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New In Coagulation

WHAT'S NEW IN COAGULATION: OCTOBER 2010

Experimental Drug May Work Better Than Aspirin For Preventing Stroke, Blood Clots In A-Fib Patients.

Bristol-Myers Squibb and Pfizer's "experimental anticoagulant drug apixaban worked better than aspirin in preventing stroke and systemic blood clots for patients who have an irregular heart rhythm disorder called atrial fibrillation.  In a study involving "5,600 patients who were unsuited for the standard treatment for atrial fibrillation, warfarin," researchers found that "patients taking apixaban had a rate of stroke or systemic blood clots of 1.6 percent a year, while those on aspirin had a rate of 3.6 percent a year, a statistically significant difference.The study's "results leave 'no competition for apixaban in the foreseeable future' for that group of patients and signal the drug could challenge warfarin.  The new drug is now expected to compete against two other new blood thinners called Praxada (dabigatran etexilite) and Xarelto (rivaroxaban).   Apixaban offers an important advantage in that "there is no need for the routine coagulation monitoring inherent in treatment with warfarin. Bristol-Myers Squibb and Pfizer will release results next year of their large 18,000-patient study comparing apixaban against warfarin in a-fib patients.

High Doses Of Plavix May Be Good For Some Patients, But Not All.

More isn't necessarily better when prescribing the two drugs commonly used to treat patients who are in danger of having a heart attack, Plavix (clopidogrel) and aspirin," according to a study. Two separate "reports on the data," one published online in The Lancet and the other published in the New England Journal of Medicine, "find that high doses of Plavix are good for some patients, but not all, while high-dose aspirin is no better than a low dose for preventing new heart attacks, other cardiac problems, stroke, and death.

Lower Dose Heparin With Fondaparinux May Not Be Better Than Standard Dose.

In patients receiving fondaparinux (Arixtra) before angioplasty, a lower dose of unfractionated heparin as an adjunct was no better than the standard dose," according to a study presented at the European Society of Cardiology Congress and published online in the Journal of the American Medical Association. Researchers found that "the rate of major or minor bleeding or major vascular access-site complications among patients with non-ST-elevation acute coronary syndromes was 4.7% with the low-dose and 5.8% with the standard dose, a nonsignificant difference." 

CURRENT-OASIS 7 Published: Double-Dose Clopidogrel in PCI Debated 

 The CURRENT-OASIS 7 trial has finally been published this week in two separate papers in the New England Journal of Medicine (NEJM) and the Lancet

The results, showing no significant benefit of doubling the dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) for the first seven days in the overall population of ACS patients referred for an invasive strategy but suggesting benefit in the patients who actually underwent PCI, were first presented and reported by heartwire at the European Society of Cardiology (ESC) 2009 Congress. The trial also addressed the issue of whether aspirin was better given at high or low dose in such patients but found no major differences between the two dosing strategies, although there was a reduction in minor bleeding with the low dose. Although conceding various limitations to the clopidogrel PCI results--mainly that they come from a postrandomization subgroup analysis and should therefore, strictly speaking, be regarded as hypothesis generating, the CURRENT-OASIS 7 they still find the argument for use of the double-dose clopidogrel in patients undergoing PCI "compelling." The reasons they give for this include the fact that the benefit is biologically plausible and is consistent with several previous smaller studies.

In the CURRENT-OASIS 7 trial, 25 086 ACS patients referred for an invasive strategy were randomized to high-dose or standard-dose clopidogrel. The high-dose clopidogrel group received a 600-mg loading dose and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard-dose clopidogrel arm received a 300-mg loading dose, 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. The main results, showing no significant difference in the primary efficacy end point but an increase in bleeding with the higher clopidogrel dose in the overall population, This paper also reports the aspirin results, showing no significant difference between higher dose and lower dose with respect to the primary outcome or major bleeding. The prespecified analysis of the 17 263 individuals who underwent PCI is the focus of a separate paper in Lancet. This shows a "nominally significant" reduction in the primary outcome and a significant reduction in definite stent thrombosis with the higher clopidogrel dose. But this was at the cost of an increase in major bleeding, although bleeding that was intracranial, fatal, or related to CABG surgery did not increase. As in the overall analysis, results for high-dose and low-dose aspirin did not differ for the primary outcome or major bleeding.

The CURRENT-OASIS 7 authors address how these results might be incorporated into clinical practice when it is not known whether a patient will ultimately receive a PCI at the time of presentation. They note that in individuals who did not receive PCI, no apparent increase was recorded in the risk of bleeding with the high-dose clopidogrel regimen, and most major bleeding events occurred after PCI rather than before PCI. Therefore, a 600-mg loading dose could be considered for all patients with ACS with planned early invasive treatment. After coronary angiography, patients receiving a PCI could continue with the double maintenance dose to complete the full-seven day regimen, whereas in those who do not have anatomy suitable for PCI, the standard dose could be used or clopidogrel could be withheld, depending on the clinical context, they suggest.

