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WHAT'S NEW IN COAGULATION: JUNE 2011

Bristol-Myers Recalling One Lot Of Warfarin.

Bristol-Myers Squibb Co. said Monday it is recalling one production lot of its blood thinner Coumadin [warfarin] after finding an oversize tablet." The company said it has notified the Food and Drug Administration about the recall. It was reported that "the recall applies to Coumadin Crystalline 5 mg tablets -- lot number 9H49374A -- in 1,000 count bottles, which are distributed to pharmacies for dispensing to customers in prescription quantities."

EU Approves Bristol-Myers Squibb, Pfizer Blood Thinner.

The European Commission approved a new blood thinner from Bristol-Myers Squibb and Pfizer for the prevention of blood clots in patients who have undergone hip or knee replacement surgery. It's the first approval for the drug, to be sold under the name Eliquis (apixaban), the companies said" in a statement released on Friday. "About 40 percent to 60 percent of people undergoing hip or knee surgery are at risk of developing blood clots, known as venous thromboembolic events, if not treated preventively, the New York-based companies said. The treatment is being studied in 60,000 patients to prevent and treat clots and strokes in a variety of health disorders. The drug was approved based on two studies that showed better outcomes for patients taking twice-daily Eliquis rather than receiving an injection of the typical current treatment. Bleeding side effects were approximately the same between the two groups." The medication "is not available in the US, though Pfizer and Bristol-Myers plan to submit it to the Food and Drug Administration later this year. The companies are seeking approval to prevent stroke in patients with a type of heart defect.

GSK, Human Genome Sciences Lupus Drug Wins Backing Of European Committee.

The GlaxoSmithKline and Human Genome Sciences said the European Medicines Agency's Committee for Medicinal Products for Human Use issued a positive opinion recommending Benlysta (belimumab) to treat lupus.  One company-funded trial showed 43 percent of patients given a high belimumab dose with standard therapies felt relief versus about 34 percent treated with a placebo and standard therapies. In addition, researchers found no further organ damage after one year of treatment with belimumab.  

Investigational Drug No Better Than Aspirin In Preventing Second Stroke.

A new drug that had shown promise in animal testing is not better than aspirin in preventing a second stroke in someone who's already had one," according to a study published online in The Lancet and presented at the European Stroke Conference. Investigators "stopped the study early because the drug, terutroban, showed no extra benefit."  The reports that research published in the American Journal of Medicine further clouds the debate surrounding the use of aspirin for preventing cardiovascular problems. Investigators looked at data from nine different studies, which included more than 100,000 individuals. The researchers found that 3.65 percent of the participants who were randomly assigned to take aspirin died during the studies, while 3.74 percent of participants not taking aspirin died.

Can Genetic Changes Predict Manifestations of SLE?

Clinical manifestations of systemic lupus erythematosus (SLE) may range from laboratory abnormalities without consequences to life-threatening organ disease.^[1] Although genome-wide association studies have identified about 2 dozen genetic intervals containing SLE-susceptibility alleles,^[2] the interplay between genetics and SLE manifestations has not been widely explored.In this study published in PLoS Genetics, which is the first to examine disease manifestations by genetic association, several hundred thousand single nucleotide polymorphisms (SNPs) previously identified through genome-wide association studies were typed in 1919 patients with SLE and 4813 matched controls, and 22 SLE-associated genetic regions were tested for their association with SLE manifestations and particular SLE subphenotypes. The analysis was done individually as well as with a composite "genetic risk score" (GRS), which takes into account the SLE risk alleles present and the odds ratio for the risk for SLE at each of the alleles.

The investigators found that renal disease and anti-dsDNA antibodies are associated with a SNP that tags HLA-DR3. These data were to be expected: Anti-dsDNA (double-stranded DNA) and renal disease are known to be highly correlated, and there is already evidence supporting a causative role of these autoantibodies in SLE renal disease.^[3] In addition, studies of HLA in patients with SLE have consistently shown a stronger relationship between SLE-associated antibodies and HLA type than with the disease itself.^[4]

However, the investigators also found that anti-dsDNA was associated with several other SNPs, including those marking the STAT4 and ITGAM genes. Younger age at diagnosis, which is a frequent correlate of severe disease, was also associated with STAT4, whereas STAT4 had a protective effect for arthritis.

