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WHAT'S NEW IN COAGULATION: MAY 2011

Dabigatran Etexilate To Be Made Available To UK AF Patients Later This Year.

Pradaxa (dabigatran etexilate) is being described as the 'holy grail' of blood-thinning drugs and the first major pharmacological breakthrough for people at an increased risk of having a stroke in" half a century. The drug was likely to be approved for patients with AF by the European Medicines Agency (EMA) in the next couple of months. There will "be a lot of interest from patients" because it would mean they "would not have to undergo regular blood checks or watch their diet so closely."

Regular Aspirin Use May Lower Pancreatic Cancer Risk.

Taking aspirin regularly can help reduce the risk of heart attack and stroke -- and now, we may be able to add pancreatic cancer to the list," according to findings presented at the American Association for Cancer Research annual meeting. Researchers analyzed medical data from "904 patients with pancreatic cancer and 1,224 cancer-free patients" and found that people who took aspirin "at least once a month were 26% less at risk of developing pancreatic cancer. Researchers also found that people "who regularly take low-dose aspirin to reduce their risk of heart disease had a 35% lower risk of pancreatic cancer."

Using aspirin at least once monthly was linked to a significant decrease in pancreatic cancer risk "even after accounting for other factors that might affect the finding, such as body-mass index and smoking history." Notably, those who had "once smoked but kicked the habit seemed to experience an even stronger protective effect with respect to aspirin use than those who had never smoked or those who continued to smoke," the study authors said. NSAID and acetaminophen use did not, however, "have any noticeable impact on pancreatic cancer risk," the authors added.

The finding is preliminary and the researchers are "cautious about its implications. 'The results are not meant to suggest everyone should start taking aspirin once monthly to reduce their risk of pancreatic cancer,' researcher Dr. Xiangt-Lin Tan, a research fellow at the Mayo Clinic in Rochester, Minn., said in a written statement. 'Individuals should discuss use of aspirin with their physicians because the drug carries some side effects.'"

Clinical Trial Finds Experimental Blood Clot Preventative No More Effective Than Standard Treatment.

Johnson & Johnson and Bayer AG (BAYN)'s experimental pill Xarelto (rivaroxaban) was no better than a standard injection to prevent blood clots in critically ill hospital patients." According to the study, which was presented the American College of Cardiology meeting, researchers looked at over 8,000 patients, who had "limited mobility because of infections, heart failure, breathing difficulties, stroke and cancer." Those who were given Xarelto for "more than 10 days" had reduced "clots in the legs and lungs by 23 percent." But longer use "more than doubled the risk of major bleeding compared with patients given a placebo after the standard 10 days of treatment with Sanofi-Aventis SA's Lovenox (enoxaparin sodium injection).

EMA Asks Drugmakers To Inform Physicians Of Potential Risks Of Prasugrel.

The European Medicines Agency (EMA) is requesting that Daiichi Sankyo and Eli Lilly inform physicians of the potential risk of hypersensitivity reactions with prasugrel." In a letter, the drugmakers warn "prescribers of the potential hypersensitivity risks, including the risk of angioedema, in patients with a previous known history of hypersensitivity reactions to thienopyridines."

Men With Prostate Cancer at Higher Risk for Thromboembolic Disease

All men with prostate cancer have a higher risk for thromboembolic disease, compared with the general population, and the risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) is "especially high" in those undergoing hormonal therapy.These results come from a new analysis of data from the Swedish National Prostate Cancer Register, published online in The Lancet Oncology. This new study focused on thromboembolic disease, but some of the findings are similar to the group's previous study on cardiovascular disease, Ms. Van Hemelrijck commented in an interview with Medscape Oncology.

For instance, the highest risk for both was seen in men undergoing gonadotrophin-releasing hormone (GnRH) agonist therapy or those who had undergone orchidectomy, whereas men who were treated with antiandrogens were at the lowest risk among those who were treated with hormonal therapies. This ties in with research suggesting that testosterone is important both in the functioning of the heart and in thromboembolism and that suppressing it completely is detrimental to both, Ms van Hemelrijck explained. With antiandrogens, there is still testosterone circulating, but it is prevented from acting on the prostate by androgen receptor blockade, she added.

