivalirudin. These direct thrombin inhibitors not only block the active site, but also block the exosite where fibrin joins. The newest direct thrombin inhibitor is Argatroban. Parenteral direct thrombin inhibitors, or IV direct thrombin inhibitors, were developed to overcome the inability of the heparin antithrombin complex to inactivate bound thrombin. Hirudin, which is extracted from the jaws and saliva of the medicinal leech, is sold exclusively by a farm in England. This website: www.biopharm-leeches.com offers two pages of facts about leeches. Leeches can measure up to 18 inches and have 32 brains. The Hirudo leech, from which hirudin is obtained, has three jaws with 100 teeth. Its bite is painless because it is equipped with its own anesthetic. After the leech drops off the wound, its direct thrombin inhibitor effects are quite potent. The wound continues to bleed for an average of 10 hours. Hirudin’s half-life in healthy volunteers is 60 minutes, cleared via the kidneys, which renders it unsuitable for patients with renal dysfunction. The results of the clinical trials with hirudin have been mixed. Where we have shown direct thrombin inhibitors to be the best approach, hirudin has not proved to be beneficial in many of the clinical trials involving unstable angina or Q-wave MIs in this patient population. If we are directly inhibiting thrombin, we pay the price of a significant increase in the risk for bleeding. As a result, other agents have been studied. Argatroban is a synthetic small molecule agent acting as a thrombin inhibitor and has no interaction with the heparin-induced thrombocytopenia (HIT) antibody, which is a concern. Argatroban has a slightly longer half-life of about 45 minutes. If the patient has liver dysfunction, the half-life could be a bit longer. Argatroban also has a rapid therapeutic effect and is now approved for patients with a history of HIT when treated with unfractionated heparin. Bivalirudin is a synthetic version of hirudin with a very short half-life of about 25 minutes. An agent with a short half-life is very attractive to this population of patients. It can be used where needed and if complications such as bleeding occur, the drug can be stopped and will quickly disappear. Renal clearance with bivalirudin is not the primary route, so it may also be safer in patients with renal dysfunction and we’re talking here about just an elevation of creatine, not full-fledged dialysis. Bivalirudin is the only direct thrombin inhibitor with an established indication for ACS and is one I have seen used increasingly at the Washington Hospital Center in all types of patients with unstable angina. Heparins have also been around for a long time. I will not discuss unfractionated heparin, as I am sure all of you have extensive experience with it. Low-molecular weight heparins such as enoxaparin have gained ground. In the ESSENCE and TIMI 11-B trials, standard unfractionated heparin was compared with enoxaparin. The ESSENCE trial showed a 16% decrease in death, MI, and recurrent ischemia, while the TIMI 11-B trial showed a 15% decrease in these events. Thus, enoxaparin appears to be a safe and effective drug and may eventually replace unfractionated heparin in patients with unstable angina. However, the agent’s limitation is apparent in cases where a patient needs urgent treatment in the cath lab. Currently, in PCI trials and in clinical practice, I have observed that when the decision is made to send the patient to the cath lab or to surgery for CABG, the low-molecular weight heparins are stopped, at which point unfractionated heparin is used, usually as a continuous infusion with a weight-based bolus. GP IIb/IIIa inhibitors. We have aspirin, Plavix, heparins, and direct thrombin inhibitors, but what about the final common pathway? An agent was needed that could effectively stop platelets from aggregating no matter which way they were activated. This problem led to the development and clinical use of a variety of glycoprotein IIb/IIIa inhibitors. The oldest, abciximab, is an antibody against IIb/IIIa, and is also referred to as the large molecule IIb/IIIa inhibitor; whereas tirofiban and eptifibatide are small molecule IIb/IIIa inhibitors. These agents do have different clinical properties. Tirofiban, a non-peptide antagonist, has shown a lower rate of death and myocardial infarction in many of the trials using tirofiban plus heparin or aspirin, or heparin and aspirin alone. Very early use of tirofiban led to a significant decrease in peak troponin, making it very effective in patients with unstable angina. However, there is a question about the need to initiate therapy early on with this agent. Studies have shown that if therapy with IIb/IIIa agents is initiated after 24 hours, there is no difference in clinical outcomes. There is a slightly increased risk of bleeding, but it is not typically severe. Eptifibatide is also a synthetic heptapeptide inhibitor the other small molecule IIb/IIIa inhibitor. The PURSUIT trial showed a reduction in the rate of death or myocardial infarction and an apparent increased benefit when administered earlier relative to the onset of pain. Also, no benefit was observed when treatment was initiated more than 24 hours out. The message we see emerging from the trials is that medical therapy can be very effective in these patients, but it is important that we identify the unstable angina patient versus the chest pain syndrome patient. Once we know that the patient has unstable angina or non-ST segment elevation, medical therapy must be initiated early in order to achieve optimal results. Abciximab, which is the monoclonal antibody fragment, has been studied extensively in trials such as EPIC and EPILOG. The GUSTO IV trial showed no benefit with abciximab in patients who did not undergo percutaneous coronary intervention. There is also some debate about whether abciximab may be a better IIb/IIIa inhibitor to use in diabetic patients, but that issue has not yet been settled. Abciximab has a much longer half-life than the other IIb/IIIa inhibitor agents, so it is difficult to reverse its effects. For these reasons, abciximab’s role in unstable angina is not yet clear. AHA 2002 Updated Practice Guidelines The 2002 Updated Practice Guidelines can be found on American Heart Association website (americanheart.org). (See also Figures 4“6) Their recommendations for the management of unstable angina and non-ST segment elevation include aspirin (you choose the dose), and either clopidogrel (load with 300“600 mg, then 75mg/day), or ticlopidine (load with 500 mg, then 250 mg b.i.d. The guidelines discuss unfractionated and low-molecular weight heparins such as enoxaparin and dalteparin (both are short-acting and weight-dosed agents). Low-molecular weight heparin offers a more predictable action than unfractionated heparin and usually does not require daily laboratory monitoring. Also included are intravenous antiplatelet agents, or IIb/IIIa inhibitors, with guidelines for abciximab, eptifibatide, or tirofiban loading. These agents are indicated for high-risk patients as defined by the Braunwald risk stratification guidelines. Evaluating Patient Risk Needs to be Our First Step I want to emphasize the point that we cannot consider these patients as just ACS patients. Rather, we must make risk stratification our first task in evaluating them. I think the TIMI risk score is an accurate and simple way to accomplish this task, as it does not require the memorization of a complex weighting or scoring method. The patients are either given one point or a zero for each risk factor. So which patients are high-risk and which are low-risk? Let’s look at Cannon (Figure 7): these are critical pathways based on the guidelines, which indicate that patients should be administered aspirin plus clopidogrel or ticlopidine. A low-molecular weight heparin is probably the best choice unless it is contraindicated. Beta-blockers and nitrates should also be given if the patient can tolerate them. Patients can then be divided into the low-risk or high-risk category. Low-risk patients have no ECG findings at presentation; their cardiac enzymes are negative, whether measuring CK-MBs or troponins; and their TIMI risk score is A Final Note Early conservative treatment is not bad. We can effectively manage the majority of unstable angina cases with aggressive medical treatment. Patients at low risk can be clinically monitored. Furthermore, some patients are clearly not candidates for revascularization, and a small number of our patients do not want intervention, so we must recognize that other treatment options exist for them. Finally, I would like to remind you not to leave the emergency department without your medications!

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