They point out that guideline committees already recommend a 600-mg loading dose of clopidogrel on the basis of previous studies, and many centers are using this higher loading dose in daily practice. In individuals who have planned conservative treatment or in whom invasive assessment might be delayed beyond 72 hours, the standard dose of clopidogrel should still be used on the basis of data from previous studies.

Although the CURRENT-OASIS 7 is the largest trial to address the question of the optimal loading dose of clopidogrel, the PCI subgroup poses several interpretive challenges. These include a postrandomization analysis subgroup that is vulnerable to confounding; the failure to achieve a significant treatment effect in the overall cohort; and a nominally significant interaction unadjusted for multiple comparisons. He also believes that the modest excess in major bleeding with the double-dose clopidogrel suggests that the benefit of double-dose clopidogrel does not outweigh its risk.

Lupus Study Suggests Antiplatelet Drugs May Help 

Scientists studying systemic lupus erythematosus (SLE) have found that blood platelets are key in its development and say their findings in the lab suggest platelet inhibitors may offer a new way to treat patients. The researchers found that lupus patients have an excess of platelets and, after tests on mice, suggest that treating them with a drug like clopidogrel (Plavix) could prevent flare-ups of the disease. For this study, researchers collected platelets from patients experiencing lupus flares. They found these platelets had an abundance of CD154 - a protein normally activated for clotting - and that they triggered production of interferons. In the murine models of lupus, they found that if they wiped out platelets by injecting an antibody to destroy them, inflammation of the kidneys - an organ often affected by lupus - was significantly decreased.

As well as experiencing less kidney damage, the clopidogrel-treated mice also lived for an extra three months.

Sci Transl Med. Published September 2010. Abstract 

FUTURA/OASIS-8: Standard-Dose Heparin Recommended During PCI to Avoid Catheter Thrombosis With Fondaparinux

ACS patients undergoing PCI being treated with fondaparinux as the main anticoagulant should receive standard-dose unfractionated heparin during the procedure to avoid catheter thromboses, according to the conclusions drawn from the FUTURA/OASIS-8 trial [1]. The trial has resolved this important issue with fondaparinux. It has shown that we can reduce the problem of catheter thrombosis without increasing major bleeding. This means that ACS patients on fondaparinux can undergo PCI safely with adjunctive [intravenous] IV heparin."

The FUTURA/OASIS-8 trial was conducted to deal with the issue of catheter thrombosis, which has been associated with the use of fondaparinux alone in ACS patients undergoing PCI and has limited the widespread adoption of the drug in this setting. In the large-scale OASIS-5 trial in ACS patients, fondaparinux was shown to be preferable to enoxaparin, halving major bleeding rates, which was associated with a mortality reduction at 30 days. However, the one downside of fondaparinux in this trial was the excess of catheter thrombosis seen in patients undergoing PCI (0.9% vs 0.4% with enoxaparin).

The OASIS investigators thus proposed that patients undergoing PCI on fondaparinux should receive additional anticoagulation with unfractionated heparin during the procedure. This recommendation was based on an analysis of 306 patients from OASIS-5 and OASIS-6 (another trial of fondaparinux, but this time in STEMI patients) who had received open-label unfractionated heparin while on fondaparinux and experienced a low rate of catheter thrombosis (0.3%). However, this was based on only a small number of patients, and there was uncertainty over the optimum dose.

To look into this issue further, the OASIS investigators conducted the FUTURA/OASIS-8 study, in which 2026 patients undergoing PCI within 72 hours of ACS initially treated with fondaparinux received either low-dose unfractionated heparin (50 U/kg, regardless of use of GP IIb/IIIa blocker use) or standard-dose unfractionated heparin (85 U/kg or 60 U/kg with GP IIb-IIIa inhibitors), adjusted by activated clotting time (ACT).

Results showed that the low fixed-dose of heparin was not superior to standard ACT-guided heparin in terms of preventing peri-PCI major bleeding or major vascular access-site complications. Thrombotic events were not significantly different between the treatment groups. Catheter thrombosis was said to be "rare"--five cases (0.5%)--in the low-dose heparin group and "very rare"--one case (0.1 %)--in the standard-dose heparin group.

References

1. FUTURA/OASIS-8 trial group. Low-dose versus standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux. The FUTURA/OASIS-8 randomized trial. JAMA 2010; DOI:10.1001/jama.2010.1320. Available here.

AVERROES: Apixaban Yields Significant Reductions in Stroke, No Increased Bleeding

Patients with atrial fibrillation unable to take warfarin who are treated with apixaban (Pfizer/Bristol-Myers Squibb), an investigational oral factor Xa inhibitor, had a significantly lower risk of stroke and systemic embolic events compared with patients treated with aspirin.

Importantly, the benefits of apixaban did not come at a cost of increased bleeding, with no observed increases in the risk of major bleeding, minor bleeding, or intracranial hemorrhage, among other end points, in those treated with apixaban.