Viewpoint

This study is a first approximation of identifying which manifestations of SLE are genetically determined. Some manifestations or subphenotypes of SLE were associated with single genes, whereas others were associated with total genetic burden as assessed by the calculated GRS. (Of note, the GRS was not very different between patients and controls, indicating that these SLE risk alleles are common in the population and are not predictive for disease, either individually or when combined.) A third group was not associated with any of the studied alleles.

However, it is not clear how helpful these subphenotype categorizations may be clinically. For example, the presence of "hematologic disorder" was associated with the GRS. However, the hematologic criteria for SLE classification includes lymphopenia, which is present in a large proportion of patients with active disease but has no known clinical consequences. By contrast, the classification also includes thrombocytopenia and autoimmune hemolytic anemia, both of which are found in only 10%-20% of patients with SLE but are medically serious complications of the disease.

Similarly, this first step in determining how alleles of STAT4 contribute not only to SLE but also to more severe disease could lead to interventions designed to treat or prevent severe manifestations of SLE. However, translating these findings into new approaches to SLE may be years away.

Finally, the SNPs studied in this work were identified by genetic association with SLE itself; genes for particular SLE manifestations that are not risk factors for the overall SLE phenotype were not studied. More than anything, studies such as this one highlight the fact that much work lies ahead to determine the genetics of SLE manifestations.

New Study Refutes Role of PON1 Gene in Clopidogrel Treatment

A new study has refuted previous data suggesting that PON1 gene polymorphisms are involved in the activation of clopidogrel. The study in the European Heart Journal, found that PON1 polymorphisms did not influence platelet response to clopidogrel or the risk of stent thrombosis in clopidogrel-treated patients, whereas the CYP2C19*2 genotype had an impact on both antiplatelet effect of clopidogrel and risk of coronary stent thrombosis.

"With the results reported here, we can confirm the previously indicated key role of CYP2C19*2 on clopidogrel treatment efficacy and refute a significant impact of the PON1 QR192 genotype in this regard," the researchers conclude in their paper.  Nature Medicine paper reported a common polymorphism (Q192R) in the PON1 gene that was associated with increased platelet aggregation and worse clinical outcomes in clopidogrel-treated PCI patients.

Sibbing's team wanted to see if they could replicate these findings. They thus conducted a two-part study. For the first part, the researchers genotyped and assessed ADP-induced platelet aggregation in 1524 patients. The relationship between the PON1 Q192R polymorphism and degree of platelet aggregation was investigated. The other gene polymorphism known to be involved in clopidogrel metabolism--CYP2C19*2--was used as a positive control. For the second part of the study, the clinical impact of both genetic variants was investigated by comparing their frequencies in the 127 patients from the first part of the study who experienced early stent thrombosis with their frequencies in the approximately 1400 patients who did not have an early stent thrombosis.

Results from the first part of the study showed that for PON1, platelet-aggregation values were similar across all genotype groups. "Indeed, median aggregation values were virtually identical across PON1 genotype groups and even numerically lower in Q192R-allele carriers," the researchers write. But for CYP2C19 genotypes, significantly higher aggregation values were found in patients either heterozygous or homozygous for the *2 allele when compared with those with wild-type alleles. In the second part of the study, no differences were observed for PON1 Q192R genotype distributions between patients with and without stent thrombosis, whereas CYP2C19*2 genotypes were found to be more frequent in the patients with stent thrombosis vs those without stent thrombosis.

Sibbing says he can't explain why the PON1 association was seen in the Nature Medicine paper, but he suggested that perhaps that study was not big enough to show a true result and that the distribution of the PON1 genotypes may not have reflected the normal situation. "They had a relatively low number of cases (41) and controls (only 70). This could make it easily subject to bias. Our study is more reliable, as we have a lot more control patients--more than 1400." He also pointed out that the control patients in his study were not selected in any way. They were consecutive patients who were included in the platelet-aggregation study.

Sibbing also pointed out that the PON1 Q192R genotype distributions markedly differed between the control groups in the Nature Medicine study and the current study, but "the genotype distribution in our large control group is in line with that reported in other studies assessing PON1 Q192R-genotype distributions in large cohorts of patients with coronary artery disease." The researchers say: "Specifically for the results reported here, it seems unlikely that the PON1 Q192R genotype might be a useful risk marker for guiding antiplatelet therapy after stenting. For CYP2C19*2, however, this question can now be addressed only in dedicated randomized trials that randomize *2 allele carriers to an intensified treatment regimen." They add that the TARGET-PCI trial is currently addressing this issue with a combined approach of both platelet-function testing and genotyping.

