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New In Coagulation

Thursday, February 2, 2012

WHAT'S NEW IN COAGULATION: FEBRUARY 2012

Analysis Slams Use of Clopidogrel Loss-of-Function Gene Test

A new meta-analysis has concluded that although there is an association between clopidogrel loss-of-function genotypes (CYP2C19 alleles) and responsiveness to the drug, there is no significant association of the genotype with CV events [1]. For example, in the clopidogrel-based studies ithere was strong evidence of small-study bias and identified evidence for selective outcome reporting bias. Taken together, these observations cast doubt on the association of CYP2C19 genotype with clinical cardiovascular end points.The study provides no evidence to support CYP2C19 genotype testing, and therefore, physicians should use such tests "rarely, if ever, and interpret the results with caution.

But other doctors are up in arms about the meta-analysis, saying it is misleading and contains numerous flaws. At the heart of their argument is the fact that they maintain that clopidogrel is most efficacious in preventing events in patients receiving stents. However, this review looks at clopidogrel use in many different settings and uses CV outcomes that are too broad, they argue. Moreover, when the authors drill down to individual end points, they do find a significant increase in risk of myocardial infarction and stent thrombosis in patients with the loss-of-function genotype, the critics state.

They included studies "where patients were managed conservatively--where there hasn't really been any debate about the importance of the CYP2C19 variant. Moreover, they include other studies of clopidogrel, such as those [in patients] with stable coronary disease, or patients with atrial fibrillation who happen to get clopidogrel, where there is a modest, if any, benefit of clopidogrel. So in that sense, it's really somewhat silly to say that they've found that genetic variants that alter clopidogrel metabolism weren't important in those settings.

These pharmacogenetic analyses require a strong understanding not only of statistics, but of genetics and clinical cardiology. If one doesn't have all those elements, it can be easy to fall into traps and make mistakes.

In the meta-analysis, Holmes et al examined 32 studies that evaluated CYP2C19 genotyping as a predictor of response to clopidogrel therapy, including 42 016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. The analysis is unique and differs from previous ones in that studies were considered in two separate groups.Firstly, they took all those studies in which all patients were exposed to clopidogrel--26 in total--termed "treatment only" trials, and looked at the association of genotype with outcome. Individuals with one or more CYP2C19 alleles had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding, and higher risk of CVD events (relative risk 1.18).But there was evidence of publication bias among these studies, the authors say, whereby larger associations were reported among smaller studies (those with <99 events had a point estimate for hazard ratio for CV morbidity and mortality of 1.83). When analyses were restricted to studies with 200 or more events, the point estimate was 0.97, indicating no evidence of a less favorable outcome in slower metabolizers.

The other part of the analysis centers on six randomized clinical trials in which subgroup analyses were used; patients had received clopidogrel or placebo, and had at least one CYP2C19 loss-of-function variant or not. This is "the most robust approach," and in these trials, the CYP2C19 genotype was not associated with the modification of the effect of clopidogrel on CVD end points or bleeding.You have to look at outcomes that clopidogrel is known to reduce. It's been shown to reduce CV death, myocardial infarction, stroke, and particularly, stent thrombosis. In this meta-analysis, they lump together a far broader range of events, and include what we would describe as softer CV events; but clopidogrel doesn't affect those events, so obviously, genetic variants affecting clopidogrel will have no impact.

Three studies that only reported stent thrombosis as a primary outcome were excluded from the overall analysis. Holmes says this is true, because when they looked at the totality of evidence, they couldn't include studies that reported a single end point. But these three studies were included in the analysis of stent thrombosis as a separate outcome.

The issue of identifying poor responders to clopidogrel--either through genetic testing or platelet function tests--has been a controversial topic since the US FDA put a boxed warning on the drug 18 months ago. This stated that pinpointing poor responders to clopidogrel could allow doctors to implement "alternative treatment strategies." At the time, the American Heart Association and American College of Cardiology issued a consensus statement that conflicted with the FDA's position, stating that the evidence base was "insufficient to recommend either routine genetic or platelet function testing at the present time.The FDA warning "came out at a time when there wasn't easy access to genotyping, and they didn't give specific guidance as to what alternative therapy to give." The field has moved on rapidly since then, he argues, and while genotyping may be a "moot point" if people are using newer antiplatelet drugs for stenting, clopidogrel still remains the dominant agent used. And 25–30% of patients (depending on ethnicity) will harbor a genetic variant that affects clopidogrel function. When these patients receive a stent, the risk of CV events--most notably stent thrombosis--"is quite clear..

