Daiichi Sankyo/Eli Lilly and Company Reactive Statement on Archives of Internal Medicine Articles

Daiichi Sankyo/Eli Lilly and Company Reactive Statement on Archives of Internal Medicine Articles

The following statement is in response to the three primary points suggested in the editorial and opinion published in the Archives of Internal Medicine (Kaul S, Diamond GA. Arch Intern Med. 2010;170(12):1010-1012) (Floyd JS, Serebruany VL. Arch Intern Med. 2010;170(12):1078-1080).  It is important to note that the hypotheses by Serebruany have been previously presented and published as well as reviewed, discussed at length and addressed by the U.S. Food and Drug Administration (FDA).


Prasugrel is unlikely to be linked to cancer

Independent oncology experts, FDA's Division of Drug Oncology Products, FDA's Cardiovascular and Renal Drugs Advisory Committee (February 3, 2009), Daiichi Sankyo, Inc. and Eli Lilly and Company carefully and thoroughly reviewed data from the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel).  The FDA concluded that a causal link was unlikely in considering the higher rate of tumors detected in the prasugrel arm during the course of the pivotal trial.  The prasugrel label states the following with regard to malignancies:


During TRITON-TIMI 38, newly diagnosed malignancies were reported in 1.6 percent and 1.2 percent of patients for prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. It is unclear if these observations are causally-related or are random occurrences. 

According to an article published in the New England Journal of Medicine, Ellis F. Unger, M.D., Deputy Director, Division of Cardiovascular and Renal Products Office of Drug Evaluation-I Office of New Drugs CDER, FDA stated that "several factors were weighed in considering whether prasugrel was causally related to the higher rate of tumors."  He went on to add that "we concluded that causality was unlikely; the advisory committee agreed.  The imbalance is described in the adverse-reactions section of prasugrel's label but is not a warning. The sponsors have a postmarketing requirement to collect baseline and subsequent data on cancer in a large, ongoing clinical trial."1


Further, FDA's pharmacologist and other experts have interpreted the preclinical data as not indicative of tumor growth enhancement.  Oncology experts have concluded that there is no biologic plausibility that prasugrel would be a tumor stimulator.2


Personalized patient prescribing can limit bleeding risk while maintaining efficacy for majority of ACS-PCI patients

Bleeding is a side effect of all antiplatelet medications, including prasugrel.  This is a very important issue to consider when prescribing these medications.


In TRITON-TIMI 38, the risk of clinically significant bleeding was significantly higher in patients treated with prasugrel compared with patients treated with clopidogrel. Rates of non-CABG TIMI major or minor bleeding were 4.5 percent for prasugrel and 3.4 percent for clopidogrel (P=0.002).

A retrospective analysis, found that the risk of bleeding was highest in patients age 75 and older and in patients weighing less than 60 kg.
o When these patients and patients with a history of TIA or stroke were removed from TRITON-TIMI 38, the risk of non-CABG TIMI major or minor bleeding was still higher on prasugrel compared with clopidogrel, but the differences between treatment groups was reduced. Among patients aged less than 75, who weigh more than 132 lbs and have no history of TIA or stroke, the observed non-CABG TIMI major bleeding was 1.7 percent in prasugrel-treated patients and 1.4 percent in clopidogrel-treated patients.

In TRITON-TIMI 38, the rates of non-CABG TIMI major or minor bleeding in patients with diabetes were 4.9 percent for prasugrel and 4.5 percent for clopidogrel. In STEMI patients, the rates were 4.8 percent and 4.4 percent. 

Duration of Therapy

In accordance to AHA/ACC guidelines, patients who had implanted stents during PCI should receive an antiplatelet therapy for 12 months.  In TRITON-TIMI 38, patients were treated for a minimum of 6 months (actual median 14.5 months).


In the TRITON-TIMI 38, prasugrel has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to clopidogrel.  The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death.


