Overview of the Antiplatelet Drug Prasugrel (EFFIENT)

Prasugrel (EFFIENT) is an oral platelet inhibitor (antiplatelet drug) that was approved by the Food and Drug Administration (FDA) in July 2009[1] as an add-on treatment to aspirin. It prevents platelets from collecting and forming clots that may cause a heart attack or stroke in patients with acute coronary syndrome — escalating heart-related chest pain (unstable angina) or a heart attack in progress — before and after procedures to open up the blood vessels supplying the heart, including angioplasty (balloon inflation) with or without stent (mesh tube) placement.

Like clopidogrel (PLAVIX), prasugrel belongs to an antiplatelet class known as thienopyridines.[2] Both medications are prodrugs that are converted in the body to active substances that bind to the platelets, preventing their activation and subsequent blood clot formation.

In 2009, Public Citizen’s Health Research Group raised several concerns about the effectiveness and safety of prasugrel and asked the FDA to halt its review of the drug.[3],[4] Since then, we have recommended against the use of prasugrel because it does[5] not have a better risk-benefit balance than clopidogrel does;[6] the latter is the more well-studied standard treatment for patients with acute coronary syndrome.

Prasugrel’s approval was based on a single 15-month clinical trial[7],[8] that compared dual treatment using prasugrel and aspirin with dual treatment using clopidogrel and aspirin in patients with acute coronary syndrome who were undergoing coronary artery angioplasty. As discussed in our 2009 letters to the FDA, this trial overstated prasugrel’s effectiveness over clopidogrel’s in several ways.[9]

First, the trial compared a suboptimal dose of clopidogrel with a more potent dose of prasugrel.[10] In addition, over one-half of the patients in the clopidogrel group were given their initial doses after their angioplasty procedure instead of at least three to four hours before the procedure, which is the minimum time needed for the drug’s platelet inhibition effect to begin. This delay favored prasugrel, which has a faster onset of action than clopidogrel. As a result, the trial did not offer a “fair,” valid comparison of prasugrel with clopidogrel.[11]

Second, although the trial concluded that prasugrel was associated with a slight reduction in deaths from cardiovascular causes, nonfatal heart attacks and nonfatal strokes compared with clopidogrel, the use of this combined outcome as a primary endpoint increased the chance that the statistical analysis would favor prasugrel.[12] In fact, when the three individual components of this primary outcome were examined separately, prasugrel only slightly lowered the number of nonfatal heart attacks, which occurred in 7 percent of prasugrel users, compared with nearly 10 percent of clopidogrel users. Prasugrel did not reduce deaths due to cardiovascular causes or the rate of nonfatal stroke relative to clopidogrel. Prasugrel also did not reduce overall deaths relative to clopidogrel. A subgroup analysis of nearly 600 subjects who underwent coronary artery angioplasty without stent placement did not show a significant advantage for prasugrel over clopidogrel in lowering the aforementioned combined outcome.[13] Additional subgroup analyses showed that the risk-benefit balance of prasugrel was particularly unfavorable in patients who weighed less than 132 pounds, those over 75 years of age and those with a history of stroke or transient ischemic attack.[14]

Third, prasugrel increased the risk of life-threatening bleeding by 50 percent and the risk of fatal hemorrhage by fourfold compared with clopidogrel in the trial.[15] A particularly concerning finding was that major bleeding occurred in 13 percent of prasugrel users undergoing coronary artery bypass graft surgery, compared with just 3 percent of their clopidogrel counterparts.[16] Misleadingly, the researchers excluded this critical type of bleeding from the trial’s primary safety endpoint. The actual bleeding risk for prasugrel in the general population with acute coronary syndrome is likely to be even greater because the trial excluded patients who already had an increased bleeding risk.

We also criticized the removal of a regular voting member with substantial knowledge of prasugrel from the FDA’s Cardiovascular and Renal Drugs Advisory Committee shortly before the committee met to consider whether the drug should be approved.[17] We believe that this action significantly limited the committee’s critical discussion about prasugrel’s safety. In addition, the FDA’s Drug Safety and Risk Management Advisory Committee, which sometimes joins other committees that evaluate the safety of particularly risky drugs, was not asked to participate in the review of prasugrel. Possibly as a result, the FDA advisory committee voted unanimously in favor of approving prasugrel in a “family picnic” atmosphere, as described by one participant.

The findings of a second prasugrel trial[18] that was published in 2012 failed to demonstrate that dual treatment using prasugrel and aspirin is any more effective in lowering the combined endpoint (death from cardiovascular causes, heart attack and stroke) relative to clopidogrel and aspirin in acute coronary syndrome patients who did not undergo coronary artery angioplasty. Although this 17-month trial did not show a significant increase in the rate of severe or life-threatening bleeding among prasugrel users, the drug’s rate of major or minor bleeding was significantly higher than that of clopidogrel in subjects under the age of 75. Therefore, prasugrel has not been approved for use in acute coronary syndrome patients who do not undergo coronary artery angioplasty.