The results of the study, known as the Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, were presented today here at the European Society of Cardiology 2010 Congress by lead investigator Dr Stuart Connolly (McMaster University, Hamilton, ON). Asked his impression of the reduction in stroke risk, coupled with the safety of apixaban, in these difficult-to-treat patients, Connolly called the novel anticoagulant "superb."

"It's a very easy to use drug to give," Connolly told heartwire . "You take it twice a day, and it's well tolerated. It didn't have any liver toxicity, no particular adverse events that we saw. If anything, it's extremely safe. We consider aspirin to be a drug we can just about give any patient, but aspirin does cause bleeding. It's not completely benign."

AVERROES Trial Stopped Early

Briefly, AVERROES included 5600 patients with atrial fibrillation from 36 countries who were unsuitable for or intolerant of warfarin. The study began in September 2007, with patients randomized to 5 mg of apixaban or 81 to 324 mg of aspirin for up to 36 months or until the end of the study.

As previously reported by heartwire , the AVERROES trial was stopped early when the data and safety monitoring board performed a prespecified interim analysis showing significant benefit with apixaban. The analysis was repeated three months later and the benefit confirmed, leading to the early termination of the trial.

Treatment with apixaban significantly reduced the risk of stroke or systemic embolic events 54%, a statistically significant reduction. The benefit of treatment, however, occurred without a corresponding increase in the risk of bleeding. Overall, the risk of major bleeding increased 14%, but this increase was statistically nonsignificant. Regarding specific types of bleeding, there was no increased risk of fatal or intracranial hemorrhage, two particular concerns with atrial-fibrillation patients who receive anticoagulation therapy.

Patients in AVERROES had all types of atrial fibrillation, as well as different risks for stroke based on their CHADS₂ score. Patients were roughly divided into three groups, with 36% of patients at low risk, having a CHADS₂ score of 0–1, while 37% had a CHADS₂ score of 2 and 27% had a CHADS₂ score of 3 or greater. According to Connolly, the patients included in AVERROES were similar to those included in the ACTIVE and RE-LY studies.

"The baseline risk of these patients is high," said Connolly. "On standard therapy, which is aspirin, these patients had a 3.6% annual risk of stroke, so that speaks for itself. With these patients, our first goal is to put them on warfarin. If they haven't been on it before, the physician has to make a decision about how well they'll do on warfarin. It's a difficult treatment, tricky to use, and a lot of patients have trouble with it. And for many patients, they're not candidates for warfarin, so they get put on aspirin, and with aspirin they have a higher risk of stroke."

What Do the Results Mean?

Dr Harald Arnesen (Oslo University Hospital, Norway), the scheduled discussant during the late-breaking clinical-trials session, called AVERROES a "landmark study" and predicted the use of aspirin will drastically decrease once the drug becomes available. In addition, Dr Thomas Lüscher (University of Zurich, Switzerland), who commented on the results of the study for heartwire , said the findings were "impressive," particularly the equivalent risk in bleeding compared with aspirin.

"As a proof of principle, it's exciting, because these new drugs are so selective just on one factor, like factor Xa, whereas warfarin is much less selective, inhibiting around five factors, so it makes sense that bleeding tends to be lower in these new drugs," he said. "The fact that the [bleeding] risks are quite similar to aspirin is really quite exciting."

To heartwire , Dr Martin Jan Schalij (Leiden University Medical Center, the Netherlands) said that the present study is encouraging, but most doctors will be waiting for head-to-head comparisons between warfarin and apixaban in atrial-fibrillation patients. Patients at low risk, those with a CHADS₂ score of 0–1, are not treated with warfarin and usually given aspirin alone. For those with a higher risk, it is already known that aspirin is insufficient to stave off the risk of stroke.

"Most patients are treated with warfarin, and I don't know how it is in other countries, but in Western Europe it's an effective therapy, and it's cheap," said Schalij. "The drugs cost only a few cents a day. On the other hand, we do have problems with respect to the therapeutic goals we need to reach, and it's a problem. Bleeding is not usually the major problem, but rather getting patients into the therapeutic range. It seems that with the new drugs this problem is more or less solved, but we still have to wait, because this study looked only at patients unsuitable for warfarin."

A number of experts questioned the definition of "unsuitable for warfarin," noting that the definition can change from one physician to the next. In AVERROES, 61% of the included patients were expected to be unsuited for warfarin, while 39% used the drug and discontinued it. Connolly said the decision about which patients are unsuitable for warfarin rests with the clinician. If they have not taken warfarin in the past, doctors typically question whether the patient will return for regular clinic visits to adjust or to maintain the international normalized ratio (INR). Patients with alcohol problems or those who take other medications that interact with warfarin are not candidates for the drug. He said that in most general-hospital clinics, roughly 25% of patients might not be candidates for warfarin, although this number is lower in specialized tertiary-care centers.