However, an accompanying editorial points out that several factors limit the observation that antiandrogens were associated with a more modest increase in the risk of thromboembolism compared with GnRH agonist or orchidectomy.Editorialists Philip Saylor, MD, and Annmarie Fogerty, MD, from the Massachusetts General Hospital Cancer Center in Boston, note that the antiandrogen subset was small. These patients were also less likely to have metastatic disease than patients in the other treatment groups. In addition, antiandrogen monotherapy "is not currently the standard of care in any setting," they point out.

The most important point from these studies, Ms. van Hemelrijck says, is that men with prostate cancer who are being treated with hormonal therapies should be monitored for cardiovascular disease (as suggested by the first study) and also for thromboembolic disease (as suggested by this present study), because they are at increased risk of both.The new study analyzed data collected in Sweden from 1997 to 2007 on 76,600 men with prostate cancer. Of these, 30,642 were treated with hormonal therapies, specifically, 9066 with a GNRH agonist, 5340 with orchidectomy, 3391 with antiandrogens, and 1199 with a combination of other drugs. The remaining men received either curative treatment, such as prostatectomy (n = 26,432) or active surveillance (n = 19,526).

Thromboembolic disease developed in 1881 of these men: 767 had a DVT, 873 had a PE, and 241 had an arterial embolism (AE). This incidence of thromboembolic disease is higher than is seen among men in the general population, and this is "not surprising, as cancer is known to increase the risk of thromboembolism."The risk was increased (nearly doubled) for DVT and PE but not for AE (although the AE numbers were small, the researchers point out).

The results are expressed as a standardized incidence ratio (SIR), defined as the ratio of the observed number of a particular thromboembolic disease to the expected number of that disease.The SIRs for all men with prostate cancer were 1.9 for DVT, 1.85 for PE, and 1.02 for AE. The increase in risk was seen regardless of the treatment received, but the magnitude of this increased risk varied. The largest absolute risk (more than doubled) was seen for DVT for men receiving endocrine treatment.

The SIRs for men with prostate cancer undergoing endocrine therapy were 2.48 for DVT, 1.95 for PE, and 1.0 for AE.For men who had undergone curative treatment, the SIRs were 1.73 for DVT, 2.03 for PE, and 0.95 for AE, whereas for men undergoing surveillance the SIRs were 1.27 for DVT, 1.57 for PE, and 1.08 for AE.

They point out that men treated with endocrine therapy had a greater proportion of metastatic or otherwise poor-risk disease, and advanced cancer is a known risk factor for venous thromboembolism. This group of patients also included the highest proportion of men older than 75 years, and advanced age is also a known risk factor for venous thromboembolism in patients with cancer, they add.

Nevertheless, these latest data raise the question of whether endocrine therapy increases the risk of venous thromboembolism, they concede. They hope that the new findings will "stimulate further study of potential interactions between androgen deprivation and blood coagulability."

Lancet Oncol. Published online April 14.

Antipsychotic Drugs and Risk of Venous Thromboembolism: Nested Case-Control Study

Objective. To determine whether antipsychotic drugs are associated with an increased risk of venous thromboembolism, and to examine risks by type of antipsychotic, potency, and dose.
Design. Population based nested case-control study.
Setting. The UK QResearch primary care database.
Participants. Patients (cases) with a first ever record of venous thromboembolism between 1 January 1996 and 1 July 2007; each was matched with up to four controls by age, calendar time, sex, and practice.
Main outcome measures. Odds ratios for venous thromboembolism associated with antipsychotic drugs adjusted for comorbidity; concomitant drug exposure.
Results. There were 25 532 eligible cases (15 975 with deep vein thrombosis and 9557 with pulmonary embolism) and 89 491 matched controls from a study population of 7 267 673. Individuals prescribed antipsychotic drugs in the previous 24 months had a 32% greater risk of venous thromboembolism than non-users, despite adjustment for potential risk factors (odds ratio 1.32, 95% confidence interval 1.23 to 1.42). Patients who had started a new drug in the previous three months had about twice the risk (1.97, 1.66 to 2.33). The risk was greater for individuals prescribed atypical rather than conventional drugs (adjusted odds ratio 1.73, 1.37 to 2.17, for atypical drugs; 1.28, 1.18 to 1.38, for conventional drugs). It also tended to be greater for patients prescribed low rather than high potency drugs (1.99, 1.52 to 2.62, for low potency; 1.28, 1.18 to 1.38, for high potency). The estimated number of extra cases of venous thromboembolism per 10 000 patients treated over one year was 4 (3 to 5) in patients of all ages and 10 (7 to 13) for patients aged 65 and over.
Conclusions. There is an association between use of antipsychotic drugs and risk of venous thromboembolism in a large primary care population. The increased risk was more marked among new users and those prescribed atypical