Many of those in favor of testing for CYP2C19 genotypes are "still grappling with whom to test and what to do about it. I think [the FDA] have appropriately highlighted an issue with this medication, and now it's up to us as clinicians to figure out what the reasonable options would be and what is the most effective strategy. We need to put the information together to develop a sensible algorithm.

Montalescot says a large randomized, controlled trial is impractical and "impossible to imagine." He notes that a recent risk model developed in Paris that incorporates two genetic risk factors--the CYP2C19 genotypes and ABCB1 genotypes--provides greater discriminatory power in defining stent-thrombosis risk compared with a model that incorporates clinical risk factors only.

Bayer Seeks FDA Approval For Rivaroxaban To Use In ACS.

Barely two months after rivaroxaban (Xarelto) was approved in the US for stroke prevention in patients with atrial fibrillation, the drug's maker, Bayer HealthCare, is asking the FDA to approve it for secondary prevention after acute coronary syndrome (ACS)." According to the ATLAS ACS 2 trial, "rivaroxaban, an oral direct factor Xa inhibitor, in combination with standard antiplatelet therapy, reduced the composite rate of death from cardiovascular causes, myocardial infarction, and stroke to 8.9%, compared with 10.7% among those on antiplatelet therapy alone." If rivaroxaban receives approval, "it would be the first factor Xa inhibitor to be approved for secondary prevention in ACS."

Ischemic Events May Not Be Higher Overall In Patients Using Dabigatran.

Although there is a signal of a higher risk of myocardial infarction with dabigatran (Pradaxa) compared with warfarin when used for stroke prevention in atrial fibrillation, the net clinical benefit favors dabigatran, a post-hoc analysis of the RE-LY trial showed." Investigators found that "the annual rate of myocardial infarction (MI) was 0.82% with the 110-mg dose of dabigatran and 0.81% with the 150-mg dose, nonsignificantly higher than the 0.64% annual rate with warfarin (P>0.05 for both)." However, "the annual rate of a composite of events that went into calculating the net clinical benefit -- all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death -- was lower with both the lower dose (7.34%) and higher dose (7.11%) of dabigatran than with warfarin (7.91%).

NICE Says It Will Not Sanction Use Of Rivaroxaban For Now.

The UK National Institute for Health and Clinical Excellence (NICE) has said it will not, for the time being, sanction the use of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for the prevention of stroke in people with atrial fibrillation (AF)." NICE "has requested more information from the manufacturer, Bayer, and says that those wishing to comment on these draft recommendations have until January 30, 2012 to do so." While "rivaroxaban is technically approved for use in AF in the UK -- because it was cleared for marketing through the centralized EU procedure -- NICE guidance indicates how the drug will be reimbursed in England and Wales and how it will be used, because the drug will generally not be purchased without a NICE endorsement."

Dabigatran May Increase Risk Of Heart Attack, Severe Chest Pain.

Pradaxa [dabigatran] may be linked to an increased risk of heart attack. Investigators looked at "data from seven studies - involving 30,514 people - that compared dabigatran to warfarin, the injected blood-thinner enoxaparin or a placebo. The majority "of the data came from the same clinical trials that had earlier led to approval of dabigatran, called the RE-LY studies. The researchers found that, "of 20,000 patients taking Pradaxa, 237 had a heart attack or chest pain, compared with 83 patients out of 10,514 on the standard drug warfarin or a placebo. Recently, the FDA "said...it would evaluate the Pradaxa studies following reports of serious bleeding events in patients. There was a 33 percent increase in relative risk for a heart attack among those taking Pradaxa, the absolute increased risk -- that is, the added risk for any one individual of having a heart attack if on Pradaxa -- was 0.27 percent. Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.