The next study, known as the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation(ARISTOTLE) trial, is a comparison of apixaban 5.0 mg twice daily vs warfarin adjusted to an INR of 2.5 in patients with atrial fibrillation. The trial is currently under way, and results are expected in April 2011.

The study was sponsored by Bristol-Myers Squibb and Pfizer. Connolly reports research support and lecture and consulting fees from the sponsor.

NSAID Use Associated With Future Stroke in Healthy Population

Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of stroke in a Danish population study including only healthy individuals. First we found an increased risk of MI with NSAIDs. Now we are finding the same thing for stroke. This is very serious, as these drugs are very widely used, with many available over the counter.

For the current study, Gislason and colleagues examined the risk of stroke and NSAID use in healthy individuals living in Denmark. He explained to heartwire that information on each individual in the Danish population is kept in various national registries. His team started with the whole population of Denmark aged over 10 years. To select just the healthy individuals, they excluded anyone admitted to the hospital within the past five years or those prescribed chronic medications for more than two years. This left a population of around half a million, who were included in the study. By linking to prescribing registries, the researchers found that 45% of these healthy individuals had received at least one prescription for an NSAID between 1997 and 2005. They then used stroke data from further hospitalization and death registries and estimated the risk of fatal and nonfatal stroke associated with the use of NSAIDs by Cox proportional-hazard models and case-crossover analyses.

Results showed that NSAID use was associated with an increased risk of stroke. This increased risk ranged from about 30% with ibuprofen and naproxen to 86% with diclofenac.

Gislason noted that there was also a dose-relationship found, with the increased risk of stroke reaching 90% (HR 1.90) with doses of ibuprofen over 200 mg and 100% (HR 2.0) with diclofenac doses over 100 mg. He pointed out that the results were particularly striking, given that this study was conducted in healthy individuals.

He conceded that his results could have some confounding but noted that the data were controlled for age, gender, and socioeconomic status and the patient population did not include those with chronic diseases. "We also have to think about the degree of confounding needed to nullify risk. It would have to increase risk four- to fivefold, which is very unlikely," he commented.

He said he did not find the results that surprising in view of the accumulating evidence of increased MI risk with these drugs, adding that the mechanism was probably the same. There have been several hypotheses about the mechanism linking NSAIDs with cardiovascular events, including increased thrombotic effect on platelets, the endothelium, and/or atherosclerotic plaques; increasing blood pressure; and effect on the kidneys and salt retention. The public needs to be protected by not allowing NSAIDs to be bought without a prescription. He has had some success in this regard in Denmark at least, where diclofenac became available over the counter recently, but after some of the MI data came out, Gislason's group campaigned the health authorities, and it has now become a prescription-only drug again. But he noted that many more NSAIDs are available over the counter in the US.He believes the harmful effects of these agents are relevant to huge numbers of people. "If half the population takes these drugs, even on an occasional basis, then this could be responsible for a 50% to 100% increase in stroke risk. It is an enormous effect."

Bayer CEO Sees Blood Thinner Market Reaching Up To $15 Billion A Year.

The market for new blood thinners including Johnson & Johnson and Bayer AG's Xarelto could eventually reach $12 billion to $15 billion a year," according to Bayer Chief Executive Werner Wenning. "Safety and effectiveness will determine how the anti-clotting pill fares against rivals from Pfizer Inc., Bristol-Myers Squibb.

Study Links Low Daily Dose Of Aspirin To Reduced Bowel Cancer Risk

A study in the medical journal Gut found that "people who take even a very low dose of aspirin every day for five years can cut the risk of developing colon cancer by almost a third." According to researchers, "as little as 75 milligrams of aspirin a day...lowered the risk of colon cancer by 22 percent after just a year." While it was already know that aspirin can protect the colon, the "study showed for the first time that a low dose of aspirin is sufficient to ward off cancer, and that the drug needs to be taken for at least five years to get the full benefit. Aspirin has not as yet been recommended for primary chemoprevention of colorectal cancer...because of unanswered questions on dose, duration, and effects on survival 

Clopidogrel-PPI Interaction More Relevant in Noncarriers of CYP2C19 Loss-of-Function Gene

Sue Hughes

September 9, 2010 (Stockholm, Sweden) — A small pharmacodynamic study has suggested that the interaction between clopidogrel and proton-pump inhibitors (PPIs) may be more important in patients who do not carry any CYP2C19 loss-of-function alleles.

Presenting the results at the European Society of Cardiology (ESC) 2010 Congress last week, Dr Jen-Kuang Lee (National Taiwan University, Taipei) said: "We found noncarriers of the CYP2C19 loss-of-function alleles were more susceptible to the effects of the PPI-clopidogrel interaction than carriers were."

Lee explained to heartwire that as PPIs and clopidogrel are both metabolized by the CYP2C19 enzyme, it would be of interest to find out whether individuals carrying CYP2C19 loss-of-function genes were particularly affected by the PPI-clopidogrel interaction. But bizarrely, they found the opposite result.