Anti-Bleeding Drug May Not Benefit Trauma, Surgery Patients.

A powerful, costly drug approved in 1999 for a small group of patients who may bleed uncontrollably during surgery is now used in a host of other surgical situations, sometimes with serious negative effects," according to two new studies in the Annals of Internal Medicine.  "The drug, sold as NovoSeven (Coagulation Factor VIIa (Recombinant)), was approved for people who lack a gene to make a particular blood-clotting protein called Factor VIIa and for certain people with hemophilia who can't tolerate another drug that can stop bleeding."  However, most "of the time when it is used in hospitals, it is given to patients with other reasons for bleeding, including having heart surgery or a hemorrhagic stroke."

The research published today looked at treatment records in 615 US hospitals from 2000 to 2008 and examined 64 studies of NovoSeven to assess outcomes and side effects." The use of the drug "increased 140-fold in hospitals from 2000 to 2008, as physicians prescribed it for off-label, or unapproved, conditions such as surgical bleeding, trauma and hemorrhages, researchers said" on Monday. "The patients who make up that surge in use aren't more likely to survive because of the drug and some are injured or killed when the treatment causes unintended clotting that blocks blood flow, according to the studies."

Physicians should be more cautious with the drug until there's more research into whether it's appropriate to use in certain cases. The drug also costs about $10,000 per dose.

Low-Dose Heparin Looks Good in PCI: DEDICA

A low dose of heparin (50 IU/kg) seems to be sufficient for use in PCI if aspirin and clopidogrel are on board, according to the results of the DEDICA study.Current guidelines still recommend a standard dose of heparin (100 IU/kg) during coronary interventions and that this dose has been used as a gold standard in trials comparing heparin with new anticoagulants, but it is unclear whether this dose is still necessary when patients are pretreated with aspirin and clopidogrel.

To investigate the use of lower doses of heparin, Pasceri and colleagues designed a randomized, single-blind trial comparing the standard 100-IU/kg dose of heparin, with a target activating clotting time (ACT) >300 seconds, with a low dose (50 IU/kg), with a target ACT >180 seconds, in 713 consecutive patients undergoing coronary intervention. The study included both stable and unstable patients. Treatment with other anticoagulants or GP IIb/IIIa antagonists was excluded. Radial access was used in 62% of cases in both groups.

Results showed that at 30 days of follow-up, patients receiving low-dose heparin had a similar incidence of cardiac events, with a trend toward a reduction in bleeding. However, Pasceri noted that bleeding was low in both groups, probably due to the high use of radial access.

ATOLL at 6 Months: Better Survival With Enoxaparin Persists

Six month results from the ATOLL study of enoxaparin in primary PCI have shown that the strong trend toward a reduction in mortality observed at 30 days in the enoxaparin group persists over longer follow-up.

The ATOLL study randomized 910 patients undergoing PCI for acute STEMI to receive either intravenous enoxaparin or unfractionated heparin (UFH) with the procedure. The main results, reported at last year's European Society of Cardiology, showed no significant difference in the primary end point--the 30-day rate of death/MI complications/procedural failure/major bleeding--between the two groups, although the enoxaparin group showed a strong favorable trend. In addition there was a significant improvement in the enoxaparin group in many of the secondary end points, including death/complications of MI. All-cause death showed a strong trend toward benefit in the enoxaparin group, and this remained out to six months.