Data from animal studies raised the possibility that prasugrel may increase the risk of several kinds of cancer,[19] although clear evidence from human clinical trials is inconclusive about this increased risk.[20]

In summary, the available evidence shows that prasugrel offers, at best, a limited benefit (mainly a slight reduction in the risk of nonfatal heart attack) relative to clopidogrel. In addition, prasugrel at its current approved dose is unsafe, as it results in excess hemorrhage (especially during restoration of blood supply to the heart) and may be associated with an increased risk of tumors.[21],[22]

What You Can Do

Do not use prasugrel to prevent blood clots due to acute coronary syndrome, whether you undergo coronary artery angioplasty or not. Instead, you should use clopidogrel in combination with aspirin.

References

[1] Eli Lilly and Company. Label: Prasugrel (EFFIENT). July 12, 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fe9c118-c44b-48d7-a142-9668ae3df0c6&audience=consumer. Accessed March 5, 2018.

[2] Passacquale G, Ferro A. Oral antiplatelet agents clopidogrel and prasugrel for the prevention of cardiovascular events. BMJ. 2011;342(Jun. 17):d3488.

[3] Serebruany V, Floyd J, Wolfe S. Letter urging the FDA to halt its review of prasugrel (Effient). June 3, 2009. https://www.citizen.org/our-work/health-and-safety/letter-urging-fda-halt-its-review-prasugrel-effient. Accessed March 5, 2018.

[4] Floyd J, Wolfe S. Letter to FDA about safety of prasugrel (Effient) and removal of advisory committee member. February 19, 2009. https://wwwa.citizen.org/our-work/health-and-safety/letter-fda-about-safety-prasugrel-effient-and-removal-advisory. Accessed March 5, 2018.

[5] Applying the life-saving 7-year rule: An antiarrhythmic and 3 anticoagulants. Worst Pills, Best Pills News. April 2012. /newsletters/view/788. Accessed March 5, 2018.

[6] Prasugrel. After angioplasty and stenting: continue to use aspirin + clopidogrel. Prescrire Int. 2009;29(308):406-409.

[7] Wiviott S, Braunwald E, McCabe C, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.

[8] Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373(9665):723-731.

[9] Serebruany V, Floyd J, Wolfe S. Letter urging the FDA to halt its review of prasugrel (effient). June 3, 2009. https://www.citizen.org/our-work/health-and-safety/letter-urging-fda-halt-its-review-prasugrel-effient. Accessed March 5, 2018.

[10] Serebruany V, Shalito I, Kopyleva O. Prasugrel development - claims and achievements. Thromb Haemost. 2009;101(1):14-22.

[11] Serebruany V, Floyd J, Wolfe S. Letter urging the FDA to halt its review of prasugrel (effient). June 3, 2009. https://www.citizen.org/our-work/health-and-safety/letter-urging-fda-halt-its-review-prasugrel-effient. Accessed March 5, 2018.

[12] Prasugrel. After angioplasty and stenting: continue to use aspirin + clopidogrel. Prescrire Int. 2009;29(308):406-409.

[13] Pride YB, Wiviott SD, Buros JL, et al. Effect of prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation: a TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)–Thrombolysis in Myocardial Infarction (TIMI) 38 substudy. Am Hear J. 2009;158(3):e21-e26.

[14] Prasugrel. After angioplasty and stenting: continue to use aspirin + clopidogrel. Prescrire Int. 2009;29(308):406-409.

[15] Serebruany V, Floyd J, Wolfe S. Letter urging the FDA to halt its review of prasugrel (effient). June 3, 2009. https://www.citizen.org/our-work/health-and-safety/letter-urging-fda-halt-its-review-prasugrel-effient. Accessed March 5, 2018.

[16] Wiviott S, Braunwald E, McCabe C, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.

[17] Floyd J, Wolfe S. Letter to FDA about safety of prasugrel (Effient) and removal of advisory committee member. February 19, 2009. https://www.citizen.org/our-work/health-and-safety/letter-fda-about-safety-prasugrel-effient-and-removal-advisory. Accessed March 5, 2018.

[18] Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297-1309.

[19] Food and Drug Administration. NDA 22,307 prasugrel. Stent thrombosis results in TRITON. Karen A. Hickes, Medical Officer. Review of supplemental stent thrombosis reports. May 13, 2009. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_medr_p18.pdf. Accessed March 5, 2018.

[20] Kaul S, Diamond GA. Prasugrel and cancer: an uncertain association or a credible risk that meaningfully alters the benefit-risk balance. Arch Intern Med. 2010;170(12):1010-1012.

[21] Serebruany V, Floyd J, Wolfe S. Letter urging the FDA to halt its review of prasugrel (effient). June 3, 2009. https://www.citizen.org/our-work/health-and-safety/letter-urging-fda-halt-its-review-prasugrel-effient. Accessed March 5, 2018.

[22] Prasugrel. After angioplasty and stenting: continue to use aspirin + clopidogrel. Prescrire Int. 2009;29(308):406-409.