AntiPlatelet Therapy: Widening Options & Opinions

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The FDA approved the third thienopyridine agent, prasugrel (Effient, Eli Lilly/Daiichi Sankyo), in July 2009, challenging the U.S. market dominance of clopidogrel (Plavix, Bristol Myers Squibb/Sanofi Aventis). Yet, some cardiologists are being cautious about rapid, widespread adoption, and uptake has been slower than expected. Meanwhile, other options—such as reversible agents—loom on the horizon.

Cath lab decisions broaden

Now that prasugrel has become available in most hospitals, interventionalists, along with their cath lab managers, have to decide when and how to utilize the newest antiplatelet drug.

Three concerns remain obstacles to wider adoption of prasugrel, says Paul A. Gurbel, MD, director of the Sinai Center for Thrombosis Research at the Sinai Hospital in Baltimore. Those include the dosing regimens utilized in the TRITON-TIMI 38 trial, bleeding risks and uncertainty about the optimal duration of therapy.

Steven V. Manoukian, MD, medical director of cardiology at Hospital Corporation of America and director of cardiovascular research at Sarah Cannon Research Institute in Nashville, Tenn., says that while cost is always a consideration, confusion exists “about the relative efficacy and safety between clopidogrel and prasugrel, and clinicians are looking to better understand the results of recent clinical trials.” As a result, purchasing groups, who rely on the expertise of their clinicians, are poised in a wait-and-see mode until clinicians have a more clear consensus.

David J. Cohen, MD, director of cardiovascular research for Saint Luke’s Mid America Heart Institute in Kansas City, Mo., concurs that a cath lab’s bottom line isn’t influencing their choice of adoption. “From the hospital perspective, the cost difference is trivial, as prasugrel costs 60 cents more per pill,” says Cohen. If a patient is in the hospital for two days, and he or she receives a loading dose and a single maintenance dose, it would be a difference of $4 for the patient’s visit. “Hospitals drop that much in gauze pads on the floor during every procedure,” he says.

Clinically, physicians are trying to weigh the tradeoff between ischemic versus bleeding events in making the daily decisions about who receives which drug, says Cohen, an investigator for TRITON-TIMI 38.

As a result of these clinical considerations, prasugrel is experiencing slow adoption in the U.S., according to Robert A. Harrington, MD, director of the Duke Clinical Research Institute at Duke University Medical Center in Durham, N.C. While clinicians may gain experience with the agent in higher risk subgroups, he predicts that the uptake may remain flat for awhile.

TRITON questions reign

There is still “a lot of controversy” about whether prasugrel would remain superior to clopidogrel if patients were given the standard 600 mg dose, as opposed to the 300 mg dose administered in the TRITON-TIMI trial, says Gurbel. He adds that prasugrel should only be used in the two doses that were studied in TRITON-TIMI (60 mg loading dose and 10 mg maintenance dose).

“If TRITON had emerged in the clinical trial vacuum of the previous years, and if standard-dose clopidogrel were the only foreseeable alternative, the results of the trial would have been more compelling through its reduction in clinical events—albeit at the expense of clinically significant bleeding,” states Manoukian, who was an investigator in the earlier prasugrel trial, JUMBO. “Confounding TRITON results, the recently reported CURRENT OASIS-7 trial revealed that the way clopidogrel was studied in TRITON doesn’t mimic clinical practice and that double-dose clopidogrel is often the norm.”

Most practices administer 600 mg of clopidogrel and a large percentage of patients are pretreated with clopidogrel several hours prior to an elective or urgent PCI. In TRITON, 75 percent of patients received clopidogrel peri-procedurally and all patients received a clopidogrel loading dose of 300 mg.

CURRENT OASIS-7 showed an early administration of clopidogrel with a 600 mg dose around the time of PCI, followed by 75 mg twice a day for one week, could achieve “prasugrel-like results—an increase in efficacy, but also with a potential for excess bleeding, although not by the commonly used TIMI bleeding scale,” Manoukian says.

Additionally, Gurbel disagrees with the FDA’s decision to consider lowering the maintenance dose of prasugrel to 5 mg in patients weighing less than 60 kg. “It’s a totally inappropriate and premature recommendation, as this dose of prasugrel was never studied in a clinical trial, and could be potentially dangerous,” he says. For example, in many elderly patients who have high platelet reactivity, their platelet function may not be dropped enough on 5 mg.

“Ordinarily,” Harrington says, “the FDA requires clinical outcome data to make dosing recommendations, but they’ve made the assumption—which is not unreasonable—that the clinical effect of the drug is attributable to its pharmacokinetic dynamic interaction.” He adds that he doesn’t disagree with the agency’s decision, but will wait to clinically employ the dose until more clinical data emerge.

