Washington, DC—A "hot" thread weaving throughout the Cardiovascular Research Technologies 2013 program was showcased in "The Big Antiplatelet Debate," presenting arguments as to whether prasugrel is preferable to ticagrelor or vice versa. That was, however, but one image within a much broader tapestry. Let's not forget that:

• the uptake of newer, more powerful antiplatelet agents has been weak,
• hospitals are discharging patients on clopidogrel after short courses of newer agents,
• universal use of newer more effective agents may not be cost effective, and
• the value, or lack thereof, of platelet reactivity testing is in question.

In an oral presentation, Washington Hospital Center's Joshua P. Loh, MD, laid out the basic findings of the TRITON TIMI-38 trial (prasugrel) and the PLATO trial (ticagrelor) that showed benefit of these newer-generation antiplatelet agents over clopidogrel up to 1 year in patients with ACS undergoing PCI. "However, in our institution," Dr. Loh said, "ACS patients initially loaded with these new agents before PCI are switching to clopidogrel from prasugrel or ticagrelor after PCI."

Dr. Loh and colleagues compared the characteristics and in-hospital outcomes of ACS patients undergoing PCI who were initially given prasugrel (n = 203) then switched back to clopidogrel (n = 72), versus those continued on prasugrel at discharge (n = 131). In-hospital bleeding complications, the need for urgent CABG, and vascular access site complications were the main reasons for switching antiplatelet therapy from prasugrel to clopidogrel prior to discharge. More patients switched to clopidogrel due to urgent CABG (5.2% vs. 0%), and hospital or ICU stay were significantly longer in the group switched to clopidogrel.

"Our aim," Dr. Loh said, "was to compare the two groups at hospital discharge to understand the differences and perhaps come up with a reasoning on the differing practices." Also, he added, studies should be done exploring other dosing regimens and their long-term impact for ACS patients undergoing PCI.

Should Cost Be a Factor?

What if a strategy of universal ticagrelor were compared with one in which only patients with high platelet reactivity (HPR) were given ticagrelor and the rest given generic clopidogrel? Craig I. Coleman, PharmD, from the University of Connecticut, used a hybrid decision tree/Markov model with event rates from CURE, PLATO, and TRITON-TIMI-38 and costs from TRITON-TIMI-38 and a handful of pharmacy chains to run a cost-effectiveness analysis for an assumed cohort of 65-year old ACS patients with an HPR incidence at discharge of 32%.

The cost of the platelet reactivity assay, Dr. Coleman said, was about $30 ($14-$60), and the cost of clopidogrel was $639 ($48-$1,160) per year, compared with $3,348 ($1,982-$4,014) for ticagrelor. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) for ticagrelor was $68,182—well above the $50,000 benchmark. Dr. Coleman added that a similar analysis for prasugrel found about an $80,000 ICER per QALY. Ticagrelor is "a bit cheaper, but there's a slightly higher bleeding rate early on."

His take-home message: "I believe it is cost effective to use a VerifyNow platelet reactivity test to determine who should be receiving clopidogrel and who should be receiving one of the newer agents." At ACC.13, he offered a similar message based on an analysis demonstrating that a platelet reactivity-driven treatment strategy was more cost effective than using a universal approach of generic clopidogrel in all PCI patients. The phenotype-driven ticagrelor and prasugrel strategies were cost-effective compared to universal clopidogrel (ICERs = $40,100 and $49,143/QALY); however, universal ticagrelor and prasugrel strategies were not (ICERs = $61,651 and $96,261/QALY). Thus, even in the age of generic clopidogrel, phenotype-driven selection of new antiplatelet agents appears to be a cost-effective strategy in ACS patients compared to universal clopidogrel.

Debaters "Do Not Prefer"

Both "combatants" in the debate quickly shed their partisan robes and confessed to liking both new agents in different circumstances. Dominick J. Angiolillo, MD, PhD, from the University of Florida, admitted to favoring prasugrel, saying, "The benefit of prasugrel is enhanced where we really need a new agent—in STEMI patients, in patients with diabetes, with recurrent events and with stent thrombosis." He did say, though, that increased bleeding in elderly and low-weight patients makes him lean toward clopidogrel in these populations, particularly for long-term management.