ASA-STAT: Aspirin/Statins Fail in Pulmonary Arterial Hypertension

Neither low-dose aspirin nor simvastatin showed any clinical benefit in patients with pulmonary arterial hypertension (PAH) in the ASA-STAT study.In pulmonary arterial hypertension, the small muscular pulmonary arteries show endothelial proliferation and smooth-muscle hypertrophy, which leads to right ventricular failure. While current treatments are targeted toward correcting abnormalities in prostacyclin, nitric-oxide, and endothelin-1 levels, many other mechanisms are thought to play a role in the condition, such as increased thromboxane, platelet activation, oxidative stress, and inflammation.

Aspirin reduces thromboxane levels and inhibits platelet aggregation, while statins reduce oxidative stress and have beneficial endothelial effects.

For the 2x2 factorial study, 92 patients with PAH were randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was six-minute-walk distance at six months.

Stopped early due to futility

The trial was stopped early after 65 patients had been enrolled because of futility in reaching the primary end point for simvastatin. Results showed no difference in the six-minute-walk distance at six months between aspirin and placebo or between simvastatin and placebo. The simvastatin group actually showed a trend toward a worse six-minute-walk distance and more dyspnea. In terms of side effects, there was a trend toward more major bleeding episodes with aspirin than with placebo (four events vs one event).

In addition to showing no difference in the primary end point, there was also no effect of aspirin or simvastatin on any secondary end point, such as N-terminal pro-brain-type natriuretic peptide (NT-proBNP) levels or quality of life. He suggested that it may have been difficult to show a benefit of aspirin and simvastatin because the patients were already taking several drugs known to be effective for PAH. He noted that aspirin did reduce thromboxane by more than 90%, but the effect was not as great as was expected, which might have been due to possible aspirin resistance or perhaps the generation of vascular thromboxane, which would not be affected by aspirin.

1.     Kawut SM, Bagiella E, Lederer DJ, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension. ASA-STAT. Circulation 2011; DOI: 10.1161/CIRCULATIONAHA.110.015693

Prognostic Claim for VerifyNow Platelet Test in EU

The platelet-function test VerifyNow P2Y12 (Accumetrics), has been granted a CE mark in Europe for a new, updated claim for prognostic use to help identify patients with high residual platelet reactivity who are poor responders to antiplatelet agents such as clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis). The claim is based on a number of published studies, including a patient-level meta-analysis comprising more than 3000 subjects presented at the American College of Cardiology (ACC) meeting recently. Based on this meta-analysis, a cutoff point of platelet reaction units (PRU) of 230 or above was determined for characterizing patients who are poor responders to clopidogrel, and this information has been incorporated into the EU package inserts for the VerifyNow P2Y12 test,

There's a large body of data that points to 230 being a good cutoff . Not included in the meta-analysis and not covered in the claim are two recently completed clinical trials that have failed to show a benefit of treatment adjustments based on point-of-care testing with the VerifyNow P2Y12 assay: the GRAVITAS study, which looked at doubling the clopidogrel dose in poor responders, and TRIGGER PCI, which compared clopidogrel with prasugrel (Effient, Eli Lilly/Daiichi Sankyo) based on platelet reactivity but was stopped early due to too few events. Both of these trials were performed in patients with stable coronary artery disease, which is thought to be one reason event rates were too low to show significant differences between groups based on responses to antiplatelet therapy. The CE mark is based on self-verification by the company. The claim was substantiated on the basis of the consistent and overwhelming body of data supporting the prognostic utility of the VerifyNow P2Y12 test," she commented. In the US, VerifyNow P2Y12 is approved, but it does not have this additional prognostic claim, she noted.

VerifyNow Well Validated, But Cost May Be a Barrier to Use

In the meta-analysis reported at ACC and provided to support this new prognostic claim for VerifyNow PY212, those patients with a PRU of 230 or greater had two-and-a-half times the risk of stent thrombosis compared with those with a PRU <230 (hazard ratio 2.5; p=0.005).The only possible obstacle to its use is cost, he noted; in his hospital the test is around €40.

