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New In Coagulation

WHAT'S NEW IN COAGULATION: FEBRUARY 2011

Johnson & Johnson Requests FDA Approval To Sell Blood Thinner.

Johnson & Johnson said Wednesday that it requested approval to sell its blood thinner rivaroxaban for the prevention of stroke and embolism in patients with atrial fibrillation." J&J said "it filed for marketing approval with the Food and Drug Administration" and also said it "submitted new information about the use of rivaroxaban as a preventive treatment for deep vein thrombosis and pulmonary embolism in patients having hip or knee replacement surgeries."

Blood Thinner Also Submitted For Approval In Europe. Germany's Bayer AG says it has submitted an application seeking authorization to sell its new anti-clotting drug Rivaroxaban within the European Union." In the US, "the drug would be sold by Johnson & Johnson's Ortho-McNeil division."

Warfarin in Haemodialysis Patients with Atrial Fibrillation: What Benefit?

Warfarin is commonly used to prevent stroke in patients with atrial fibrillation; however, patients on haemodialysis may not derive the same benefit from warfarin as the general population. There are no randomized controlled studies in dialysis patients which demonstrate the efficacy of warfarin in preventing stroke. In fact, warfarin places the dialysis patient at increased risk for haemorrhagic stroke and possibly ischaemic stroke. Additionally, warfarin increases the risk of major bleeding and has been associated with vascular calcification. Routine use of warfarin in dialysis for stroke prevention should be discouraged, and therapy should only be reserved for dialysis patients at high risk for thrombo-embolic stroke and carefully monitored if implemented.

Patients on dialysis have an increased risk of bleeding at baseline due to multiple factors. There is an acquired defect in primary haemostasis as a result of defects in platelet secretion, aggregation, and altered interactions between the platelet and vessel walls.^[10] In particular, uraemia causes altered arachidonic acid metabolism which leads to a multitude of abnormalities: decreased thromboxane A2 production, abnormal intracellular calcium mobilization, and decreased platelet ADP, epinephrine, and serotonin production. Uraemia also impairs binding between IIb–IIIa receptors and the von Willebrand factor, leading to impaired platelet aggregation.^[11] Finally, uraemia results in increased endothelial production of prostaglandin I2 and nitric oxide, agents which have vasodilatory and antiplatelet properties.^[10]

Patients with very low GFR or on dialysis are at increased risk for haemorrhagic stroke. The devastating effects of cerebral haemorrhage are evident in the fact that among anticoagulated patients in the general population, 76% of patients with intracranial haemorrhage either died or had severe disability at hospital discharge.The risk of bleeding is not limited to haemorrhagic stroke. In fact, the most serious source of bleeding is gastrointestinal bleeding. It accounts for ~3–7% of all deaths in the dialysis populationGiven that most dialysis patients are exposed to anticoagulation of extracorporeal circuit three times a week, the high rate of bleeds is not a surprise. Finally, dialysis patients frequently have an increased need for invasive procedures and therefore are at risk of additional bleeding complications.

The decision to anticoagulate patients for atrial fibrillation is often guided by the CHADS₂ scoring system.^] In the general population, treatment with warfarin reduces the annual stroke risk by 50% compared with no treatment.  One of the major limitations to the CHADS₂ scoring system is that the majority of patients are classified as intermediate risk, including patients who may actually be at low risk. As a result, a fair number of individuals may be recommended for anticoagulation where there may be little or no benefit. A recent modification to the CHADS₂ scoring system has been proposed by Lip et al. ^[27] to identify patients who are at truly low risk for thrombo-embolism.

The benefit of stroke prevention in any patient is counterbalanced by the risk for haemorrhage. A pooled analysis of five trials with warfarin in atrial fibrillation demonstrated an annual rate of major bleeding of 1.0% in the control patients vs. 1.3% in non-dialysis patients treated with warfarin.^[32] The annual rate of intracranial haemorrhage was 0.1% in controls vs. 0.3% in non-dialysis patients treated with warfarin. Determining the risk of bleeding in a dialysis patient on warfarin is difficult. A number of scoring systems have been created to predict bleeding with warfarin treatment (Table 2). However, none of these bleeding risk models were created or validated specifically using a dialysis population.