Low-Dose Aspirin May Not Reduce Risk Of Dying From Cardiovascular Disease, Cancer.

According to research published online in the Archives of Internal Medicine, low-dose aspirin use may not benefit healthy individuals. Low-dose daily aspirin therapy does not reduce risk of dying from cardiovascular disease or cancer, according to" the study. Investigators looked at data on roughly 102,000 individuals and found that "daily low-dose aspirin resulted in a 10 percent reduction in heart attack or stroke, mainly driven by a reduction in nonfatal heart attacks." However, "there was no reduction in death from heart disease, stroke or cancer seen among people taking low-dose aspirin.

More Frequent Aspirin Use Associated With More Severe AMD

The risks for early age-related macular degeneration (AMD) and wet late AMD are associated with frequent aspirin use, and the risk increases with greater aspirin consumption. The results, from the large, population-based, cross-sectional European Eye Study, suggest caution in recommending aspirin to patients with early or late AMD who may take it for other conditions, such as prevention of cardiovascular disease (CVD).When adjusted for all potential confounders of age, sex, education, smoking, body mass index, diabetes, CVD, angina, cholesterol, and systolic blood pressure, daily aspirin users had a greater than 2-fold increased risk for wet AMD when compared with participants who never consumed aspirin.

Field workers interviewed the participants about sociodemographic, health, and lifestyle factors. Aspirin use was quantified as never (n = 2760), monthly or less (n = 766), weekly but not daily (n = 326), or daily (n = 839). Digitized color fundus images were recorded at each participating center and sent to Rotterdam, the Netherlands, where 2 staff members graded them according to the International Classification and Grading System for Age-Related Maculopathy and AMD.

Grades 1, 2, and 3 corresponded to early AMD, and grade 4 corresponded to late AMD, which was subdivided into dry or wet AMD. Wet AMD was defined as serous or hemorrhagic detachment of the retinal pigment epithelium, a subretinal neovascular membrane, subretinal hemorrhage, or other signs. Participants with grade 0 (macula free of drusen or pigmentary irregularities or with hard drusen) were the control patients. The main outcome measure was the odds ratio (OR) for AMD in aspirin users. Daily aspirin users were older, were less likely to smoke, and had lower blood pressure and cholesterol levels, but more CVD and angina. Among all participants, 36.4% had early AMD, and 3.3% had late AMD, of whom about two thirds had wet and one third dry AMD. More frequent aspirin use was associated with higher grades of AMD. One third of the individuals with wet AMD consumed aspirin daily compared with only 16% of control participants.

Similar trends in ORs were seen when investigators adjusted only for age and sex, or for age, sex, and CVD (both P < .001 for the trends). There was no significant association for aspirin with wet AMD according to the presence or absence of CVD or angina (ie., AMD was independent of CVD or angina).For the 42 cases of dry AMD with information on aspirin use and potential confounders, dry AMD was not associated with aspirin use after adjustment for age and sex.Significant trends for aspirin use and early AMD for grade 1 (n = 1652) and grade 2 (n = 463) AMD were also seen when adjusted for all potential confounders (P = .001 and P < .001, respectively, for trends). However, no such association was seen for grade 3 (n = 114; P =.9).Limitations of the study include its cross-sectional and retrospective nature, with the possibility of recall error about aspirin use and possible confounders. In addition, there were no data on the doses of aspirin or the use of other antiplatelet or anticoagulant drugs.

There has not been a consistent trend among studies looking at this question, and differing inclusion criteria and definitions of AMD severity make it difficult to compare studies.

Hemophilia B Gene Therapy Receives Orphan Status in United States

A promising gene therapy for hemophilia B that received orphan designation in the European Union in November 2011 received the same status from the US Food and Drug Administration on January 4, 2012, as reported in a press release by Amsterdam Molecular Therapeutics (AMT), a leader in the field of human gene therapy.Orphan disease status applies to conditions that affect fewer than 200,000 individuals in the United States. The Orphan Drug Act of 1983 provides up to 7 years of market exclusivity after regulatory approval.