Societal costs of prasugrel

In a recent economic analysis of 6,705 TRITON patients, Cohen et al found treatment with prasugrel compared with clopidogrel reduced total hospitalization costs over 14.7 months, not including the cost of study drugs, by $530 per patient. The cost offset estimate includes bleeding-related costs that a sensitivity analysis showed were not a major driver of the overall cost difference between the two treatments, according to the authors.

The reduction in total hospitalization costs were mainly attributed to two causes: reduced MI events, related to both stent thrombosis and new events; and a statistically significant reduction in repeat PCIs that were not related to MIs—the latter of which was not an anticipated benefit, according to Cohen. As a result, the net costs at the end of the study period were approximately $220 less with prasugrel than clopidogrel. The study drug costs were based on the net wholesale price as of August 2009, which was $5.45 per day for prasugrel and $4.62 per day for clopidogrel.

The analysis also compared prasugrel to generic clopidogrel at a hypothetical cost of $1 per day using a sensitivity analysis. When compared to clopidogrel at this lower cost, treatment with prasugrel as a whole was cost-saving during the first 30 days of treatment, but not after 31 days.

“The hypothetical comparison with generic clopidogrel is important because the patent exclusivity for clopidogrel will expire in 2011 or 2012. Results from this comparison to generic clopidogrel will be useful information for the medical community, especially payors, in the future,” says Cohen.

Who should get prasugrel?

Regardless of these uncertainties, interventionalists have reached some consensus about which patients are most appropriate for prasugrel administration, mainly due to the agent’s properties:
  • Prasugrel has a more consistent degree of platelet inhibition and a shorter time of onset, compared with clopidogrel. Therefore, if a STEMI patient, who is not on dual-antiplatelet therapy, presents at the cath lab, prasugrel offers advantages to clopidogrel because the time to onset of action is going to be shorter.
  • The patient, who despite good clopidogrel compliance has experienced an event, should be switched to prasugrel. Hypo-responders to clopidogrel also might be good candidates for prasugrel, which is currently being assessed in the GRAVITAS trial.
  • Patients in whom stent thrombosis would be malignant and, therefore, the ischemic risk strongly outweighs the bleeding risk may warrant a more potent and longer course of antiplatelet therapy.
  • In patients with non-STEMI or unstable angina with high-risk features requiring intervention in 12 hours or less, prasugrel may be the appropriate choice. While pretreatment with clopidogrel is recommended, it has the drawback for the 10-15 percent who will require CABG. Prasugrel has the potential advantage of not requiring pretreatment.

Length of dual-antiplatelet therapy

Even though the FDA guidelines recommend dual-antiplatelet therapy for a minimum of one year, some question the clinical certainty of that period of time.

“I’ve never known platelets to wear a wristwatch,” says Gurbel. “The one thing we know with certainty is that in the early period around PCI and acute coronary syndrome, the platelet reactivity is greatest, but we don’t know how it varies over time, such as beyond one month. We’ve shown that responsiveness to clopidogrel increases, whereas platelet reactivity falls at one month after elective PCI. Beyond that, we really don’t have any data.”

Harrington says that a minimum of a year of dual-antiplatelet therapy, particularly in high-risk patients with ACS or acute MI, seems “most reasonable. Beyond a year, a lot more personal judgment is involved, as there are a lot less data.” His interpretation of the available observational data is that the risk of stent thrombosis continues to accrue after one year, and prolonged dual-antiplatelet therapy could attenuate that risk.

The DAPT trial (Dual-Antiplatelet Therapy), a $100 million four-year study seeking to enroll 20,000 patients, is examining whether 30 months of dual-antiplatelet therapy is better than 12 months for preventing stent thrombosis and major adverse cardiovascular and cerebrovascular events in patients receiving either bare-metal or drug-eluting stents.

However, the trial’s design is receiving some criticism. “The DAPT trial is using an arbitrary period of time, which could be detrimental in some patients,” Gurbel says. “We have no substantial data on platelet physiology at this stopping point to say this is safe for patients.” He recommends the investigators measure platelet function and link it to outcomes.

For those patients who are tolerating dual-antiplatelet therapy well out to one year and are willing to incur the associated costs, Harrington encourages physicians to address the continued treatment with their patients. “After a year, it becomes an individualized decision, but the DAPT trial will properly inform us on these issues,” he says.

Platelet function tests

There is increasing support to employ platelet reactivity tests in clinical practice. In fact, the majority of prescribed drugs, including antihypertensives, antibiotics and beta blockers, are titrated to dose responsiveness. Most cardiologists, however, are
waiting for the results of the GRAVITAS trial, Cohen says.