Bivalirudin vs Low-Dose Heparin in PCI: ARMYDA BIVALVE

Bivalirudin was associated with lower bleeding complications than low-dose unfractionated heparin in PCI patients at high bleeding risk in the ARMYDA-BIVALVE study. Bivalirudin, a direct thrombin inhibitor, has been shown to be as effective as unfractionated heparin, with decreased bleeding risk, in patients with acute coronary syndromes undergoing PCI. But there has been no study specifically designed to evaluate effectiveness of bivalirudin vs heparin in patients at high risk of bleeding complications with PCI. This was therefore investigated in the ARMYDA-BIVALVE study.

In previous studies comparing bivalirudin with heparin, such as HORIZONS, ACUITY,and REPLACE-2, the heparin group systematically received GP IIb/IIIa inhibitors, which may at least partially have contributed to the higher bleeding rate. "However, in ARMYDA-BIVALVE, we showed a reduction in bleeding complications without systematic use of GP IIb/IIIa inhibitors in the opposite arm."

ARMYDA-BIVALVE compared bivalirudin with a much lower dose of heparin (75 IU/kg) and still showed a reduced level of bleeding.In the study, 401 patients at high bleeding risk (over 75 years of age, diabetes, reduced renal function) scheduled for PCI were randomized to bivalirudin (0.75 mg/kg bolus followed by 1.75 mg/kg per hour during the procedure) or unfractionated heparin (75 IU/kg). Provisional GP IIb/IIIa blockers were used in both groups.

The 30-day results showed that major adverse cardiac events (MACE)--death, MI, target vessel revascularization, or stent thrombosis--were similar in the two groups, but bleeding rates were vastly reduced in the bivalirudin group. Patti said this was essentially due to a reduction in hematoma at the entry site associated with the PCI femoral approach. The bleeding reduction was seen in both ACS and stable patients.

During the discussion of the study, one commentator suggested that it would now be desirable to compare bivalirudin with an even lower dose of heparin in such patients and in the context of a radial approach to PCI, which is associated with lower bleeding rates. It would also be interesting to look at whether the lowest-risk patients, rather than the highest, also derive any benefit of bivalirudin over heparin.

FDA Explains Decision on Dabigatran 110-Mg Dose

The FDA's surprise decision not to approve the 110-mg dose of dabigatran (Pradaxa, Boehringer Ingelheim) when it approved the 150-mg dose last fall. The data in favor of a 110-mg dose were suggestive but not entirely convincing. Now, in a perspective published online April 13, 2011 in the New England Journal of Medicine, three FDA officers offer a full explanation and some numbers for that decision [1].

As previously reported by heartwire , the pivotal RE-LY trial showed that both the 150-mg and the 110-mg doses were noninferior to warfarin. The higher dose was significantly better than both the lower dose and warfarin for the primary end point of stroke or systemic embolism but caused more bleeding than the lower dose (at a rate similar to warfarin). By contrast, the lower dose was superior to warfarin for major bleeding.

But the question the FDA zeroed in on was whether the 110-mg dose provided a meaningful option for the kinds of patients who, in theory, could benefit from less bleeding: namely, patients at high risk of bleeding, elderly patients, or patients with impaired renal function.

The high-risk-for-bleeding group was the simplest: according to the FDA's analysis, 57% of patients in RE-LY who had a major bleed during the study resumed taking their study drug or never stopped taking it in the first place. And rates of additional bleeds were no different among the three groups. While "exploratory," these numbers "do not support the strategy of transitioning patients to the lower dose," Beasley et al conclude.

Older patients made up 40% of the RE-LY population: in this group, the rate of stroke was slightly lower in the higher-dabigatran-dose group than in the 110-mg group, but the rate of bleeding was higher.

The impaired-renal-function group was identified as the most likely to derive benefit from a lower dose, because dabigatran is cleared primarily by the kidney. According to the analysis of RE-LY patients with moderate renal impairment (creatinine clearance >30 to 50 mL/min) cited by Beasley et al, the rate of stroke in the higher-dose group was actually half that of the lower-dose group, while bleeding rates were no different. 

