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What's New in Coagulation: September 2009

WHAT'S NEW IN COAGULATION: SEPTEMBER 2009

USPTO to reconsider Sanofi patent on Plavix.Bloomberg News (8/19, Decker) reports, "Sanofi-Aventis SA's patent on the blood-thinner Plavix [clopidogrel bisulfate] will be reconsidered by the US Patent and Trademark Office to determine if it should have been issued, according to information on the agency's website." An appeals court "upheld the patent's validity in December," preventing "Apotex Inc. from selling a copy of the drug until November 2011." Apotex, which "submitted the request at the patent office," also "filed court papers yesterday" in a civil case in New York "where Bristol-Myers and Sanofi are seeking reimbursement for some of the sales lost when Apotex briefly entered the market with a generic version of Plavix in 2006 after a settlement agreement fell apart." Apotex is "asking the federal judge in Manhattan to rule there are limits to how much the drugmaker would be able to get because of the terms of that failed settlement."
In its request for the patent to be re-examined, Apotex claims that "certain drug research conducted prior to the Plavix patent's 1989 issuance should render the patent invalid," Dow Jones Newswires (8/19, Loftus) reports. The company contends that "the US Plavix patent should be reconsidered because so-called 'prior art' anticipated the claims, including information in Sanofi's application for a Canadian drug patent. This prior art would have taught anyone skilled in the art of drug development how to invent Plavix." Reuters (8/19, Krauskopf) also covers the story.

CMS Will Cover Warfarin Gene Tests In Clinical Trials, But That's It

Medicare will only cover genetic testing for individual response to the blood-thinner warfarin in the context of controlled clinical studies, effective immediately, CMS said Aug. 3. Prior to the decision, there was no national policy on pharmacogenomic testing to predict warfarin response, nor were there any local coverage determinations on the topic. The agency says there is not enough evidence to show that Medicare beneficiary health outcomes are improved by adjusting warfarin dosing based on assessment of mutations to the CYP2C9 or VKORC1 genes. But data does suggest some link between the mutations and a patient's sensitivity to experiencing potentially fatal excessive bleeding in response to the drug. That is enough for a coverage-withevidence- development policy, where beneficiaries enrolled in qualifying trials are covered. Such a policy is appropriate where additional data gathered in the context of clinical care would further clarify the impact of these items and services on the health of Medicare beneficiaries,
Under the new policy, CMS will permit coverage for beneficiaries who have not been previously tested for CYP2C9 or VKORC1 alleles; have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and are enrolled in prospective, randomized, controlled clinical studies that meet
specified standards. A covered clinical trial must compare the frequency
and severity of major and minor hemorrhaging, various thromboembolic events, and mortality in patients whose warfarin management includes
genetic testing and in those who undergo a standardmanagement program.

Research suggests VTE patients treated with enoxaparin may incur lower hospital costs.

MedPage Today (8/20, Emery) reported, "Costs were lower for patients who received preventive treatment for venous thromboembolic disease (VTE) with the anticoagulant enoxaparin...than patients treated with unfractionated heparin (UFH), a new industry-sponsored study found." In fact, those "who received...enoxaparin, a low molecular weight heparin sold as Lovenox and Clexane, incurred an average adjusted hospital cost of $6,443, which was $1,080 less than the costs incurred by" the UFH patients, according to data appearing in the Journal of Thrombosis and Thrombolysis. The work is noteworthy, because "more than 600,000 nonfatal, symptomatic cases of VTE and nearly 300,000 deaths attributable to VTE occur in the US each year." And, "based on 1997 US hospital discharge data...the nationwide expenditures related to VTE are estimated at $1.5 billion per year." In light of that, "national performance measures" were initiated "requiring US hospitals to successfully implement VTE prophylaxis guidelines, which may encourage physicians to rethink the effectiveness and cost of various medications."
August

Study suggests Brilinta may prevent more heart attacks, strokes than Plavix.