Deficiency of factor IX coagulation factor (FIX) causes hemophilia B (Christmas disease), which is X-linked recessive. Since the late 1960s, treatment of hemophilia B has been intravenous injection of FIX 2 to 3 times a week, which is not curative, is very costly, and can lead to production of inhibitors. Gene therapy delivers the FIX gene in an AAV8 vector into hepatocytes via peripheral vein infusion. A liver-specific promoter helps to target the vector, which has a natural affinity for the liver, and a codon-optimized factor IX construct increases transgene expression.

As reported previously, the investigators delivered a single low, intermediate, or high dose of the gene-carrying vector into the peripheral veins of 6 men with severe hemophilia B, and then measured the patients' FIX levels for from 6 to 16 months. In all participants, FIX levels increased to between 2% and 11% of normal in a roughly dose-dependent manner. Studies had shown that elevating FIX levels just slightly above 1% of normal could restore clotting ability.

The improved FIX production after gene therapy enabled 4 patients to discontinue prophylactic FIX without spontaneous hemorrhaging, and the other 2 patients to require injections less frequently.These early findings are the first to demonstrate long-term expression of a blood protein associated with clinical improvement. The effect, both clinically and financially, could be substantial if further results validate the gene therapy.

The lifetime cost of intravenous factor IX can exceed $20 million per patient, whereas the cost of the vector per patient is $30,000. Successful gene therapy has the potential to dampen what is otherwise a severe bleeding disorder into a considerably milder form, or even to ameliorate the phenotype entirely.

Dabigatran: New Data on MI and Ischemic Events

The question of MI risk with dabigatran (Pradaxa, Boehringer Ingelheim) is in the spotlight once again, with two new papers on the subject published within the last few days. In one paper--published online on January 3, 2012 in Circulation--RE-LY investigators looked more closely at their data for any type of ischemic event and at the subgroup of patients with existing ischemic heart disease and found reassuring results for dabigatran. However, lead authors of both papers agreed that they did not think the two new studies were conflicting. There is a signal of MI with dabigatran in the RE-LY results, no question, and the same thing is seen in this new meta-analysis. We are not arguing about that. But when we look at the totality of all ischemic events in RE-LY there is no signal at all. We have also shown that the MI issue is not increased in patients with a history of ischemic heart disease, and there is a net clinical benefit of dabigatran over warfarin, regardless of whether patients have coronary heart disease or not.

Our paper shows an increase in MI when other studies are considered as well as RE-LY. And the Circulation paper looks into greater detail of those events in RE-LY and emphasizes the overall benefit of dabigatran. It is important to note that the increase in MI risk is small, and if used for AF, there is a net clinical benefit for dabigatran. When we wrote our paper, we weren't aware of this new data from RE-LY, and I think there was a concern about dabigatran in patients with ischemic heart disease. I think the Circulation paper has helped clarify that the risk of MI is not increased more in people who had a history of coronary heart disease, but the benefit of dabigatran is still there. It is reassuring on that point. On the basis of that data, I would not be concerned about using dabigatran in patients with ischemic heart disease.

The RE-LY data only deals with the AF population, and I think that if dabigatran is used in other indications, questions still remain and this needs more study. In the venous thromboembolism [VTE] population, the absolute risk of MI is very low, and I would doubt the benefit-risk ratio would be reversed.

The MI numbers in RELY (previously reported) showed 80 such events in the 5983 patients in the dabigatran 110 mg group, 79 events in the 6059 patients in the dabigatran 150 mg group, and 63 events in the 5998 patients in the warfarin group. In addition, when you look at the totality of benefits with dabigatran--the reduction in hemorrhagic stroke, ischemic stroke, and bleeding vs the increased number of MI--there is clearly a net clinical benefit in favor of dabigatran over warfarin.