Where the FDA made an exception, however, was for patients with severe renal impairment--a group excluded from RE-LY. It was for these patients that the agency opted to approve the surprise, untested, 75-mg dose. This decision, they explain, "was based not on efficacy and safety data, but on pharmacokinetic and pharmacodynamic modeling."But that 75-mg dose is only for this renal subgroup. "What's needed is [a reduced dose for] those patients in whom the bleeding risk is considered to be sufficiently high that they wouldn't want to use the 150-mg dose," Connolly said. "Without the 110-mg dose available, there are, I think, a lot of patients who now will not receive dabigatran at all--these are patients for whom warfarin was not being used because the bleeding risk was considered to be high, or patients who have some bleeding on the dabigatran 150-mg dose for whom there is no alternative available."

Of note, Health Canada approved both the 110-mg dose and the 150-mg dose for the prevention of stroke and systemic embolism in AF patients last October. A 75-mg dose (as well as a 110-mg dose) is already on the market in the European Union, where dabigatran was approved in 2008 for the prevention of venous thromboembolism in patients undergoing hip or knee replacement. On Thursday, a spokesperson for Boehringer Ingelheim told heartwire that the company "continues to believe that there is a place for the 110-mg dose in reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation" and that it "will continue to discuss the 110-mg dose with the FDA as we remain committed to providing clinicians with appropriate options for the treatment of patients."

1.     Beasley BN, Unger EF, Temple R. Anticoagulant options-- Why the FDA approved a higher but not a lower dose of dabigatran. New Engl J Med 2011; DOI: 10.1056/NEJM/1103050. Available at: http://www.nejm.org.

Drospirenone Associated With Increased Risk for VTE

Women without risk factors for venous thromboembolism (VTE) who are taking the third-generation oral contraceptive drospirenone have an increased risk for nonfatal VTE compared with women taking the second-generation contraceptive levonorgestrel, according to the findings of 2 new case-control studies.According to the researchers, a series of case reports beginning in 2002 first raised concerns about an increased risk for VTE in users of oral contraceptives containing drospirenone. This risk has since been assessed in several studies that included women with risk factors for VTE. However, the risk attributable to oral contraceptives in the absence of other causes was unknown.

In the current studies, 1 conducted in the United Kingdom and the other in the United States, the study populations, both consisting of women aged 15 to 44 years, was restricted to patients with idiopathic VTE, each matched with up to 4 control case patients by age and calendar time of drug exposure.

Data for the UK cohort came from the UK General Practice Research Database, which contains data from more than 3 million people. Data for the US cohort were acquired from the PharMetrics database, which contains prescription data on 55 million people reaching back to 1995. The UK study included 61 cases of idiopathic VTE among current users of drospirenone and levonorgestrel; these patients were matched with 215 control patients. All patients were receiving oral contraceptives containing 30 μg estrogen in combination with either drospirenone or levonorgestrel. The US study included 186 cases of idiopathic VTE; these patients were matched with 681 control patients, with contraceptives including either drospirenone or levonorgestrel.

Although the absolute risk was low, both studies showed a 2- to 3-fold increased risk for nonfatal VTE with drospirenone compared with levonorgestrel. The UK study showed an odds ratio of 3.3 (95% confidence interval [CI], 1.4 - 7.6), and the US study showed an odds ratio of 2.4 (95% CI, 1.7 - 3.4).In the UK study, the incidence rates for idiopathic VTE were 23 (95% CI, 13.4 - 36.9) per 100,000 woman/years with drospirenone and 9.1 (95% CI, 6.6 - 12.2) per 100,000 woman/years with levonorgestrel. The corresponding incidence rates in the US study were 30.8 (95% CI, 25.6 - 36.8) per 100,000 woman years with drospirenone and 12.5 (95% CI, 9.61 - 15.9) per 100,000 woman years with levonorgestrel.

BMJ. Published online April 21, 2011. Full text

A Post-Stroke Hemorrhagic Rash

A hospitalized 84-year-old white man presents with a new onset of hemorrhagic rash.The patient has a history of hypertension and a remote stroke. He was hospitalized after a right posterior cerebral artery ischemic stroke with resultant left-sided hemiparesis and severe left-sided neglect. His medications included metoprolol and a daily multivitamin. He had been taking warfarin since his initial stroke; however, the medication was stopped 1 year before this admission.