Bloomberg News (8/31, Cortez) reports that "AstraZeneca Plc's experimental blood-thinner Brilinta [ticagrelor] prevented 16 percent more heart attacks, strokes, and deaths than standard therapy with Sanofi-Aventis SA's and Bristol-Myers Squibb Co.'s Plavix [clopidogrel] in a study" presented at the European Society of Cardiology meeting.
The AP (8/31, Cheng) reports that investigators "followed 18,624 patients worldwide from 2006 to 2008." Approximately "half the patients were taking...Plavix, while the other half were taking" AstraZeneca's "experimental drug." The researchers found that "those on Brilinta had a 4.5 percent chance of dying, versus a 5.9 percent death risk for patients on Plavix." Investigators "also found Brilinta was safer for patients since they were less likely to have bleeding problems, one of Plavix's known side effects." However, Brilinta "had its own adverse effects, including breathing and heart rhythm abnormalities." The AstraZeneca drug "is not yet on the market."
The Los Angeles Times (8/30, Maugh) Booster Shots blog reported that, "like Plavix and Effient...Brilinta acts by preventing blood platelets from clumping together to form clots. One advantage it has is that its effects disappear within a couple of days; the other drugs last a week or so." Thus, "patients given Plavix or Effient when they arrive at a hospital with heart problems usually must wait five or six days for surgery to give the drugs time to wear off. Brilinta patients can undergo surgery sooner."
The UK's Press Association (8/31) reports that "AstraZeneca now plans to apply for regulatory approval for Brilinta in the United States and Europe during the final quarter of the year, with a view to making it available as soon as possible, and possibly by the end of 2010."

Dabigatran may reduce stroke risk for patients with atrial fibrillation better than warfarin, study suggests.

The AP (8/31, Cheng) reports, "An experimental drug," called dabigatran etexilate, "reduces the stroke risk in patients with irregular heartbeats by more than three times, compared with the popular drug warfarin," according to research presented at the European Society of Cardiology meeting. But, individuals "taking the new drug...were slightly more likely to have heart attacks or stomach pain," according to the research. The AP points out that dabigatran "has not yet been approved in the United States but is sold as Pradaxa in 40 countries to prevent blood clots."
The UK's Telegraph (8/30) reported that "more than 18,000 patients from 44 countries took part in the three year RE-LY (randomised evaluation of long term anticoagulant therapy) trial, the largest of its kind ever conducted." The participants, all of whom "suffered from atrial fibrillation," were "randomly assigned to treatment either with Pradaxa or warfarin."
The Wall Street Journal (8/31, Winslow) reports that at least three other drug compounds are in or are close to late stages of development as alternatives to warfarin. Bloomberg News (8/31, Cortez), MedPage Today (8/30, Peck), Reuters (8/31, Hirschler), HeartWire (8/30, Stiles), and the UK's Press Association (8/31) also covered the story.

Otamixaban prevents death, cardiac complications for those with mild heart attacks better than standard treatment, study suggests.

Bloomberg News (8/31, Cortez) reports, "Sanofi-Aventis SA's experimental anti-clotting drug," called otamixaban, "prevented deaths and cardiac complications in people with mild heart attacks and severe chest pain better than standard treatment," according to a study presented at the European Society of Cardiology meeting. Those taking "otamixaban were 40 percent less likely to have a second heart attack, need an emergency procedure to open clogged arteries or die than those given heparin and Schering-Plough Corp.'s Integrilin [eptifibatide]."
Dow Jones Newswires (8/31, Douglas) adds that Sanofi said the "odds of death, another heart attack or other complications was cut by between 27% and 42% among patients getting otamixaban, depending on the dose." The trial of 3,241 patients used five different doses of otamixaban and patients "receiving the lowest dose were stopped following a review by an oversight board." Dr. Marc Sabatine, an investigator in the study and a cardiologist at Brigham and Womens Hospital, Harvard Medical School, said, "The data show that intermediate dosages of otamixaban may offer substantial reduction in major coronary complications in patients presenting with acute coronary syndrome, with bleeding rate comparable to current therapy."
MedPage Today (8/30, Peck) also reported that the trial "of otamixaban in patients with non-ST-elevation (N-STEMI) acute coronary syndromes showed only moderate efficacy at intermediate doses, a benefit that was not compelling."
Study indicates double dose of clopidogrel may fail to prevent more heart attacks, strokes than standard dose.
Dow Jones Newswires (8/30, Loftus) reported, "A double dose of popular anti-clotting drug Plavix [clopidogrel] failed to meet researchers' primary goal of preventing more heart attacks, deaths and strokes than the standard dose -- and it increased the risk of bleeding," according to a study presented at the European Society of Cardiology meeting. However, the study, which included approximately 25,000 heart patients, "did show that within a subgroup of patients -- those undergoing a common artery-opening procedure -- the higher Plavix dose was able to prevent more heart attacks and certain procedure complications than the standard dose." Dow Jones notes, "Although the study missed its primary goal, the positive subgroup finding could support use of the higher Plavix dose." In addition, a "previous clinical trial showed Effient [prasugrel] to be superior to standard-dose Plavix, but with an increased risk of major bleeding." HeartWire (8/30, O'Riordan) also covered the story.