In the meta-analysis data from seven studies of dabigatran were combined--the RELY and PETRO trials vs warfarin in AF patients; three studies of short-term prophylaxis of deep venous thrombosis with enoxaparin as control; one study in acute VTE with warfarin as control; and one study in ACS vs placebo. Results showed dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group. This meta-analysis is helpful in that it is always good to have people raising safety issues so we get as much information as possible, but meta-analyses have their own problems. In this case, they have combined very different patient populations--those with AF and those with VTE. There are also different control groups--warfarin, enoxaparin, or placebo." He noted that Boehringer Ingelheim had conducted various meta-analyses and found that in trials comparing dabigatran to warfarin, there was a signal of increased MI, but in studies comparing dabigatran to enoxaparin or placebo, there was no difference in MI.The message from the meta-analysis is that there does appear to be an increased risk of MI with dabigatran vs warfarin. We would not argue with that. But if you compare all the bad things that can happen with both drugs, then dabigatran definitely has the advantage."

Aspirin in Primary CVD Prevention: Risks Outweigh Benefits

A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1]. The current study did not find a significant reduction in cancer mortality. However, the lead author of a previous meta-analysis that did show a reduction in cancer death with aspirin says follow-up in the current study was not long enough to show such an effect. The new analysis included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal MI, but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.

The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk. An editorial accompanying the paper suggests that aspirin may be considered in patients with a CHD risk of more than 1% per year.

There may be a benefit in higher-risk individuals, and there is a case for personalized medicine here. But we showed that as the event rate increased in the placebo group, the reduction in MI with aspirin also increased, but so too did the bleeding risk. The bleeding risk is always greater than the MIs prevented, but it depends on whether you think a nonfatal MI is worse than a significant bleed. So we could do better if we knew who would bleed and who would have an event.

The UK newspapers were full of reports saying there is no benefit of aspirin in cancer prevention, exactly the reverse of the headlines after Rothwell's study came out last year. The message today that aspirin does not prevent cancer is premature. The current study should not change advice on taking aspirin as a healthy person. It does not offer any additional information that we don't already know. We need to think about both risk of heart disease and cancer, and in general heart disease risk is coming down while cancer risk is increasing. There does appear to be a cancer benefit with long-term use, so if there is a family history of cancer I would think about taking aspirin. We have more studies with individual patient data coming out soon that will shed more light on the issue.

At the moment, the guidelines on primary prevention are just focused on heart disease. They have not looked at the cancer data. There are some new guidelines due to come out over the next year, and these should start to discuss the cancer findings. The cancer data are far from certain. The major reason to give aspirin is to prevent heart attacks and strokes, and in healthy people this benefit is outweighed by the risk of bleeding. Aspirin is not the same as statins, which are known to reduce mortality in primary prevention. Aspirin doesn't affect atherosclerosis; it modifies plaque rupture, which is the final step. That is why it works better in patients with established heart disease. Primary-prevention efforts are much better directed at the basics of diet, exercise, and smoking and reducing cholesterol and blood pressure.

US Bleeding ADRs Higher With Dabigatran Than Warfarin

Concerns about bleeding with dabigatran (Pradaxa, Boehringer Ingelheim) continue, with a new report that adverse drug reactions (ADRs) involving hemorrhage reported to the US FDA were higher for the new oral anticoagulant than for warfarin in the first quarter of 2011 [1]. Many of the bleeding events with dabigatran involved intracranial hemorrhage in elderly patients. The latest data show that there were 505 reports of hemorrhage with dabigatran in the first quarter of 2011, which QuarterWatch says is "more than any other monitored drug, including warfarin, which ranked second, with 176 cases of hemorrhage."

While more study is needed, it may turn out to be a major drug safety mistake for the FDA to have approved a one-dose-fits all drug intervention as risky and sensitive as anticoagulation in older patients. Of the reported bleeds with dabigatran, 120 cases appeared to relate to hemorrhagic stroke. The bleeding events tended to occur mainly in elderly patients (median age of 80), which the report suggests "raises a question regarding safe dosing and monitoring in older patients." It notes that dabigatran was approved in a "one-size-fits-all" dose of 150 mg twice a day, and that the FDA rejected the lower 110-mg twice-daily dose tested in the RE-LY trial, instead approving a 75-mg twice-daily dose just for patients with severe renal impairment.