On admission, the patient was started on a heparin drip. Warfarin was started 2 days later. On hospital day 5, new hemorrhagic lesions were noted on the patient's left forearm, proximal to the heparin infusion site. Similar dark, nontender, nonpruritic, pinpoint blisters were also noted distant from the infusion site on his right distal lower extremity, hard palate, and right wrist. Additional inpatient medications included acetaminophen, docusate, finasteride, pantoprazole, and simvastatin.

Physical Examination

On exam, numerous blood-filled 1- to 3-mm vesicles with perilesional erythema were visible on the patient's left distal upper extremity (Figures 1, 2), right wrist, right lower leg (Figure 3), and at the border of the hard and soft palates

Laboratory Studies

• Hemoglobin: 12.2 g/dL (normal range, 13.7-17.5 g/dL);
• Prothrombin time: 12.4 seconds (normal range, 11.9-14.7 seconds);
• Partial thromboplastin time: 76 seconds (normal, 22.3-35.3 seconds);
• International normalized ratio: 1.2 (normal range, 0.9-1.1);
• Platelet count: 167 x 10³/µL (normal, 163-369 x 10³/µL);
• Herpes simplex viral culture (by nucleic acid amplification tests): negative;
• Varicella zoster virus culture: negative; and
• Liver and renal function tests: within normal limits.

Histopathology

A shave biopsy specimen obtained from an intact vesicle on the left forearm (Figures 5, 6) revealed subcorneal and intraepidermal collections of red blood cells with solar elastosis and extravasated red blood cells in the dermis and a minimal inflammatory component with no evidence of vasculitis or thrombosis

Diagnosis and Management

On the basis of the pathology and clinical history, the diagnosis of heparin-induced hemorrhagic bullous dermatosis was made. Heparin was discontinued and the patient was started on fondaparinux (a synthetic direct pentasaccharide Factor Xa inhibitor) and continued on warfarin. He developed no new bullae and his existing lesions were resolving at time of discharge a week later.

Heparin-induced bullous hemorrhagic dermatosis is a unique entity first reported in 2006 with 3 cases, with 3 additional case reports since that time. In published reports, 5-20 days after initiation of heparin therapy, asymptomatic, tense hemorrhagic bullae develop on otherwise normal skin distant from the heparin injection site. These lesions resolve spontaneously after discontinuation of heparin.

Laboratory data usually exhibit a normal platelet count and metabolic panels. Prothrombin time may be prolonged but coagulation studies are otherwise normal. Skin biopsy specimens reveal subcorneal and intraepidermal bullae filled with erythrocytes and a moderate dermal inflammatory infiltrate without vasculitis or capillary thrombosis. The mechanism of blister formation is unknown but is likely caused by a systemic effect of the drug rather than a local reaction, given the presence of lesions at sites distant to the injection.

Only rarely are unfractionated and low-molecular-weight heparins associated with cutaneous side effects such as local reactions including hematoma formation at injection site, heparin-induced thrombocytopenia (HIT), contact dermatitis, urticaria and skin necrosis. HIT is a reduction in platelet count below 50% from baseline, occurring at least 5 days after beginning unfractionated or low-molecular-weight heparins. HIT comes in 2 types:

• HIT type 1 is the benign form and is the result of a direct interaction between heparin and circulating platelets. This type generally resolves with continued heparin administration; and
• HIT type 2 is the severe form, caused by IgG antibodies that bind to heparin and platelet factor 4 complexes. This leads to platelet activation, aggregation, and subsequent thrombocytopenia. HIT 2 is associated with thrombotic complications and can lead to heparin-induced cutaneous necrosis.

In heparin-induced cutaneous necrosis, thrombosis and necrosis are present at the injection site as well as distant cutaneous sites and internal organs. Treatment includes switching heparin to alternative anticoagulants, such as argatroban, danaparoid, or lepirudin.