GRAVITAS, which intends to enroll approximately 2,800 non-STEMI patients with a six-month follow-up, seeks to determine whether adjusting antiplatelet dose, based on individualized platelet-function monitoring, can safely improve clinical outcomes after drug-eluting stent implantation.

Current data, gleaned from about 1,700 patients in trials like POPular, show a strong link between ex vivo measurements and outcomes. Gurbel points out, however, that these data reflect only one measurement at the time of discharge. “We need to conduct large-scale studies where we follow platelet function, correlate those data with outcomes and assess personalized therapies,” he says, noting that GRAVITAS is a “first step forward, but not the final answer, because it will still be unclear how often we should be taking these measurements to optimize patient outcomes.”

Cohen notes that if the results of GRAVITAS are positive, it would provide a “fairly strong incentive to test and switch.” However, the tests aren’t entirely practical, especially for a patient already receiving an agent like prasugrel. “In this case, there is no variability to test, as everyone is inhibited.”

Reversible agents loom large

Reversibility as a component of a drug profile has strong advantages (surgical anatomy and bleeding complications), as well as potential disadvantages. However, there may be greater risk associated with patient noncompliance.

The two most promising reversible antiplatelet drugs are ticagrelor (Brilinta, AstraZeneca) and cangrelor (The Medicines Company). In November 2009, AstraZeneca submitted its new drug application for ticagrelor. Meanwhile, cangrelor failed to meet its primary endpoint in both CHAMPION randomized controlled trials, the results of which were presented at AHA09.

In PLATO STEMI, presented at AHA09, STEMI patients who received both aspirin and ticagrelor had fewer cardiac events and less mortality than patients on aspirin and the popular irreversible clopidogrel. Gurbel notes that this mortality reduction is “unprecedented,” suggesting ticagrelor may have off-target effects, such as adenosine metabolism.

Despite the fast-effecting onset of the drugs, there are greater concerns with noncompliance. “If the agent’s half-life is too short, then missing a dose or two—which commonly occurs in real-world patients—could be a considerable problem, leading to greater risk for stent thrombosis,” Cohen says. However, if a patient skips a dose of clopidogrel or prasugrel, it irreversibly inhibits platelets.

“While that was an initial concern with ticagrelor, the PLATO trials have laid to rest that concern, as it has a half-life longer than 12 hours,” Cohen says.

Most interventionalists are not counting cangrelor out, despite the outcome of the CHAMPION trials.

There also are questions about the design of the CHAMPION trials, including the potential interaction between cangrelor and the clopidogrel active metabolite, and the duration of the infusion. Yet, Gurbel says the drug may still “play a role in intervention, especially for patients needing bypass surgery, as it has a faster offset than ticagrelor. I wouldn’t discount it based on the results of the CHAMPION studies.”

Harrington, who was the principal investigator in CHAMPION PCI, concurs there remains a need for a reversible agent—particular an intravenous, short-acting reversible agent. Cangrelor has a half-life of a few minutes, according to Harrington. He adds that it remains “unclear and disappointing” why investigators failed to meet their primary endpoints in the trials, but to “stay tuned” as they will sift through the data. Due to these clinical outcomes, it will be challenging to demonstrate in the conventional, regulatory process that the agent is safe and efficacious, Harrington notes.

Also, The Medicines Company hasn’t given up on cangrelor either, and is enrolling patients in the BRIDGE trial, which aims to establish the cangrelor dose that achieves more than 60 percent inhibition of platelet aggregation for five days. The BRIDGE study plans to enroll approximately 200 patients with the goal of showing safe “bridging” of patients during the pre- and post-surgical period of risk. “We’ve not heard the last of cangrelor as it has a role in the field of interventional cardiology,” says
Manoukian, who is an investigator in the BRIDGE trial.

It would be very beneficial to have a reversible agent on the market, according to Cohen, especially an agent as reversible as cangrelor. Yet, he stresses that the desire for cangrelor in the U.S. will be dependent on it being “very reasonably priced because if the oral reversible agent ticagrelor gets approved, it will likely be less expensive.”

However, decision-making for clinicians will become even more challenging if ticagrelor gains FDA approval. “We are already assessing the three trials—TRITON, CURRENT OASIS-7 and PLATO—in order to make cross-trial comparisons that can aid our decision-making. The recurring theme from these trials is that more potent platelet inhibition is associated with improved clinical outcomes from the ischemic side at the expense of an increase in bleeding in one or more scales,” Manoukian states.
Cardiologists will continue to weigh the safety and efficacy of these drugs, as well as their costs, to make the best decisions for their patients, according to Manoukian.