The place for ticagrelor, he said, is in patients with prior TIA/ischemic stroke, for those undergoing primary PCI with STEMI, in diabetes patients with ACS, the setting of recurrent ACS while on clopidogrel, and in patients with stent thrombosis.

Paul Gurbel, MD, of Johns Hopkins University School of Medicine, pointed out that ticagrelor has a faster offset after maintenance dosing than prasugrel, which may be important for patients going on to surgery, and may be related to lower bleeding in CABG patients compared to clopidogrel-treated patients. "Ticagrelor does a stellar job eliminating high platelet reactivity, while prasugrel is associated with a higher frequency of the HPR associated with worse outcomes," he said, though neither drug has been well-vetted in ACS in terms of pharmacodynamics. Ticagrelor's significant CV death advantage over clopidogrel in PLATO (4.0% versus 5.1%, p = 0.001) may be "the trump card for ticagrelor in ACS."

Penetrating Question

CRT 2013 chairman Ron Waksman, MD, posed the key question, "So why is the penetration of both of these drugs under 20%?" Drs. Angiolillo and Gurbel cited the availability of generic clopidogrel as a strong factor. "The clinical trial results," Dr. Gurbel said, "say that we should be giving our patients either of these drugs because they are better than clopidogrel, which is essentially a placebo in up to 30% of patients. That's a very serious problem."

In a post-debate interview, Dr. Gurbel said he had recently chosen prasugrel over ticagrelor for a STEMI patient with lung disease because of ticagrelor's side effect of dyspnea. But he underscored that the TRITON TIMI-38 exclusion of patients pretreated with clopidogrel was an "artificial" situation running against guideline recommendations for a P2Y12 inhibitor or GP IIb/IIIa inhibitor on top of aspirin in patients with high-risk ACS. The fact that PLATO patients were pretreated with clopidogrel blunted the treatment effect of ticagrelor early, explaining the delayed separation of treatment curves with ticagrelor. The difference in the trials, he said, "makes it hard to come up with anything clear-cut, but still you have to use the data you have."

Finally, Dr. Gurbel discounted the series of trials (GRAVITAS, TRIGGER, ARCTIC) showing no advantage for changing antiplatelet therapy based on platelet reactivity testing. They were underpowered, he said, had protocol issues (ARCTIC), used double-dose clopidogrel (GRAVITAS/ARCTIC) known to be a poor regimen for overcoming HPR, and included very low-risk patients. "It would be a huge mistake to consider platelet function testing useless based on evidence [in these three trials]."

Clopidogrel First, Then Switch?

So why aren't all ACS patients treated with clopidogrel, tested for HPR, and, based on those test results, switched to newer, more potent agents if necessary? "You're preaching to the choir," Dr. Gurbel said. "That's what we do." A trial to test such a strategy in high-risk ACS patients, he speculated, would need 7,500 or more patients and be prohibitively expensive. "Will we ever get past this quagmire?" he wondered aloud.

"Platelet reactivity is a great marker of patients' risk, but what's lacking is any evidence to show that treating that with an antiplatelet therapy impacts care," said Steven Steinhubl, MD. "Using it or any measure of platelet function clinically is just not evidence-based." Like Dr. Gurbel, he added, given ticagrelor's mortality benefit in ACS, "I have a very difficult time arguing that ticagrelor is not a better drug long term for everybody. Prasugrel is probably a very good drug, but TRITON did not reflect real-world practice, and I don't know how to implement its findings." That said, he noted that patients at his institution are loaded with prasugrel, especially those with STEMI, and discharged on clopidogrel.—by Walter Alexander

Keywords: Stroke, Platelet Aggregation Inhibitors, Thiophenes, Ticlopidine, Piperazines, Dyspnea, Platelet Membrane Glycoprotein IIb, Stents, Incidence, Thrombosis, Phenotype, Organoplatinum Compounds, Diabetes Mellitus, Quality-Adjusted Life Years, Lung Diseases

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