Apixaban May Not Minimize Bleeding Risk but May Not Be Noninferior to Enoxaparin for Thromboprophylaxis

Apixaban may minimize bleeding risk but may not be noninferior to enoxaparin for thromboprophylaxis after knee replacement, according to the results of a double-blind, double-dummy study reported in the August 6 issue of the New England Journal of Medicine. Low-molecular-weight heparins [LMWHs] such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin. Apixaban, a specific factor Xa inhibitor, may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use.
As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. The results support the view that specific factor Xa inhibition has the potential to combine effective thromboprophylaxis with a low risk of bleeding and may have a favorable benefit-to-risk ratio as compared with that for low-molecular-weight heparins.
N Engl J Med. 2009;361:594-604. Abstract

Prasugrel Also Reduces Cardiovascular Events in Patients Who Receive GP IIb/IIIa Inhibitors

An analysis of the TRITON-TIMI 38 trial has shown that prasugrel (Effient, Daiichi Sankyo/Eli Lilly) significantly reduces the risk of cardiovascular events even in the setting of potent platelet inhibition with a GP IIb/IIIa inhibitor [1]. Like the overall study, bleeding risks were higher with prasugrel, but the use of a GP IIb/IIIa inhibitor did not heighten the relative risk of bleeding when compared with clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb).
The results of the current study suggest that more potent platelet inhibition with prasugrel compared with clopidogrel significantly reduces the risk of death, MI, or stroke at 30 days by 22% to 24%, regardless of whether a GP IIb/IIIa inhibitor is used. Although prasugrel increased the risk of bleeding as compared with clopidogrel, the use of a GP IIb/IIIa inhibitor did not accentuate the risk of bleeding with prasugrel as compared with clopidogrel.
At 30 days, and similar to the overall findings, there was a significant benefit of prasugrel over clopidogrel in reducing the primary end point of cardiovascular death, MI, and stroke in patients who received GP IIb/IIIa inhibitors and those who did not. Like the main trial, the reduction was driven primarily by a reduction in the risk of MI. Investigators also report reductions in stent thrombosis and urgent target vessel revascularization in patients who received and those who did not receive GP IIb/IIIa inhibition.

FDA Approves Antihemophilic Factor for Routine Prophylaxis in Children With Hemophilia A

The US Food and Drug Administration (FDA) has approved a new indication for antihemophilic factor (recombinant) intravenous injection (Helixate FS, CSL Behring) for routine prophylaxis to reduce the frequency of bleeding episodes and the risk for joint damage in children aged 16 years or younger with hemophilia A and no preexisting joint damage. The recommended dose is 25 IU/kg administered every other day.
The approval was based on data from a multicenter, open-label, prospective randomized study of 65 boys younger than 30 months, showing that prophylactic use of antihemophilic factor yielded less joint damage than episodic treatment, as detected by magnetic resonance imaging or radiography (7% vs 42%; P = .002). The mean annual frequency of bleeding episodes was likewise reduced (index joint hemorrhages, 0.63 bleeds/year vs 4.89 bleeds/year).
On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints; ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study.
The study data also demonstrated that antihemophilic factor is safe and effective for routine use. Adverse events most commonly reported with product use are inhibitor formation in previously untreated or minimally treated patients, skin-associated hypersensitivity reactions, infusion site reactions, and central venous access device line-associated infections. Serious adverse events may include systemic hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to antihemophilic factor.
Antihemophilic factor intravenous injection previously was approved for the control and prevention of bleeding episodes in hemophilia A in patients aged 0 to 16 years.

