Evolving Evidence Prompts Changes in Treatment Paradigm for ACS

Warren J. Wexelman, MD

New York University (NYU) Langone Cardiology Associates, Brooklyn, NY

NYU School of Medicine, New York, NY

President, the American Heart Association, Brooklyn, NY

This article was sponsored by AstraZeneca

Acute coronary syndrome (ACS) refers to a spectrum of clinical disorders, including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI).¹ In the United States, ACS accounts for 1.14 million hospitalizations annually and an estimated 7.6 million adults have a history of myocardial infarction (MI).² Individuals with a history of an ACS event have a markedly elevated risk of subsequent thrombotic cardiovascular (CV) events, including MI, stroke, and CV death.^3—5

Dual antiplatelet therapy, which consists of a P2Y₁₂ inhibitor plus low-dose aspirin, is a significant part of the treatment paradigm in patients with ACS and has been shown to significantly reduce the risk of subsequent thrombotic CV events.^6—8 Recently, evolving science regarding P2Y¹² inhibitors has prompted a reassessment of the role of Plavix^® (clopidogrel bisulfate) tablets and its generic equivalents, with the potential to have significant implications for the management of patients with ACS.⁹

In March 2016, the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guidelines released the ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy. The update revised prior guidance to include additional recommendations regarding the use of newer P2Y₁₂ inhibitors over clopidogrel across a broad spectrum of patients with ACS.¹⁰

More recently, the US Food and Drug Administration (FDA) amended the indication for Plavix^® (clopidogrel bisulfate), removing the reduction of CV death and death from any cause from the indication for the treatment of ACS.^11,12 Additionally, the indication for the treatment of patients with STEMI was revised and is now specific to medically managed patients only.¹²

With these recent changes, should physicians critically reconsider their management strategy in a broad spectrum of patients with ACS. The aim of this article is to briefly summarize the potential implications for patient management, while highlighting these changes.

ACC/AHA Clinical Practice Guidelines Updated to Reflect Evolving Evidence

The ACC/AHA Task Force on Clinical Practice Guidelines is responsible for conducting ongoing assessments of evolving evidence to ensure that ACC/AHA guidelines reflect current knowledge and optimal medical care. The task force published a focused update with revised recommendations for the use of dual antiplatelet therapy.¹⁰

The recommendations in the focused update supersede prior corresponding recommendations in six relevant ACC/AHA guidelines.^13—18 The P2Y₁₂ inhibitors included in the guideline have class I* recommendations as treatment options in patients with ACS for at least the first 12 months. However, the changes included additional class IIa† recommendations for the newer P2Y₁₂ inhibitors as preferred over clopidogrel across a broad spectrum of patients with ACS.¹⁰

FDA Revises ACS Indication for Plavix^® (clopidogrel bisulfate) Tablets

The FDA conducts routine post-marketing surveillance of evolving data for all marketed drugs. When the FDA determines that new data has the potential to alter the benefit/risk analysis for a drug it notifies healthcare providers and patients and amends the product label as necessary to ensure that it accurately reflects the available evidence. These decisions are made following careful analysis and expert consultation and then communicated to the public through various channels, including drug safety communications or amendments to prescribing information.

On November 16, 2014, the FDA issued a Drug Safety Communication entitled: "FDA reviews long-term antiplatelet therapy as preliminary trial data shows benefits but a higher risk of non-cardiovascular death."¹⁹ This communication was developed in regard to the DAPT trial, a randomized controlled trial evaluating the effect of aspirin plus either clopidogrel or prasugrel for 12 versus 30 months in patients undergoing percutaneous coronary intervention (PCI) with implantation of a drug-eluting coronary stent.⁹

In November of 2015, the FDA issued an additional updated Drug Safety Communication entitled: "FDA review finds long-term treatment with blood-thinning medicine Plavix^® (clopidogrel) does not change risk of death," which included a further analysis of the DAPT trial, as well as meta-analyses of other large long-term clinical trials of clopidogrel.²⁰ These analyses found no evidence of an increased risk of overall death, including cancer-related deaths, associated with the extended use of clopidogrel. The FDA concluded that long-term administration of clopidogrel does not appear to increase or decrease overall risk of death in patients with, or at risk for, heart disease.

Under the section titled "Additional Information for Health Care Professionals" of the 2015 FDA Drug Safety Communication, the FDA stated that when selecting antiplatelet therapy for patients with ACS who are managed with coronary stent implantation, prescribers should consider that newer oral P2Y₁₂ inhibitors have been shown to be superior to clopidogrel when used in this patient population.²⁰

In September 2016, the FDA sent the manufacturer a supplement approval letter which included the revised US prescribing information for Plavix^® (clopidogrel bisulfate) tablets. This resulted in two significant revisions to the approved indications (figure 1).¹² Notably, the ACS indication for clopidogrel was amended to exclude reduction in CV death and death from any cause, thus limiting the ACS indication to reducing the rate of MI and stroke. Additionally, the indication for the treatment of acute STEMI is now specific to medically managed patients only. Typically, in the US only a small minority of patients with STEMI are managed medically (the vast majority undergo primary PCI).

Figure 1. Plavix^® (clopidogrel bisulfate) labeling revisions^‡12

‡Additions are shown as underlined text; deletions are shown as strikethrough text.

The indication for Plavix^® (clopidogrel bisulfate) in patients with acute STEMI includes support from the COMMIT trial.^11,21 COMMIT was a randomized, double-blind, placebo controlled trial, which included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting electrocardiogram (ECG) abnormalities. Patients were randomized to receive Plavix® (clopidogrel bisulfate) tablets or placebo, in combination with aspirin, for 28 days or until hospital discharge, whichever came first. Only 3% of the patients in the COMMIT trial underwent PCI. Accordingly, the previous STEMI indication in the Plavix^® (clopidogrel bisulfate) label stated that the benefit for patients who undergo primary PCI is unknown. In the 2016 prescribing information, the statement regarding the unknown benefit in this population was removed from the indication and the STEMI indication is now limited to medically managed patients only.

The use of dual antiplatelet therapy in managing patients with ACS has evolved substantially over the last two decades. Data from recent clinical trials evaluating dual antiplatelet therapy have provided additional insights that have led to further refinement of existing treatment guidelines and prescribing information, which should prompt physicians to critically re-evaluate their therapeutic treatment approach for patients with ACS.

*Class I recommends that the procedure/treatment should be performed/administered

†Class IIa states that it is reasonable to perform procedure/administer treatment

or as he is also known as, "The Rockdoc", is a life-long Brooklynite and has been a practicing cardiologist in Brooklyn for over 30 years. He served as Associate Chief Medical Officer, Director of Clinical Therapeutics and was the Founding Director of the Cardiac Rehabilitation & Exercise Program at Maimonides Medical Center. Dr Wexelman is presently on the faculty of the NYU Langone Medical Center and the President of the American Heart Association in Brooklyn. Warren has extensive media experience with numerous appearances on CNN, Good Day NY, NBC, and as a regular guest on Fox on Health. Warren's critically acclaimed radio show "Second Opinion" aired in New York City 1999-2001. Warren is a lifelong piano and keyboard player, who with his band has played clubs all over the tristate area. He presently appears as "himself” on the reality series, "Big Ang Show” and "Mob Wives", and he occasionally takes a break from mending hearts by playing piano in his rock band, restoring classic cars, and enjoying great food!

Warren J. Wexelman, MD,

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