Choosing a management option for ACS

An expert reviews antiplatelet, antithrombotic, and invasive options.

The typical patient with acute coronary syndrome (ACS) has a constellation of familiar symptoms, such as radiating chest pain or pressure that is often associated with dyspnea, abdominal pain, or nausea. But don't overlook the atypical presentations, advised Marlene S. Williams, MD, during her ACP CME 30 talk, “Management of Acute Coronary Syndromes.”

Photo courtesy of Dr Williams
Photo courtesy of Dr. Williams

“There are those who present atypically, specifically those who are older age and those who are diabetics, and they can present with, for example, indigestion or epigastric pain or even a stabbing-like pain,” said Dr. Williams, who is an associate professor and cardiac ICU director at Johns Hopkins Bayview Medical Center in Baltimore.

A diagnosis of ACS is more often missed with atypical presentations—23.8% of such patients missed versus 2.4% of those with typical symptoms, according to the GRACE study, which was published in CHEST in August 2004, Dr. Williams said—and mortality rates may be higher. “Appropriate treatment is often withheld because of the atypical presentation,” she said.

As part of her talk, Dr. Williams reviewed the appropriate treatments for non-ST-segment-elevation ACS, the cornerstones being antithrombotic therapy, antiplatelet therapy, and coronary revascularization.

Antithrombotic therapy

Antithrombotic therapy in addition to antiplatelet therapy is recommended for all patients, regardless of whether their early treatment is invasive or conservative, she noted.

One option, unfractionated heparin, has a long history of use, and response is easily assessed with a partial thromboplastin time. “The con is that there's some variable response, and it really should be weight-adjusted,” Dr. Williams said. Also, she said, “There's a small percentage of patients that develop heparin-induced thrombocytopenia and therefore cannot be treated with unfractionated heparin.”

Low-molecular-weight heparin has been found to be superior to unfractionated heparin in patients with ACS, Dr. Williams said. However, its effect must be measured through heparin Xa levels, which cannot always be readily assessed in laboratories, and it cannot be given to patients who have a creatinine clearance of less than 30 mL/min. In addition, it requires renal adjustment.

Bivalirudin, a direct thrombin inhibitor, has been proven effective in patients with ACS who go on to require percutaneous coronary intervention (PCI), Dr. Williams noted. “It can be used for patients who develop heparin-induced thrombocytopenia, but it's quite expensive, and its use has really significantly decreased of late,” she said.

Antiplatelet therapy

“All patients with acute coronary syndrome should be on aspirin,” Dr. Williams said. Current guidelines from the American Heart Association and the American College of Cardiology recommend 162 to 325 mg of nonenteric-coated chewable aspirin at initial presentation, then 81 to 162 mg/d indefinitely thereafter. She noted that patients taking dual antiplatelet therapy should be on the lower end of the range for long-term aspirin therapy: 81 mg/d based on U.S. guidance and 75 mg/d in Europe.

Other antiplatelet options include clopidogrel and prasugrel, P2Y12 inhibitors that act as ADP receptor antagonists. Because clopidogrel and prasugrel are prodrugs, Dr. Williams explained, they need to be intestinally absorbed and then metabolized into their active form to take effect. “The key point to understand in regards to clopidogrel and prasugrel is . . . metabolism,” she said.

Eighty-five percent of clopidogrel is converted by esterases to an inactive form, so only 15% goes on to the active form to bind the ADP receptor, Dr. Williams said. Prasugrel, in contrast, is completely metabolized to its inactive form by esterases but is then converted again through the cytochromes to 100% of its active metabolite. Both drugs are irreversible ADP receptor blockers.

Another antiplatelet agent, ticagrelor, is not a prodrug but is directly active, is intestinally absorbed, and binds to an alternate area of the P2Y12 receptor. Because of this, its effects are reversible, Dr. Williams said. Cangrelor, meanwhile, is the only ADP receptor blocker that is delivered intravenously and is used when a patient is not a candidate for oral therapy, she noted.

Dr. Williams reviewed the three major industry-funded trials of clopidogrel, prasugrel, and ticagrelor in patients with ACS, all of which were published in the New England Journal of Medicine (NEJM). The CURE trial, published in 2001, compared clopidogrel to placebo in 12,562 patients presenting with ACS. Those who received clopidogrel had a 20% relative risk reduction in myocardial infarction (MI), stroke, and death but an increased risk of both major and minor bleeding.

Prasugrel was assessed in the TRITON-TIMI 38 trial, which was published in 2007 and compared aspirin and clopidogrel with aspirin and prasugrel in 13,600 patients with ACS. There was a 13% reduction in MI, stroke, and death with the latter combination, as well as a significant reduction in stent thrombosis, although major and minor bleeding were again increased. Of note, patients who were older than age 75 years or who weighed less than 60 kg did not have a reduction in the combined end points, and patients who had either transient ischemic attack or a history of stroke had increased mortality. “Therefore, there was a black-box warning placed on prasugrel for these three categories of patients,” Dr. Williams said.

In the PLATO trial, which was published in 2009, 18,624 patients presenting with ACS were treated with either aspirin and ticagrelor or aspirin and clopidogrel. Patients in the ticagrelor group had a 23% reduction in death, MI, and stroke and a significant reduction in stent thrombosis. “And unlike clopidogrel and prasugrel, there was a 22% reduction in all-cause mortality. The other agents had not previously shown that,” Dr. Williams said. No increase was seen in major bleeding with ticagrelor, but minor bleeding was more common, as was dyspnea, she said.