TPA for Stroke Out to 4.5 Hours

In May, the American Heart Association (AHA)/American Stroke Association (ASA) gave the green light to the use of tissue plasminogen activator (tPA) to treat acute ischemic stroke between 3 and 4.5 hours after symptom onset. The AHA/ASA Science Advisory, published online May 28 in Stroke, however, still emphasized that time is of the essence when it comes to treatment of stroke. Number 1 liniitation of use is still the number of people in the public with acute symptoms getting to urgent medical attention. There are still too many people who don't call 911 quickly enough to get in during that very tight time window to be eligible for tPA.
The second issue is the organization of stroke care. Not every hospital in the United States is equipped with 24/7 capability of providing acute tPA for stroke patients. Over the last few years, with the certification of primary stroke centers, the number of primary stroke centers is rapidly growing, but there are still segments of the population in the United States that don't have adequate access to rapid stroke care.
This new evidence from ECASS 3, in conjunction with the prior meta-analysis and in conjunction with the SITS-MOST study and other publications that have shown that tPA is safe and efficacious up to 4.5 hours after acute stroke, led the AHA/ASA to issue this new advisory, giving tPA a class 1, level B recommendation for use in the 3-to-4.5-hour window.
The big issue is we don't want clinicians to delay treatment. So even though we now can treat with intravenous tPA out to 4.5 hours, that doesn't mean you should wait. We don't want to send the wrong message to the public. It's still clear to everyone, and all the data shows, that the earlier you treat the better the outcomes.
Resistance still comes from the fear of causing hemorrhage. What we try to educate clinicians about is - even accounting for this risk of hemorrhage, which is there with tPA - there is still clear and substantial benefit. But you know clinicians always want to avoid causing harm, and therefore minimize risk, and so to me that is one of the main reasons that people may not use tPA. But it's so clear from all of the trials - the trials that preceded the guidelines and this more recent trial that confirms the efficacy and reasonable safety in the expanded time window - that tPA is of clear benefit for acute stroke, despite the risk of hemorrhage.

First Genomewide Data on Gene Variant Affecting Clopidogrel Response

The common variant of the CYP2C19 gene that has previously been associated with a blunted response to clopidogrel does indeed affect platelet aggregation, according to the results of the first genomewide association study (GWAS) looking at this issue. Clopidogrel was administered to a population of healthy Amish people and then genotyped the participants to identify the loss-of-function variant CYP2C19*2, which they found to be associated with a diminished response to the drug. They then replicated the findings in an independent sample of 227 patients undergoing PCI and found that among those taking clopidogrel, those who had the CYP2C19*2 variant were twice as likely as those without the variant to sustain an ischemic event in the following year.
This loss-of-function CYP2C19 genotype is common, with 24% of white people, around 18% of Mexicans, 33% of African Americans, and 50% of Asians carrying at least one allele. And 3% to 4% of the population carries two copies of the allele, with those individuals being more severely affected in terms of a blunting in their response to clopidogrel, he noted.
Shuldiner says that if a physician suspects that an individual is homozygous for the CYP2C19*2 variant, "then maybe a genetic test could be indicated in that circumstance, because those individuals might be better off on a higher dose of clopidogrel or a different medication altogether." But he maintains that it is far too soon to begin routine testing for this genotype, adding that CYP2C19*2 is likely only one of "several genetic variants to be discovered that will predict response to clopidogrel. It may be that in the future a panel of tests may be most predictive."

Use of Low-Dose Aspirin in Primary Prevention of Cardiovascular Events Not Recommended

The use of low-dose aspirin in the primary prevention of cardiovascular events in healthy individuals with asymptomatic atherosclerosis is currently not warranted.
In the randomized trial of 3350 subjects deemed at high risk for cardiovascular and cerebrovascular events because of a low ankle-brachial index (ABI) (<0.95), aspirin had absolutely no effect on reducing events compared with placebo, However, aspirin did increase the risk of major hemorrhage.
.
The results of the trial are in conflict with findings from a meta-analysis from the Antithrombotic Trialists' (ATT) collaboration, which was published earlier this year in the Lancet Between 1998 and 2001, the AAA trialists invited men and women 50 to 75 years of age to undergo screening for asymptomatic atherosclerosis by measuring their ABI. A low ABI in otherwise-healthy individuals has been shown to be related to an increased risk of future cardiovascular events. Because it is simple and noninvasive, the ABI has the potential to be used as a screening test to detect high-risk individuals, Fowkes explained.
They were randomly allocated to 100-mg enteric coated aspirin daily or to placebo and followed for a mean of 8.2 years. The primary end point of the trial was the composite of an initial fatal or nonfatal coronary event, stroke, or revascularization. Secondary end points were all vascular events, which included a composite of initial fatal or nonfatal coronary event, stroke, or revascularization, angina, intermittent claudication, transient ischemic attack, and all-cause mortality.
Patients in both groups were matched for age (mean age 62 years), gender (roughly 30% were men), and comorbidities. One-third of the study population consisted of smokers. Aspirin had no effect in terms of reducing cardiovascular and cerebrovascular events. In all, there were 357 events, 181 (10.8%) in the aspirin group and 176 (10.5%) in the placebo group (hazard ratio 1.03, 95% CI 0.84-1.27).
40% of patients were noncompliant and did not take their aspirin as prescribed over the duration of the trial. Such a low compliance rate could have affected the results. "The 60% compliance rate is the typical level of compliance that you will find in the primary-prevention setting, and obviously there are many reasons that people stop taking aspirin. So whether aspirin is beneficial in clinical practice among patients who have a low ankle-brachial index and who are fully compliant with aspirin is unknown, and so our results cannot be extrapolated to that situation," he said.