Elderly patients often have mild to moderate renal impairment, which can cause plasma levels of dabigatran to increase to up to three times those in normal renal function. The FDA and the manufacturer should reevaluate dosing in the elderly or those with moderate renal impairment to determine optimal dosing and monitoring requirements.

The phase 3 clinical-trial data demonstrated a 50% reduction in intracranial hemorrhage with dabigatran in comparison with warfarin, adding that it was difficult to interpret the current adverse-event data, as the numbers of patients taking the drug were not known, and that adverse events are always reported far more often with new drugs than with older established drugs like warfarin.Given physicians' reluctance to prescribe warfarin to the elderly and the demonstration of lower rates of intracranial hemorrhage in the clinical trials, it is likely that more elderly patients, who otherwise would not have been given anticoagulants, were prescribed dabigatran. These older people, who are known to have diminished renal function, would be more likely to bleed, particularly with the 150-mg twice-daily dose. It is not known if the 75-mg twice-daily dose would be effective in such patients. The 110-mg twice-daily dose available in many countries would likely be safer in individuals 70 to 75 years of age or over.

Boehringer Ingelheim is quoted as attributing the high number of bleeding events to "the drug’s rapid acceptance and active sales force with extensive physician contact." The company said it is working with the FDA to provide better guidance to physicians on treating elderly patients, especially those with transient or chronic impaired renal function. There were 932 serious adverse events with dabigatran reported to the FDA during the first three months of 2011, including 120 deaths, 25 cases of permanent disability, and 543 cases requiring hospitalization. The drug was launched in the US in October 2010 to reduce the risk of stroke in patients with atrial fibrillation.

Study Finds That Daily Aspirin Is Not For Everyone

New research shows that aspirin is not for everyone, and that in some patients this so-called wonder drug is doing more harm than good." The study "analyzed nine randomized studies of aspirin use in the United States, Europe and Japan that included more than 100,000 participants" and "the study subjects had never had a heart attack or stroke." The researchers found that "aspirin users were about 30 percent more likely to have a serious gastrointestinal bleeding event, a side effect of frequent aspirin use" and "over all, for every 162 people who took aspirin, the drug prevented one nonfatal heart attack, but caused about two serious bleeding episodes."

Experimental Anti-Blood-Clotting Drug May Benefit Patients Before Heart Surgery

Cangrelor, "an experimental anti-blood-clotting drug, can serve as a replacement for other drugs such as Plavix [clopidogrel bisulfate] in the days before heart surgery," according to a study published in the Journal of the American Medical Association. Investigators "gave cangrelor or a placebo to 210 patients who were about to undergo coronary artery bypass grafting." The participants "had been treated with a thienopyridine (such as Plavix) but went off the drugs prior to surgery as recommended, then received cangrelor or placebo for at least 48 hours until one to six hours before surgery. Researchers found that "more patients had low levels of platelet reactivity -- under 240 platelet reactivity units (PRU) -- throughout the treatment period compared with placebo." The investigators also reported that "there was no significant difference in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor.

US Group Seeks Re-Vote on Drospirenone Clot Risk

A U.S. watchdog group on Thursday urged the Food and Drug Administration to hold a new vote about blood clot risks from popular birth control pills, after advisers to the agency were shown to have ties to the pill makers. The FDA asked outside experts in December to discuss the safety of birth control that contains the compound drospirenone, including Bayer's Yaz and Yasmin.The panel decided by a four-vote margin that the benefit of pregnancy prevention from these pills outweighed their risk of dangerous blood clots.

But according to court and public documents, three of the FDA's 26 advisers had research or financial ties to Bayer. A fourth adviser had a connection to a manufacturer of generic copies of Yaz, Barr Laboratories, now part of Teva Pharmaceuticals. All four of these advisers voted that the drugs' benefits outweighed the risks, meaning the pills could stay on the market, according to the Project on Government Oversight (POGO). The FDA is not required to follow the recommendations of its advisers, but often does, leading to scrutiny of who is providing advice.

An FDA study estimated that 10 in 10,000 women taking the drospirenone-containing drugs would get a blood clot per year, compared with about six in 10,000 women taking older contraceptives.Some consumer groups have urged the FDA to take the pills off the market, since women have other options available for birth control. Former FDA head David Kessler has also said Bayer withheld reports of blood clots from the agency and did not adequately warn patients about safety problems.