Warfarin works by blocking the production of vitamin K-sensitive factors by the liver (factors II, VII, IX, X, protein C and protein S). Protein C has critical anticoagulant activity and acts to prevent the distal spread of clot from the initial point of coagulant activation. As a result of its short half-life, with warfarin administration, protein C is the first of these factors to drop. The rapid decline in protein C causes the patient to be initially hypercoagulable. As such, patients started on warfarin are initially bridged with heparin until the patient is anti-coagulated on warfarin.

Warfarin necrosis is a rare disorder presenting 2-5 days after initiation of warfarin during this initial hypercoagulable state. Clinically, these patients present with painful plaques on the breasts, thighs, and buttocks that progress to hemorrhagic blisters and necrotic ulcers. This process is secondary to occlusive thrombi and ischemic infarcts. Patients with hereditary protein C deficiency are at highest risk. Therapy includes discontinuation of warfarin, initiation of heparin anticoagulation, and administration of vitamin K or intravenous protein C concentrate.

Off-Label Use of Recombinant Factor VIIa Very Common in US

A new study finds that in the United States, recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk) is only rarely used for what it is specifically approved for — treatment of bleeding in patients with hemophilia A or B, and as an antibody inhibitor against standard-factor replacements.

Instead, the drug is far more likely to be used for the off-label treatment of, or prevention of, bleeding in other conditions, such as cardiovascular surgery and body and brain trauma.

They report that the use of rFVIIa in hospitalized patients without hemophilia grew more than 140-fold during the 9-year period, such that by the end of 2008, 97% of 18,311 in-hospital uses were off-label (95% confidence interval [CI], 96% - 98%). In contrast, in-hospital use for the approved indication (hemophilia) increased less than 4-fold and accounted for only 2.7% of its in-hospital use (95% CI, 1.9% - 3.5%).

One of the most common off-label uses was for cardiovascular surgery (29%; 95% CI, 21% - 33%) in both adults and children. "In 2008, more than 1 in 4 patients who received rFVIIa were treated in the context of cardiovascular surgery," despite "limited evidence to support this use," the authors note.The other most common off-label uses were for body and brain trauma (29%; 95% CI, 19% - 38%) and intracranial hemorrhage (11%; 95% CI, 7.7% - 14%).

In general, report Dr. Logan and colleagues, "use of rFVIIa is growing in the absence of clear evidence of therapeutic efficacy and without close surveillance for associated harms." In the nationwide sample of hospitals they analyzed, in-hospital mortality for rFVIIa-treated patients was high, at 27% overall, and as high as 40% to 50% for several indications, they report.

Support for Off-Label Use Lacking

In the second study, first author Veronica Yank, MD, from Stanford University, who also worked on the other study, and colleagues systematically reviewed the literature on the efficacy and safety of rFVIIa used for 5 unapproved indications: intracranial hemorrhage, adult cardiac surgery, trauma, liver transplantation, and prostatectomy.

They found 64 studies from 62 articles that they deemed worthy of review and that had been published up to 2010. Most were observational studies either with a comparator (n = 26) or without (n = 22). Only 16 studies were randomized controlled trials. There was "great variability" in rFVIIa doses administered (range, 5 - 400 μg/kg).

For intracranial hemorrhage, mortality was not reduced with rFVIIa use across a range of doses, and arterial thromboembolism was increased with medium-dose rFVIIa use (risk difference [RD], .03; 95% CI, .01 - .06) and high-dose rFVIIa (RD, .06; 95% CI, .01 - .11).

There was also no mortality benefit with use of rFVIIa for adult cardiac surgery, but there was an increased risk for thromboembolism (RD, .05; 95% CI, .01 - .10). For body trauma, there were no differences in mortality or thromboembolism, but there was a reduced risk for acute respiratory distress syndrome (RD, −.05; 95% CI, −.02 to −.08).

There was only 1 randomized controlled trial on prophylactic use of rFVIIa in patients having prostatectomy, and mortality and thromboembolic events could not be evaluated because of limited events, the researchers say..

Ann Intern Med. 2011;154:516-522. Abstract

Ann Intern Med. 2011;154:529-540. Full text

Ann Intern Med. 2011;154:566-568. Full text

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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