CURRENT OASIS-7: Benefit to Doubling Clopidogrel Dose in ACS Patients Undergoing PCI

Doubling the loading and maintenance doses of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in ACS patients undergoing planned PCI significantly reduces stent thrombosis and cardiovascular events, largely driven by reductions in MI, without a significant increase in major bleeding. In the overall cohort, which included 7855 patients who did not undergo PCI because no significant CAD was identified on the coronary angiogram or who discontinued therapy because they were scheduled for CABG surgery, there was no significant difference in the primary composite end point of death, MI, or stroke in patients randomized to the standard or doubled clopidogrel doses. In addition, researchers also showed there was no difference in the safety or efficacy of higher-dose aspirin when compared with lower-dose aspirin.
The CURRENT OASIS-7 study is a 2x2 factorial, randomized trial studying the optimal dose of clopidogrel and aspirin in ACS patients presenting to an emergency department and scheduled to undergo an early invasive strategy with intent to perform PCI no later than 72 hours after randomization. Mehta said that recent data have suggested that doubling the loading and maintenance dose of clopidogrel would result in a greater and more rapid antiplatelet effect, which would translate into better clinical outcomes. Regarding aspirin, there is large variance worldwide, including disparities in the clinical guidelines, about the optimal aspirin dose for the treatment of ACS.
In this trial, patients assigned to high-dose clopidogrel received a 600-mg loading dose on day 1 and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard clopidogrel arm received a 300-mg loading dose on day 1, followed by 75 mg once daily until 30 days. Patients were also assigned in an open-label manner to 300 to 325 mg of aspirin once daily or 75 to 100 mg aspirin once daily.
Compared with low-dose aspirin, use of aspirin 300 to 325 mg did not result in any significant differences in major bleeding, defined as TIMI major bleeding or CURRENT major and severe bleeding. Mehta said that the CURRENT definitions of bleeding are more sensitive than TIMI and primarily consider other factors such as the need for inotropes, surgery, or a blood transfusion. In terms of efficacy, there was no significant difference in the primary outcome or its components, although there was a numerical reduction with the higher dose of aspirin.
In terms of the bleeding risks, there was no difference with the standard and doubled clopidogrel doses when the TIMI major bleeding definition was used. However, there was a significant increase in bleeding when the CURRENT major and severe bleeding definition was used, and this was driven by an increased need for red blood cell transfusions. Importantly, said Mehta, there was no difference in fatal bleeding, intracranial hemorrhage (ICH), or CABG-related major bleeding.