For the study, the researchers recruited 36 healthy volunteers who were given clopidogrel as a single loading dose of 300 mg and then daily maintaining doses of 75 mg for six weeks. The volunteers were then given each of three different PPIs daily for a week, with a one-week washout period between each PPI. The PPIs tested were rabeprazole 20 mg, pantoprazole 40 mg, and esomeprazole 40 mg. Results showed that the most significant impairment of the antiplatelet effect of clopidogrel by concomitant use of PPIs was found in noncarriers.

Platelet Aggregation (%) With Clopidogrel Alone and Given With a PPI

The researchers also found a dose-response effect with respect to the number of loss-of-function alleles carried. The greatest impairment of clopidogrel effect (shown by the largest increase in platelet aggregation) occurred in patients without any loss-of-function alleles and the smallest impairment in those with two loss-of-function alleles.

Platelet Aggregation (%) With Clopidogrel Alone and Given With a PPI: Dose Response Per Number of Loss-of-Function Alleles

Lee commented: "We showed a remarkable reduction in clopidogrel effect by PPIs in people not carrying any loss-of-function CYP2C19 alleles, but less effect in people with the loss-of-function alleles. This is perhaps opposite of what we might expect to be the case."

Meta-Analysis Suggests Harm With PPIs, But Discussants Critical

A separate presentation dealt with a meta-analysis to investigate the effect of concomitant clopidogrel and PPI use in a total of 160 000 patients taking clopidogrel. Of these, 34% were also taking a PPI. Results showed that PPI use was associated with increases in the risk of major cardiovascular events by 29% and MI by 31%. Mortality appeared to be unaffected, while gastrointestinal bleeding decreased by 50% in those on PPIs.

Presenting the results, Dr Jolanta Siller-Matula (Medical University of Vienna, Austria) noted that it was necessary to treat 140 patients with a PPI to prevent one gastric bleed, but that only 25 patients needed to be treated with a PPI to cause one cardiovascular event. "There is thus a sixfold higher risk of having a cardiovascular event rather than preventing a gastric bleed when a PPI is prescribed with clopidogrel," she said.  She also reported that while omeprazole was associated with adverse cardiovascular events in this meta-analysis, pantoprazole was not. She concluded that PPIs should be used only in patients taking clopidogrel with gastric symptoms, in whom pantoprazole was probably the preferred agent.

But Siller-Matula's presentation was greeted with a barrage of criticism during the discussion. It was pointed out that most of the studies included in the meta-analysis were observational and therefore unreliable, that meta-analyses themselves are problematic, and that the increase in risk attributed to PPIs (29%) was improbably large. Noting that clopidogrel reduces cardiovascular events only by 20%, one discussant questioned how a PPI, which is supposed to interfere with the action of clopidogrel, could actually increase events by more than this. "It doesn't make sense how the harmful effect of a PPI could be more than the beneficial effect of clopidogrel," he added.

Siller-Matula replied that in the absence of randomized trials, one had to rely on observational data. "While of course our results should be viewed as hypothesis generating, I don’t believe that 30% of patients need to take a PPI," she said.

FDA Will Be in Dabigatran's Corner at Next Monday's Advisory Panel Meeting

Steve Stiles

September 16, 2010 (Silver Spring, Maryland) — With all the buzz surrounding the oncoming wave of possible new oral anticoagulants, one might think they have the potential for dramatically simplifying the care of a huge and growing population of patients. And actually, that's true. Food and Drug Administration documents released today suggest that the agency will recommend to its Cardiovascular and Renal Drugs Advisory Committee on September 20 that one of those anticipated replacements for venerable but troublesome warfarin, dabigatran etexilate (Boehringer Ingelheim) should be approved for the prevention of stroke in patients with atrial fibrillation (AF) [1].

The committee isn't expected to disagree. The cardiology community has expressed few major reservations about the randomized trial on which the drug's approval application is primarily based, the 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY). And for a generation, it has longed for an oral antithrombin that's at least as safe and effective as warfarin but is more consistent in its effects and doesn't require cumbersome anticoagulation monitoring.

As reported by heartwire about a year ago, RE-LY pitted two dosage levels of dabigatran against a conventional warfarin regimen for the stroke-prevention indication. Dabigatran was noninferior to warfarin at the lower dosage and superior at the higher one, the latter achieving a 34% decline in risk (p<0.001) over a median of two years. The higher dosage was also associated with a 74% drop in hemorrhagic stroke risk (p<0.001).

On the other hand, the agency is recommending that dabigatran not be allowed to claim superiority over warfarin for stroke prevention in AF. If there are any controversies about the trial, they may be its unblinded nature and the low-dose regimen's decreased risk of major bleeding events. That risk fell by a significant 20% compared with warfarin at the lower dabigatran dosage of 110 mg twice daily and was comparable at the higher 150-mg twice-daily dosage.