Warfarin and Antiplatelet Drugs

When warfarin is combined with antiplatelet agents, the risk of bleeding in dialysis patients is even higher. Since many dialysis patients are already on aspirin for coronary artery disease, the addition of warfarin poses an additive risk. Roughly one-third of dialysis patients are on aspirin.^[3,42] Holden et al. ^[17] reported that the incidence of major bleeding on warfarin alone is 3.1% per person-years vs. 4.4% per patient-years on aspirin alone vs. 6.3% per patient-years on warfarin with aspirin. The overwhelming majority of bleeding occurred in the gastrointestinal tract. Although the absolute rates of bleeding vary widely between studies, the combination of warfarin and aspirin places the dialysis patient at high risk for bleeding.

Warfarin Pharmacokinetics

Warfarin use is complicated by a narrow therapeutic index and multiple drug–drug and drug–food interactions. These issues are magnified in the dialysis patient. Patients with severe chronic kidney disease (CKD) (GFR <30 mL/min/1.73 m²) require significantly lower warfarin doses. Additionally, they spend less time within their target range and are at a higher risk of over-anticoagulation when compared with patients with no, mild, or moderate CKD.^[43] Although warfarin is primarily metabolized by CYP2C9 in the liver, CKD can significantly reduce the non-renal clearance and bioavailability of warfarin.^[18] Animal studies have shown that there is a significant 40–85% downregulation of hepatic cytochrome P-450 metabolism in CKD.^[44] Dreisbach et al. ^[45] demonstrated a 50% increase in the plasma warfarin S-enantiomer/R-enantiomer ratio among patients with ESRD relative to control subjects, which may reflect a selective decrease in hepatic CYP2C9 activity in renal failure. Since the S-enantiomer of warfarin is five times as powerful as the R-enantiomer, this would explain the lower dosage requirements for warfarin in dialysis patients. Owing to the decrease in CYP2C9 activity in dialysis patients, maintaining a therapeutic range of warfarin may be more difficult, especially when these patients may periodically be on other medications which inhibit, induce, or compete with CYP2C9 metabolism. Dialysis patients should therefore be monitored more closely while on warfarin therapy.

All decisions regarding anticoagulation depend on an assessment of risk and benefit in the individual patient. In the dialysis patient with atrial fibrillation, the risks of warfarin are many and the benefits are unproven. Not only is there a lack of evidence for the efficacy of warfarin in preventing strokes in the dialysis patient with atrial fibrillation, but data show that warfarin increases the risk of haemorrhagic stroke, major gastrointestinal bleed, vascular calcification, and possibly ischaemic stroke. There are certain situations where the decision to start warfarin should be straightforward, such as a patient with a known atrial thrombus or a patient peri-cardioversion.

Merck Halts Trial For Experimental Blood Thinner.

Merck & Co. unexpectedly halted a late-stage trial for a potential blood-thinner and said Thursday it would stop giving the drug to stroke victims in separate study." The drugmaker "is studying vorapaxar for the prevention of cardiac events and had planned to submit the anti-clotting medication this year to the Food and Drug Administration for approval. The company would have to review the study data to understand the monitoring board's recommendations. The reasons for the changes were not explained by researchers overseeing the studies. 

Warfarin Use In Patients With Traumatic Injuries May Increase Mortality Risk.

The "risk of dying after suffering a traumatic injury is much higher for people taking" Coumadin [warfarin], according to a study in the Archives of Surgery. The researchers analyzed data from "402 trauma centers reported to the National Trauma Data Bank from 2002 to 2007" and found that of more than "1.23-million patients who went to emergency rooms with serious injuries," those taking warfarin were almost "twice as likely to die (9.3% vs. 4.8%)." Even after deaths "most probably caused by underlying illnesses were taken into account," the risk was "72-percent higher for those using" warfarin, which is the "most commonly used blood thinner in America."

Study Suggests PPIs Pose No Risk For Stroke Patients Treated With Clopidogrel.

Proton-pump inhibitors (PPIs) "as a class are not associated with an increased short-term risk for recurrent stroke or death among older adults treated with clopidogrel after stroke," suggests research in the January issue of Stroke. They conducted a "population-based, nested case-control study among residents of Ontario, Canada, who were discharged from the hospital after ischemic stroke" between April 2002 and September 2008. The researchers found no "significant association between readmission for stroke and current use of a PPI"; and they found no "statistically significant correlation between PPI use and death from any cause" among patients taking clopidogrel after stroke.       