Dr. Williams also discussed the use of the ADP receptor antagonists in different clinical situations. “We know that for loading in patients who are going on to percutaneous coronary intervention, you need to use 600 mg of clopidogrel,” she said. For medical management only, the loading dose is 300 mg, and the maintenance dose is 75 mg/d. Clopidogrel has an onset of action of two hours or less with the higher loading dose, she noted, and patients' response to the drug can vary because of how it is metabolized. “The important thing with clopidogrel is that it's generic, and that comes into play in terms of patients' ability to afford the medications,” Dr. Williams said.

For prasugrel, the loading dose before PCI is 60 mg, and the maintenance dose is usually 10 mg, Dr. Williams noted. The drug has a short onset of action of about 30 minutes. Prasugrel is contraindicated in patients who have had transient ischemic attack or stroke, and as TRITON-TIMI 38 showed, those older than age 75 years and those weighing less than 60 kg derive no net benefit. “If you're less than 60 kg, [guidelines] suggest [a dose of] 5 mg, but this was not studied in the trials,” she said.

For ticagrelor, the loading dose is 180 mg for patients who will receive medical management, as well as for those proceeding to PCI. Onset of action is 60 minutes. One important note is that the aspirin dose needs to be decreased below 100 mg/d in order for ticagrelor to be effective, Dr. Williams said. Although ticagrelor is the only drug shown to decrease all-cause mortality, patients may stop taking it due to dyspnea. Bradycardia and ventricular pauses may also occur and cause patients to stop the drug, she noted.

“So because we have options—clopidogrel, prasugrel, and ticagrelor—it's important to know, how do we switch between these agents?” Dr. Williams said. A study published in the American Heart Journal in 2017 followed 8,672 patients post-MI for a year and found that drug switching was not very common, with only 7.6% changing therapy. However, most of the patients who did switch were taking ticagrelor, followed by prasugrel and clopidogrel, with the main reason for switching being cost, she said. “As I mentioned to you before, clopidogrel is generic, and the other two are not,” she said. “In those patients who did switch from clopidogrel, a major reason for switching was some sort of unplanned revascularization, MI, or stroke.”

For clinicians who need guidance on switching patients from one of these three drugs to another, Dr. Williams recommended an algorithm published in the Aug. 18, 2015, Nature Reviews Cardiology, which covers both acute and chronic ACS. To switch patients on clopidogrel to ticagrelor in the acute phase after a cardiac event, give a 180-mg loading dose of ticagrelor. “Really, this can be done any time after the dosing of clopidogrel,” Dr. Williams said. To switch acute-phase patients from ticagrelor to clopidogrel, she said, a loading dose of 600 mg of clopidogrel should be given 24 hours after the last ticagrelor dose.

Glycoprotein IIb-IIIa inhibitors are the final common pathway to platelet aggregation, Dr. Williams said. “At one point, several years ago, this was the mainstay of therapy for patients with acute coronary syndrome, but it has significantly reduced in usage because of the advent of the newer ADP receptor blockers,” she explained. A 2009 study in NEJM looked at early versus delayed use of eptifibatide in 9,492 patients with ACS and found that in those at high risk, routine early use did not reduce the primary end point and was associated with significantly more non-life-threatening bleeding.

“Because of that, a routine strategy of administering eptifibatide in patients early after presentation could not be recommended,” Dr. Williams said. “And really, I think it was from then on that there really was not as much IIb-IIIa in patients with acute coronary syndrome. However, it is still used in very high-risk patients with high thrombotic burden.”

Cardiac catheterization

Some patients will need cardiac catheterization almost immediately, Dr. Williams said. These include patients with ongoing symptoms or congestive heart failure with new or worsening mitral regurgitation. This group is hemodynamically unstable and has ischemia at rest or with low-level activity despite intensive medical therapy.

“These are the patients that you would have given aspirin and ADP receptor blockers, they would have had either unfractionated heparin or low-molecular-weight heparin, and they're continuing to have symptoms,” she said. “You want to take them to the cath lab pretty quickly, within a couple of hours, certainly for patients who have sustained arrhythmia, such as ventricular tachycardia and certainly ventricular fibrillation.”

An early invasive strategy is defined as catheterization within 24 hours, Dr. Williams said. This strategy is used in patients with elevated GRACE and TIMI risk scores, temporal changes in troponin, or new ST-segment depression. The delayed invasive strategy, meanwhile, is used in patients who undergo catheterization somewhere between one to three days of presentation. This group includes patients with diabetes, renal insufficiency, or decreased systolic function; those who continue to have postinfarction angina; those who have had a previous PCI or coronary artery bypass graft in the past six months; and those with intermediate GRACE and TIMI risk scores.

Finally, said Dr. Williams, there is a category in which catheterization decisions may be ischemia-guided. “These are patients who score low risk on TIMI, so it's a 0 to 1 TIMI risk score, low risk on GRACE, they have negative troponin, and perhaps the patient and clinician prefer medical management initially,” she said. “These patients you would follow up with a stress test and, depending on the results of the stress test, either proceed with cath or continue medical management.”