Although that potentially argues in favor of dabigatran at the lower dosage, the agency is supporting approval at the higher dosage, as asked by Boehringer Ingelheim, and disagrees with the company's suggestion that the lower dosage should be available for patients perceived to be at increased risk of bleeding. According to the FDA, there's little evidence to support such a strategy.

Nor does the FDA seem to believe another largely unexplained observation from RE-LY, a significantly increased risk of MI, a secondary end point, in the high-dose group compared with warfarin (hazard ratio 1.38, 95% CI 1.00–1.91; p=0.048), is reason not to approve the drug at 150 mg twice daily. The MI analysis in an addendum to its primary briefing document seems to hold that any such elevated risk, if real, would likely still be outweighed by the higher dosage's likely benefits [2].

Dabigatran is currently approved in Europe and Canada for venous-thromboembolism prophylaxis during hip- or knee-replacement surgery.

Other oral anticoagulants in various stages of development include apixaban (Bristol-Myers Squibb/Pfizer), rivaroxaban (Xarelto, Bayer/Johnson & Johnson), edoxaban (Daiichi-Sankyo) and betrixaban (Portola Pharmaceuticals/Merck).

References

1. Food and Drug Administration. FDA background package: dabigatran. Accessed September 16, 2010. Available here.
2. Food and Drug Administration. Addendum to clinical review for NDA 22-512. September 2, 2010. Available here.

FDA Panel Recommends Blood-Thinning Drug For Approval.

The FDA's cardiovascular and renal drugs advisory committee on Monday unanimously recommended approval for the blood-thinning drug Pradaxa (dabigatran) to reduce the risk of stroke and blood clots in patients with atrial fibrillation. The drug aims to replace warfarin, which can react with other drugs and foods and was first approved in 1954. The panel did not vote on whether to recommend the 150-milligram dose or the 110-mg dose, but four members said they supported only the higher dose, and six panelists backed both doses to give doctors options. Reuters also notes that there will be more competing oral anti-coagulant drugs from partners Bayer and Johnson & Johnson, and Bristol-Myers Squibb Co and Pfizer. As with warfarin, bleeding is the top safety concern with dabigatran. In RE-LY, the 110-mg dose of dabigatran was associated with less bleeding than warfarin, while the 150-mg dose was associated with about the same bleeding risks, although the bleeds tended to be less serious than those seen with warfarin

Researchers To Examine Fish Oil, Aspirin's Potential To Prevent Bowel Cancer

A major study is to be carried out to find out whether taking two pills a day -- containing fish oil and aspirin -- could help prevent bowel cancer." Scientists at the University of Leeds plan to recruit "1,000 people...from the NHS Bowel Cancer Screening Programme...in England to take part in the research." The "trial is expected to begin in April or May next year and up to 30 English hospitals in will be involved."

Antipsychotic Medications May Increase Risk Of Blood Clots

Antipsychotic medications may "raise the risk of dangerous blood clots," according to a study published in the British Medical Journal. After analyzing data on more than 25,500 cases, researchers found that "people given antipsychotics in the past two years had a third greater risk of clots like deep vein thrombosis," with the risk being "even higher for the newer 'atypical' antipsychotics." Patients were at particular risk just after starting to take the medications. The greatest risk was observed with the atypical antipsychotic Seroquel [quetiapine]. Nevertheless, the study authors pointed out that the overall risks were not very great, accounting for about four additional cases of venous thromboembolism per 10,000 patients and 21 in the case of quetiapine specifically. 

Clopidogrel-PPI Interaction: Mechanistic Studies That Led to FDA Warning Now Published

Sue HughesSue Hughes

September 21, 2010 (Jacksonville, Florida) — The pharmacokinetic/dynamic studies that contributed to the FDA's decision to request a public-health warning about the interaction between clopidogrel and omeprazole have now been published [1].

The data, published online on September 15, 2010 in Clinical Pharmacology and Therapeutics, consist of four randomized crossover studies in healthy volunteers, which show a significant interaction between clopidogrel and omeprazole on the amount of clopidogrel active metabolite formed and the degree of platelet aggregation. This interaction was not mitigated by staggering the doses of the two drugs or by raising the clopidogrel dose. However, pantoprazole had much less of an interaction with clopidogrel.

Lead author Dr Dominick Angiolillo (University of Florida College of Medicine, Jacksonville) commented to heartwire : "Our results suggest that there is clearly an interaction with omeprazole that supports the boxed warning. Patients who need some gastric protection when taking clopidogrel should therefore avoid omeprazole but can take pantoprazole or a non-PPI agent such as ranitidine."

He added: "We need to think more carefully about whether a patient on clopidogrel actually needs some gastric protection before prescribing any such agent. But if they do, our data should reassure physicians that there is a PPI (pantoprazole) that can be used safely."

Enough to Convince the Skeptics?

But cardiologists who have previously voiced skepticism over the clopidogrel-PPI interaction still remain unconvinced that these data translate into any clinically relevant effect.

