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Pretreatment in non-STEMI: Where we stand and why
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At EuroPCR, I participated in a session examining pharmacological and interventional controversies in ACS, in particular pretreatment with oral P2Y12 receptor inhibitors in patients with non-STEMI. There has been a lot of debate surrounding the need to pretreat our patients coming to the cath lab with an ACS. We have practice guidelines in Europe and the United States that strongly endorse upstream treatment with a P2Y12 receptor inhibitor; however, when we look at the clinical trial data, they are somewhat weak and not that supportive.
A look at the data
The concept of pretreatment originally emerged from the CURE trial. Although it is somewhat dated, CURE is an important trial that randomly assigned patients with the intent of a noninvasive strategy to receive clopidogrel (300 mg immediately followed by 75 mg once daily) or placebo in addition to aspirin for 3 to 12 months. For patients who went to the cath lab, the median time was around 10 days, so definitely not reflective of modern-day practice. The study showed that clopidogrel is beneficial in patients with non-STEMI, but the risk for major bleeding is increased in those treated with the agent.
Dominick J. Angiolillo
Following CURE was the CREDO trial. This trial did not meet the primary endpoint at 1-month, which was intended to test the clinical impact of clopidogrel pretreatment. Subsequently we saw data from PRAGUE-8 and ARMYDA-5 that also showed no benefit for pretreatment (using clopidogrel 600 mg) vs. in-lab loading dose administration and in fact suggested a potential for harm (ie, increased risk for bleeding).
Recently, data from the ACCOAST trial were presented that looked at the benefit of a second agent, prasugrel (Effient, Eli Lilly/Daiichi Sankyo). The ACCOAST researchers found that pretreatment with the agent (30 mg loading dose) was not associated with any benefit vs. in-lab treatment (60 mg loading dose) and actually there was an increased risk for bleeding complications, which was irrespective of the duration of pretreatment and the risk profile of the patient population.
The third agent, ticagrelor (Brilinta, AstraZeneca), has never been tested in a trial of pretreatment vs. no pretreatment, because within the PLATO trial, all patients had been pretreated with ticagrelor before undergoing PCI. So, when we look at the data, the vast majority don’t support pretreatment even though it is endorsed by practice guidelines.
Improvements to patient care
The other concept to keep in mind is that over the past 10 to 15 years, the timing to bring a patient to the cath lab has reduced significantly. When we look at trial data and the average time to clinical presentation to bring the patient to the cath lab, it is now just a matter of hours when in the past it used to be days. From a practical standpoint, if I have a patient overnight who is coming in with a non-STEMI, the following morning— which may not be more than 6 to 8 hours— the patient is already in the cath lab. The only exception may be sometimes on weekends, but typically in the higher risk non-STEMI patients, we do cath them over the weekend rather than having them wait until Monday.
Given such short time delay from clinical presentation to the diagnostic coronary angiogram, many physicians prefer waiting to see the coronary anatomy first and treat in the cath lab. This is a practice pattern that is common in the United States. In addition, recent registry data show that with the introduction of the novel oral P2Y12 receptor inhibitors that act much quicker than clopidogrel, early use of these medications has further reduced.
Lingering questions
So the question remains: What do we do with these patients? There is the argument that if we are just treating with heparin and aspirin and not giving an additional antiplatelet agent, we may be undertreating these patients. One may also question what the role is of glycoprotein IIb/IIIa inhibitors (GPI) upstream. However, routine upstream use of GPI is no longer endorsed by practice guidelines, particularly after the EARLY ACS trial in which upstream eptifibatide use did not show any ischemic benefit vs. in-lab use and was associated with an increased risk of bleeding complications. I do believe that if a patient presents at the cath lab rather quickly, it is reasonable to wait and see the coronary anatomy and then consider your drug of choice in the cath lab. This is what was done in the CHAMPION PHOENIX trial, which tested a novel IV and fast-acting P2Y12 inhibitor cangrelor (The Medicines Company) showing a benefit with the use of this agent across the spectrum of clinical presentations of patients undergoing PCI who were not pre-treated with a P2Y12 receptor inhibitor.
It’s also important to keep in mind that approximately 10 to 15% of ACS patients may require CABG and any patient on an oral P2Y12 inhibitor will need to discontinue therapy for at least 5 days (clopidogrel and ticagrelor) or 7 days (prasugrel) before undergoing surgery to minimize the risk of bleeding complications. This, indeed, may also have cost implications and create burdens on availability of beds in the hospital, which is a reality in daily clinical practice.
What do you think? With the introduction of novel P2Y12 receptor inhibitors and the improvement in timing from clinical presentation to the cath lab, have you changed your perception on the need for pretreatment even though this is endorsed by practice guidelines?