Re-Ly: Oral Antithrombin Dabigatran Outshines Warfarin in Atrial Fib

An oral anticoagulant that does not go by the name of warfarin prevented strokes and peripheral embolic events in patients with atrial fibrillation (AF) significantly better than that much older drug at a higher dose and just as well at a lower dose in a huge randomized trial [1]. It was also just as safe as warfarin or better than it, respectively, with respect to major bleeding events, according to investigators reporting today at the European Society of Cardiology (ESC) Congress 2009 and in a simultaneous online release from the New England Journal of Medicine. Both dosages were associated with fewer intracerebral bleeds.
The potential new contender in AF, dabigatran etexilate (Boehringer Ingelheim), is one of several oral anticoagulants in clinical trials for the prevention of AF-related thromboembolism, venous thromboembolism (VTE), and other conditions for which warfarin had long been the only choice. A competitive thrombin inhibitor, dabigatran is currently available for VTE prevention during hip- and knee-replacement surgery in the European Union as Pradaxa and in Canada as Pradax.
In the new trial, the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY), dabigatran given at 150 mg twice a day reduced the annualized risk of the primary end point, stroke/peripheral embolic events, by 34% (p<0.001) and the risk of hemorrhagic stroke by 74% (p<0.001) compared with warfarin. The higher dabigatran dose was associated with a slightly but significantly (p=0.048) increased risk of MI, a secondary end point.
Pointing out that it takes several days to achieve therapeutic warfarin levels and that its effects have to be monitored, Ezekowitz said dabigatran "has a rapid onset of action, there are very few drug-drug interactions and those that occur have proven not to be important, and the patients don't require any form of monitoring. Operationally, warfarin is a much more difficult drug to use, and dabigatran is obviously much more user friendly for both the patients and the physicians taking care of those patients.
The relative risks vs warfarin were 0.91 (95% CI 0.74-1.11) for the low-dose (p<0.001 for noninferiority) and 0.66 (95% CI 0.53-0.82) for the high-dose group (p<0.001 for superiority).Annualized mortality was 3.75% and 3.64% for the low- and high-dose groups, respectively, compared with 4.13% for warfarin. The relative risk was 0.91 (95% CI 0.80-1.03) for the low dose (p=0.13) and 0.88 (95% CI 0.77-1.00) for the high dose (p=0.051). Hemorrhagic stroke rates were 0.12%/year (p<0.001) and 0.10%/year (p<0.001) for the low- and high-dose groups respectively, and 0.38% for warfarin.
The rates for major bleeding were 2.71 (p=0.003 vs warfarin) for the low dose, 3.11 (NS vs warfarin) for the high dose, and 3.36 for warfarin.
Significantly more patients taking dabigatran went off the drug, which Ezekowitz attributes largely to the severe dyspepsia, the main side effect that occurred more often with dabigatran than with warfarin.

PLATO Shows Benefits of Ticagrelor Over Clopidogrel

Treatment of patients with acute coronary syndrome (ACS) with the investigational oral antiplatelet agent ticagrelor (AstraZeneca) has significantly reduced the rate of MI/stroke/cardiovascular death compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in the phase 3 Platelet Inhibition and Patient Outcomes (PLATO) study, reported here at the European Society of Cardiology 2009 Congress during a hotline session and published online simultaneously in the New England Journal of Medicine [1].
Unlike clopidogrel and another newer antiplatelet agent, prasugrel (Effient, Lilly/Daiichi), which has just been approved, ticagrelor is not a thienopyridine, and its mechanism of action is unique in that it is reversible, although it does have the drawback of twice-daily dosing. There was no increase in the rate of overall major bleeding with ticagrelor as compared with clopidogrel in PLATO. Excess bleeding with prasugrel compared with clopidogrel is one of its drawbacks.
The reduction in total mortality [with ticagrelor] was the most striking result. We saved 14 lives per 1000 treated patients, and this has not been seen over the past 20 years with a new antiplatelet agent. So I think the combination of a reduction in mortality and ischemic events, without a cost in bleeding, is very impressive." In PLATO, the rates of death from any cause were 4.5% with ticagrelor and 5.9% with clopidogrel (p<0.001), with a significant relative risk reduction (22%).
In PLATO, 18 624 patients admitted to the hospital with ACS in 43 countries around the world, with or without ST-segment elevation, were randomized to receive either ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter) in a double-blind, double-dummy fashion for one year, although patients left the study at their six- or nine-month visit if the targeted number of 1780 primary end points had occurred by that time. Patients also received aspirin, at a dose of 75 mg to 100 mg day, unless they could not tolerate the drug.
At 12 months, the primary end point--a composite of death from vascular causes, MI, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those taking clopidogrel (hazard ratio 0.84; p<0.001). Predefined secondary end points were also significantly reduced with ticagrelor as compared with clopidogrel, such as MI and death from vascular causes. But there was no significant difference in the risk of No significant difference in the rates of major bleeding were found between the two agents (11.6% and 11.2% respectively; p=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to CABG than clopidogrel (4.5% vs 3.8%; p=0.03) by the PLATO definition of bleeding, including more instances of fatal intracranial bleeding, but fewer of fatal bleeding of other types.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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