Summarizing these concerns, Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) told heartwire : "I believe the data are now very compelling that certain PPIs, in particular omeprazole, appear to attenuate some of the in vitro antiplatelet effects of clopidogrel. Dr Angiolillo's work elegantly demonstrates this interaction and provides more evidence to suggest that this interaction rests at the level of the CYP2C19 enzyme. However, the question that continues to weigh on the minds of clinicians is whether this in vitro interaction translates into a higher risk of cardiovascular events in clopidogrel-treated patients. Although it seems intuitive that the pharmacodynamic effects and clinical benefit of clopidogrel should move in tandem, this has not always been found to be the case."

As background, Angiolillo explained to heartwire : "Because clinical studies have shown mixed and conflicting results about a reaction between clopidogrel and PPIs, the FDA requested that Bristol-Myers Squibb conduct pharmacokinetic/dynamic studies to the most rigorous scientific standards. These are those studies."

The studies involved 282 healthy subjects. Four different studies were conducted, all crossover in design with placebo controls:

• Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and omeprazole (80 mg) administered simultaneously.
• Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) with omeprazole (80 mg) given 12 hours later.
• Increasing the clopidogrel dose to 600-mg loading/150-mg/day maintenance and omeprazole (80 mg) administered simultaneously.
• Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and pantoprazole (80 mg) administered simultaneously.

Results (compared with clopidogrel alone) showed that exposure of the active metabolite of clopidogrel, clopi-H4, was consistently decreased by 40% to 47% when clopidogrel and omeprazole were coadministered, and this was associated with increases in the exposure of unchanged clopidogrel of 37% to 51%. Similarly, the maximal platelet aggregation (MPA) induced by ADP and vasodilator-stimulated phosphoprotein (VASP)–platelet-reactivity index (PRI) were significantly increased and the inhibition of platelet aggregation (IPA) response to clopidogrel decreased when omeprazole was coadministered.

The differences in the exposure of clopi-H4 and platelet response were observed irrespective of the timing of omeprazole administration. Although doubling of the clopidogrel doses to 600 mg/150 mg increased the exposure of clopi-H4, significant differences in exposure and platelet response were still observed.

When clopidogrel and pantoprazole were coadministered, a smaller, although still significant, decrease in the exposure of clopi-H4 was observed, as were smaller differences in MPA, IPA, and VASP-PRI.

Results of Clopidogrel-PPI Interaction Studies

The authors point out that the different results for omeprazole and pantoprazole suggest that the interaction between clopidogrel and omeprazole is not due to decreased clopidogrel absorption secondary to an elevation of gastric pH consequent to the action of the PPI but rather a metabolic drug–drug interaction at the site of the CYP2C19 enzyme, with clopidogrel as the victim and omeprazole as the perpetrator.

Addressing the high doses of PPI used in the studies, Angiolillo commented to heartwire : "We did this because we wanted to truly address if there was any interaction. If we used a lower dose we might have missed it. There are already other data suggesting an interaction with lower doses, and more specific studies are ongoing."

Are These Results Clinically Relevant?

Others who reviewed the new studies for heartwire all appeared to remain unconvinced of the clinical relevance of the new data.

Dr Peter Berger (Geisinger Health Systems, Danville, PA) said he was "confused" by the new studies, as they would indeed suggest that a clinically relevant interaction between clopidogrel and omeprazole might be present. But he noted that there was "no hint" of any interaction between clopidogrel and omeprazole taken at the same time in the >3600 patient COGENT trial, and no interactions were evident between PPIs and clopidogrel in subgroup analyses of the PLATO and TRITON randomized trials. "I believe that more has to be learned about the relationship between ex vivo platelet-function testing and clinical outcome before it should be used to guide clinical outcome," he commented.

I believe that more has to be learned about the relationship between ex vivo platelet-function testing and clinical outcome before it should be used to guide clinical outcome.

Berger added that he was even trying to figure out whether a PPI ought to be prescribed more frequently, even prophylactically, to patients on antiplatelet therapy. "There are now three randomized placebo-controlled trials that have shown many fewer adverse [gastrointestinal] GI side effects when a PPI is administered with aspirin (two studies) or with aspirin and clopidogrel (one study). And GI side effects are not only uncomfortable or even painful, they are a common cause of noncompliance with aspirin," he said.

O'Donoghue also pointed out that other drugs, including atorvastatin, have been shown to attenuate some of the antiplatelet effects of clopidogrel and yet this interaction does not appear to have clinical significance. She concedes: "Given that pantoprazole is available and is not a strong inhibitor of CYP2C19, I agree that it appears to be a cautious alternative for clopidogrel-treated patients requiring a PPI." But she added: "We need to pursue ongoing studies to better understand the nature of the relationship between platelet-function testing and clinical outcomes. This will be of critical importance as more clinicians begin to incorporate platelet-function testing into their practices."

I am not altering my antiplatelet strategies due to these . . . observations.