During the meeting in December, FDA advisers said the scientific evidence was inconclusive for a higher rate of blood clots, although they recommended stronger safety labels on the pills.POGO also asked the FDA to share the financial disclosure forms each adviser had to fill out. These forms are not currently public. It is unclear whether the FDA knew of the advisers' conflicts. Recently, lawmakers have proposed loosening conflict of interest rules for FDA advisers to make it easier to find qualified experts.

Venous Thrombosis, Pulmonary Embolism Raise Mortality Risk

Patients who experience venous thrombosis or pulmonary embolism for the first time are more than 4 times more likely to die within the next 8 years as similar individuals without venous thrombosis or pulmonary embolism, according to a study. Researchers followed-up a group of 4947 patients with first-time venous thrombosis of the leg or first-time pulmonary embolism and a control group of 6154 individuals without either condition to compare long-term survival. The study included a total follow-up period of 26,515 person-years for the patient group, and 28,433 person-years for the control group.The study consisted of all patients and control participants from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study (MEGA study), a case–control study that recruited patients between March 1999 and September 2004.

Patients with first-time venous thrombosis or pulmonary embolism were enrolled after a median period of 1 month (range, 13 - 64 days) after objectively verified venous thrombosis of the leg or pulmonary embolism; control patients were enrolled after a comparable date. The control group was made up both of partners of patients enrolled in the MEGA study (n = 3297) and of a group of individuals matched on age and sex (n = 3000) who were recruited with random digit dialing between January 2002 and December 2004.

Because the control group was too small to allow the researchers to compare cause-specific death rates, the researchers added a control group consisting of the general Dutch population to the study.

The observation period lasted until death, end of follow-up (between February 2007 and May 2009), emigration (n = 164, 1.5%), or loss to follow-up (n = 173, 1.5%), whichever happened first. Follow-up was less than 30 days for 152 participants (1.4%, 9 patients), and they were excluded from the study.The researchers collected vital status information from community registries, and primary and secondary causes of death from the Central Bureau of Statistics Netherlands. The overall mortality rate in the thrombosis group was 22.7 per 1000 person-years (95% confidence interval [CI], 21.0 - 24.6); in the control group, it was 4.7 per 1000 person-years (95% CI, 4.0 - 5.6).The standardized mortality ratio (SMR) of the control group was the same as that of the general population (SMR, 1.0; 95% CI, 0.9 - 1.2).The mortality risk in patients with cancer who have thrombosis was 17 times higher than in the control group (SMR, 17.2; 95% CI, 15.5 - 19.1), and 5 times higher than in patients with cancer and no thrombosis (SMR, 5.5; 95% CI, 5.0 - 6.1).

Mortality rates remained elevated for up to 8 years in all patients except those with a transient provoking risk factor for the thrombotic occurrence, such as surgery or trauma.

Because of our extended follow-up for up to 8 years after the thrombotic event, our most important observation is that increased mortality for thrombosis patients persists for a prolonged time.When the researchers studied only long-term survival, they found no difference in survival in patients with venous thrombosis or pulmonary embolism. "This finding indicates that the highly increased risk of death for those with [pulmonary embolism] is mainly present during the first month after venous thrombosis," write the authors.

More than half (55%) of patients with venous thrombosis and malignancy died during follow-up, and half of those died within the first year after thrombosis.We confirmed previous observations that patients with malignancy and venous thrombosis have a very poor prognosis, substantially worse than patients with cancer without thrombosis, with a 5.5-fold difference in our study. Aside from malignancies, main causes of death were diseases of the circulatory and respiratory system, report the authors.

The study results highlight the need for long-term clinical follow-up of patients who experience first-time venous thrombosis or pulmonary embolism. Our results underline the major consequences of venous thrombosis, not only with regard to morbidity but also to mortality.