Apixaban Approved in Europe for Use After Hip/Knee Surgery

The oral direct factor Xa inhibitor apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) has been approved by the European Commission for use in the 27 countries of the EU for the prevention of venous-thromboembolic (VTE) events in adult patients who have undergone elective hip- or knee-replacement surgery [1]. This is the first approval of the drug worldwide.The approval is based on the ADVANCE-2 and ADVANCE-3 clinical trials, in which apixaban given orally twice daily showed superior efficacy to enoxaparin 40 mg given once daily by injection in the prevention of VTE in total knee and total hip replacement, without increasing bleeding.

The recommended dosage for apixaban is 2.5 mg twice daily. The recommended duration of treatment is 32 to 38 days for patients undergoing hip-replacement surgery and 10 to 14 days for patients undergoing knee-replacement surgery. Apixaban is one of a host of novel oral anticoagulants nearing or already on the market. Two of these new anticoagulants--another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim)--have been available for VTE prevention for some time in a number of countries.

Of the three oral anticoagulants now approved in Europe, both rivaroxaban in RECORD and apixaban in ADVANCE have been shown superior to enoxaparin, the current standard of care for VTE prevention post–orthopedic surgery. Expert in the field, Dr Alexander Turpie (McMaster University, Hamilton, ON), has previously told heartwire that, viewing these trials side by side, the efficacy results with rivaroxaban seemed slightly better, but the bleeding slightly worse than with apixaban. He attributed these differences to the timing of administration, as rivaroxaban was given six to eight hours after surgery in RECORD, whereas apixaban was given 18 hours after surgery in ADVANCE, and the closer to surgery these drugs are given, the better the outcome but the higher the bleeding risk.

Bristol-Myers Squibb and Pfizer are using the timing of apixaban in ADVANCE to claim: "Apixaban is the only oral anticoagulant with a 12- to 24-hour postsurgery initiation window, which may help physicians to observe and stabilize postsurgical patients before beginning treatment." Rivaroxaban has the advantage, however, of being the only one of these new oral anticoagulants to have a once-daily dosing.

Dabigatran has not shown quite such good results in the orthopedic setting, being shown noninferior to current standard of care in two studies but failing to meet noninferiority in other trials.

But dabigatran has the lead in the much larger indication of stroke prevention in atrial-fibrillation patients, having been approved in this indication in the US and Canada. Rivaroxaban has also shown promising results but has not yet gained approval for this indication.

Apixaban is also being investigated in phase 3 trials for the treatment of VTE, the prevention of VTE in hospitalized acutely ill medical patients, and the prevention of stroke and other thromboembolic events in patients with atrial fibrillation. Its development for acute coronary syndromes (ACS) was dropped after an unacceptable bleeding risk was seen in the APPRAISE-2 trial.

References

1. Bristol-Myers Squibb. Eliquis (apixaban) approved in Europe for preventing venous thromboembolism after elective hip or knee replacement [press release]. May 20, 2011. Available here.

Ticagrelor Press Release Panned by Experts

A press release issued two weeks ago by AstraZeneca [1]--stating that its novel antiplatelet agent, ticagrelor (Brilinta), is a cost-effective treatment vs generic clopidogrel for treating acute coronary syndrome (ACS) patients--has been roundly criticized for claiming that the analysis "is now published," when in fact all that was available in print was an abstract of a poster to be presented at a meeting today/The abstract provides very little in the way of detail as to how the analysis was performed and the figures arrived at and will not have been peer reviewed in the way that a journal manuscript would have been, experts in the field commented to heartwire . As such, it is not an appropriate basis for the issuing of a news statement claiming such advantages for ticagrelor, they say.

Ticagrelor was approved for use in the European Union in December, but the road to approval has been much rockier in the US, with a new date set for another FDA advisory committee meeting on the product, on July 20 this year.

The poster abstract states that treatment with generic clopidogrel costs 23¢ a day (based on Swedish healthcare costs) compared with $3 to $4.65 per day for ticagrelor. Yet patients on ticagrelor plus aspirin for a year, vs those on generic clopidogrel plus aspirin for the same period, "were projected to gain an additional 0.13 quality-adjusted life-years (QALYs) at a cost range of $3110 to $7550 per QALY.

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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