In TRITON-TIMI 38, the treatment effect of Effient plus aspirin in the UA/NSTEMI and STEMI populations was apparent within the first few days and persisted to the end of the study.  More than 50 percent of the combined cardiovascular events (cardiovascular death, heart attack or stroke) during the trial occurred from day 3 to 15 months.  Treatment effect of Effient was apparent in the first few days and persisted until the end of the study. In TRITON-TIMI 38, administration of the clopidogrel loading dose was delayed relative to the placebo-controlled trials that supported its approval for ACS.


Among UA/NSTEMI patients, the rate of the combined endpoint in patients treated with prasugrel (n=5,030) was 9.3 percent vs. 11.2 percent in patients treated with clopidogrel (p=0.002).  In STEMI patients, the rate of the combined endpoint in patients with prasugrel (n=1,765) was 9.8 percent vs. 12.2 percent for patients treated with clopidogrel (p=0.019).  Patients treated with prasugrel also experienced a 50 percent relative risk reduction in stent-related clots when compared with clopidogrel, regardless of stent type.


In TRITON-TIMI, prasugrel produced higher rates of clinically significant bleeding than clopidogrel.  Rates of non-CABG TIMI major or minor bleeding were 4.5 percent on prasugrel and 3.4 percent on clopidogrel (p=0.002).  Of the 437 patients who underwent CABG during TRITON-TiMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1 percent in the prasugrel group and 4.5 in the clopidogrel group.  When patients age 75 and older, patients weighing less than 60 kg (132 lbs) and patients with a history of TIA or stroke were removed from TRITON-TIMI 38, the risk of non-CABG TIMI major or minor bleeding was still higher on prasugrel compared with clopidogrel, but the differences between treatment groups was reduced.


In terms of safety, Daiichi Sankyo, Inc. and Eli Lilly and Company continue to monitor worldwide experience in the use of prasugrel and report those findings to appropriate regulatory bodies. 


Effient is indicated to reduce the risk of future heart-related events, such as heart attack or blood clot in a stent, in patients with acute coronary syndrome (ACS) managed with a procedure called angioplasty.


About Daiichi Sankyo

The Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of patients in both mature and emerging markets. While maintaining its portfolio of marketed pharmaceuticals for hypertension, hyperlipidemia, and bacterial infections, the Group is engaged in the development of treatments for thrombotic disorders and focused on the discovery of novel oncology and cardiovascular-metabolic therapies. Furthermore, the Daiichi Sankyo Group has created a "Hybrid Business Model," which will respond to market and customer diversity and optimize growth opportunities across the value chain. For more information, please visit www.daiichisankyo.com.


Daiichi Sankyo, Inc., headquartered in Parsippany, New Jersey, is a member of the Daiichi

Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit www.dsi.com.


About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.


Important Safety Information about Effient


Antiplatelet medicines, including Effient, can increase the risk of bleeding. If patients have unexplained or excessive bleeding while on Effient, they should contact their doctor right away as some bleeding can be serious, and sometimes may lead to death. Patients should not take Effient if they have a stomach ulcer or other conditions that cause bleeding or if they have a history of stroke or "mini-stroke" (transient ischemic attack or TIA).

If patients are 75 or older, or if they weigh less than 132 pounds, or if they are taking anticoagulants (e.g., warfarin) or taking NSAIDs (e.g., ibuprofen or naproxen) for a long time, they should talk to their doctor, as they may be at an increased risk of bleeding.

If patients plan to have surgery or a dental procedure, they should tell their doctors that they are taking Effient.

Patients should not stop taking Effient without first talking to the doctor who prescribed it for them, as this may result in increased risk of a clot in their stent, a heart attack or death.


Patients should get medical attention right away if they develop any of the following unexpected symptoms:  fever, weakness, yellowing of the skin or eyes, or if skin becomes very pale or dotted with purple spots. These symptoms may be signs of a rare but potentially life-threatening condition called TTP, which has been reported with other medicines in this class.

For more information about Effient, please see the Full Prescribing Information, including Boxed Warning (http://pi.lilly.com/us/effient.pdf), and Medication Guide (http://pi.lilly.com/us/effient-ppi.pdf). You may also learn more about Effient at www.Effient.com.