Contemporary Look at VTE After Joint Surgery

A new review of studies that examined patients who underwent joint-replacement surgery and were taking the recommended anticoagulant prophylaxis estimates that one in 100 patients who undergo knee replacement and one in 200 who undergo hip replacement will suffer a symptomatic venous thromboembolic (VTE) event. Or, to put it another way, the current incidence of postoperative symptomatic VTE is about 1% after knee replacement and 0.5% after hip replacement. No estimate of VTE event rates prior to hospital discharge was previously available in the literature, say so these figures provide "contemporary benchmarks" for individual patients and clinicians when considering the risks and benefits of joint replacement, they say.

The meta-analysis of randomized clinical trials and observational studies of postoperative VTE rates carried out in almost 45 000 patients who received prophylaxis with a low-molecular weight heparin, subcutaneous factor Xa inhibitor, or oral direct inhibitor of factors Xa or IIa.The rates of symptomatic VTE events before hospital discharge following hip or knee replacement "may be suboptimal safety indicators, because the period of VTE risk extends beyond the length of hospitalization for surgery," he observes.

Based on studies to date, the postoperative risk period for VTE after hip and knee replacement is "about 10 to 12 and four to six weeks, respectively substantially beyond the period of initial hospitalization. The three-month cumulative incidence of symptomatic VTE after total hip replacement is 2.5% to 3.4% and after knee replacement is 1.8% to 2.4%, he asserts. "From the perspective of the patient contemplating elective total hip replacement or total knee replacement, these cumulative rates are likely to be most important for decision making."

Cangrelor Suited for Important Antiplatelet Niche: BRIDGE Study Published

The BRIDGE study, showing that the intravenous P2Y12 receptor antagonist cangrelor (the Medicines Company) could represent an effective bridging therapy for patients taking thienopyridine antiplatelet agents such as clopidogrel who are scheduled for surgery. Patients who are taking clopidogrel but are scheduled to have surgery are a big problem. We don't really know what to do with them. As the antiplatelet effect of clopidogrel takes a few days to wear off, it is advised to stop clopidogrel five to seven days before surgery, but we are seeing many patients who have an event during this time when there is no antiplatelet therapy on board. Some doctors give a short-acting GP IIb/IIIa blocker over this time, but these haven't been properly tested in this indication, and they don't protect against stent thrombosis as well as thienopyridines. The researchers believe cangrelor is "ideal" for this bridging role as it has a very short half-life and so a quick "on-off" effect, and because it acts at the same receptor as the thienopyridines it should be just as effective at preventing stent thrombosis.

For the current study, 210 patients taking thienopyridines for ACS or after stent placement who were awaiting CABG had their thienopyridine stopped, and they were then randomized to either cangrelor (0.75 µg/kg per minute) or placebo for at least 48 hours. Study drug was discontinued one to six hours before CABG surgery. Results showed that more patients had low levels of platelet reactivity--under 240 platelet reactivity units (PRU)--throughout the treatment period compared with placebo

There was no significant difference in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor. Topol said the bleeding data looked "very encouraging." "There was an increase in minor bleeding, which may have become significant if the trial were larger. It would be good to see results in a larger sample of patients--perhaps undergoing different types of surgeries."

As cangrelor is not yet available commercially, could it be made available for this indication based on these data? Addressing this question, Topol said: "From a regulatory view, this trial is small and only has a surrogate end point (platelet inhibition), so I couldn't say that it will gain approval. But as there is nothing else available for this population and there is a clear need for something, maybe cangrelor could be made available, with further data coming from postmarketing studies."

He added that having patients stop taking clopidogrel because of upcoming surgery is not an infrequent situation. In the paper, the researchers estimate that around 5% of patients will require some type of surgery within the first 12 months after stent implant or an ACS diagnosis. Topol commented: "At present, patients can either tough it out with no antiplatelet therapy or be given an agent unapproved for such use, which doesn't work so well. Under these circumstances perhaps we do have enough data to justify using cangrelor in these patients."

Cangrelor has previously been investigated as an alternative to a clopidogrel loading dose in ACS patients scheduled for PCI in the CHAMPION trial. But it failed to show benefit on the primary end point of death, MI, or ischemic-driven revascularization within 48 hours of the procedure.

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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