Dr Deepak Bhatt (VA Boston Healthcare System, MA) also voiced caution about making clinical decisions based on these studies: "This is a very carefully done study, and I believe the results. I think the bigger issue, though, is that while PPIs and CYP450 genetic polymorphisms affect the response to clopidogrel, the intrinsic variability of clopidogrel is greater than that due to either of these factors. Therefore, I think their clinical impact on a population level is minimal."

He added: "The idea of tailoring therapy based on an individual's platelet response remains appealing but also unproven. So, for the time being, I am not altering my antiplatelet strategies due to these pharmacokinetic/pharmacodynamic observations, nor am I changing around the PPI regimens on my patients (although I do try to make sure they really need to be on a PPI at all)."

Bhatt also questioned whether these results with 80 mg of omeprazole could be extrapolated to the 20-mg dose used most often by cardiologists or primary-care physicians. But he said: "If a doctor is really worried about it, these data suggest pantoprazole is unlikely to interact with clopidogrel. There is, however, always a risk of switching medications around in a patient who is doing well--it can create confusion, dosing errors, and lead to nonadherence."

Applicable to High-Risk Patients Only?

In response to these comments, Angiolillo said he agreed that the clinical implications of these data were not clear and the variability of clopidogrel may mean that there will be an impact in some patients but not in others. He suggested that the clinical impact may be applicable only to high-risk patients, which was also suggested in a recent meta-analysis by Dr Gilles Montalescot (Hôpital Pitié-Salpêtrière, Paris, France) et al.

NEJM Editorial Questions Price Of Drug To Help Some Patients With Superficial Vein-Thrombosis

The front page of its Business Day section that a study published in the New England Journal of Medicine on Wednesday "proved that a blood-thinning medicine," called Arixtra (fondaparinux), "could prevent problems from worsening in some people with a sometimes painful, usually short-term, blood clot near the surface of the leg, called superficial-vein thrombosis," but an editorial in the journal "took the unusual position of challenging" the study, not for its science, but for the cost of the treatment. "The exchange highlighted a growing debate" over "how much should health care providers pay for expensive treatments that make relatively small improvements." The editorialists wrote, "The paradox is, it's effective, but for a condition that's usually not considered an overwhelmingly serious medical problem In the study of 3,002 people with superficial-vein thrombosis, "the risk of death -- one in 1,000 -- was the same in both groups. And, overall, the researchers estimated that they'd have to treat 88 people with the drug to prevent one case of a deep-vein or lung blood clot. 

EU Panel Recommends Approval For Blood Thinner

The European Medicines Agency's Committee for Medicinal Products for Human Use recommended approval of" AstraZeneca PLC's Brilinta (ticagrelor) "to reduce the risk of heart attacks, strokes and death in patients with severe chest pain or earlier heart attacks. The FDA postponed a decision on the drug's approval by three months

Trial Data Reveal Increasing Mortality Benefit For ST-Elevation MI Patients Treated With Bivalirudin

According to research presented at the Transcatheter Cardiovascular Therapeutics meeting, "the final report from the HORIZONS-AMI trial revealed an increasing mortality benefit for ST-elevation MI patients treated with bivalirudin (Angiomax), compared with those who received unfractionated heparin plus abciximab (ReoPro) or eptifibatide (Integrilin)." The "trial, conducted among more than 3,000 patients, found that at three years, those patients randomized to bivalirudin had a 'significant 44% relative reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1,000 patients treated with bivalirudin.'"

Octagam Withdrawn From Market Over Unresolved Blood Clots, Embolisms 

Octapharma USA is voluntarily withdrawing all lots of immune globulin G (IgG) intravenous (human) 5% liquid preparation (Octagam) in the United States while it investigates blood clots and embolisms linked with the biologic, the US Food and Drug Administration (FDA) announced yesterday.

This intravenous IgG product is approved to treat primary immunodeficiency diseases such as congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. On August 24, the FDA announced that Octapharma USA was voluntarily recalling 31 lots of the product based on increased reports of thromboembolic events. Yesterday, at the agency's request, the company began to withdraw all lots of IgG intravenous 5% liquid preparation in the United States.

"The FDA and Octapharma agree that until a root cause of the previously reported thromboembolic events can be determined, the most prudent course of action is to suspend further administration of Octagam," the company stated in a press release. It noted that it has not learned of any additional thromboembolic events associated with the product since the August recall.

The action in the United States coincides with an recommendation today by the European Medicines Agency (EMA) to suspend market authorizations for the IgG product and recall all lots of it currently on the market in 28 European countries due to an unexpected increase in thromboembolic events. Physicians should stop administering the product and switch patients to the most appropriate alternative treatment, according to an announcement by the EMA.

The EMA stated that the increase in thromboembolic events "is thought to be related to problems with the medicine's manufacturing process."

The suspension will remain in place until the manufacturer rectifies the problem, The EMA recommendation goes to the EU's executive body — the European Commission — for its approval. 

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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