Clinical Decision Rules May Safely Rule Out Deep Vein Thrombosis 

Two different decision rules may rule out deep vein thrombosis (DVT) in the primary care setting. Despite its widespread accessibility, ultrasonography may not be needed in all patients suspected of DVT. The availability of D-dimer (dimerized plasmin fragment D) testing made it possible to combine clinical assessment with this laboratory test to rule out DVT without the need for imaging tests. A diagnostic algorithm, based on a decision rule developed by Wells and colleagues that included information from a patient's medical history and physical examination, followed by D-dimer testing, is now used to guide management in many hospitals worldwide. Although the Wells rule is effective especially in the secondary care setting, a new clinical decision rule for primary care patients — known as the primary care rule — has recently been proposed because the Wells rule is not sufficient to eliminate DVT in this setting. The goal of this study was to compare the ability of both rules to safely rule out DVT and to efficiently lower the number of referrals for leg ultrasonography that would have negative results.

Before undergoing leg ultrasonography to exclude suspected DVT, 1086 patients provided information to family physicians so that scores for both decision rules could be calculated. Using a rapid point-of-care assay, all patients had D-dimer testing. Based on scoring for each rule and the D-dimer result, patients were stratified into risk categories. The main study endpoints were ultrasonographic diagnosis of DVT and venous thromboembolic complications or death attributed to a possible thromboembolic event during 90-day follow-up. Both rules were compared in terms of the number of missed diagnoses and the proportions of patients that needed ultrasound testing.The investigators analyzed data from 1002 eligible patients. During follow-up, 7 patients had a venous thromboembolic event, despite a negative D-dimer finding and a low score with the Wells rule (7/447; 1.6%; 95% confidence interval [CI], 0.7% - 3.3%) and with the primary care rule (7/495; 1.4%; 95% CI, 0.6% - 3.0%).

Referral for further testing would not be needed in 447 patients (45%) when using the Wells rule compared with 495 patients (49%) when using the primary care rule (P < .001). Direct medical costs per patient were similar using either rule. The primary care rule is relatively compact and could prevent more unnecessary ultrasound procedures, making it slightly more convenient for both patients and physicians.

Limitations of this study include the possibility that attending physicians documented the "presence of an alternative diagnosis," one of the most important items of the Wells rule, knowing the result of the primary care rule and of the D-dimer test. In addition, the investigators compared the original Wells rule with the primary care rule without the D-dimer test by leaving out the D-dimer assay from the originally developed rule, which may possibly have underestimated the performance of the primary care rule without the D-dimer assay compared with the Wells rule.In primary care, suspected DVT can safely be ruled out using either of the 2 rules in combination with a point-of-care D-dimer test," the study authors write. Both rules can reduce unnecessary referrals for compression ultrasonography by about 50%, though the primary care rule reduces it slightly more.

Ann Fam Med. Published online January 17, 2011.

Subcutaneous Heparin Not Adequately Absorbed After Abdominal Surgery

Subcutaneously administered heparin might not provide optimal protection against venous thromboembolism (VTE) for patients who have undergone major abdominal surgery because absorption appears to be decreased in these patients, researchers said here at the Society of Critical Care Medicine 40th Critical Care Congress.Subcutaneous heparin is the current standard of care for VTE prophylaxis, Reports that a surgical oncologist was using low-dose heparin infusion in the [intensive care unit with] found no difference in bleeding between those who got subcutaneous heparin and those who got intravenous (IV) heparin.To explore the use of IV heparin further,  randomized 50 intensive care unit (ICU) patients immediately after major abdominal surgery to receive subcutaneous heparin (5000 U) 3 times daily — the standard of care — or an IV heparin infusion titrated to a target activated partial thromboplastin time range of 40 to 45 s.

The majority of patients in the study had cancer. Daily blood heparin activity levels, daily whole blood coagulation parameters, and screening of the lower extremities with ultrasound for 10 days after surgery were also performed.The patients were well matched demographically. Most were slightly overweight, with a body mass index of 27 kg/m²; their average Acute Physiology and Chronic Health Evaluation (APACHE) score was 13.

The researchers found that patients receiving subcutaneous heparin had no detectable levels of anti-Xa activity 5 days after surgery. Their peak levels of anti-Xa activity were 0. Undetectable In contrast, patients receiving IV heparin showed statistically significant increases in anti-Xa activity on day 3 (0.04 vs 0.00 U/mL; P = .01) and day 4 (0.05 vs 0.00 U/mL; P = .03).

Using a whole blood coagulation device called the Sonoclot, the researchers found that the patients who received subcutaneous heparin had a hypercoagulable profile for up to 5 days after surgery, but that patients who received IV heparin had a normal profile. These patients do not seem to be anticoagulated per se, but they are normalized. This is important in a postsurgical population at high risk of bleeding. No lower-extremity deep vein thrombosis was found on screening ultrasounds in either group, nor were there any episodes of major bleeding or heparin-induced thrombocytopenia.There were no differences in ICU length of stay or 28-day mortality. 

High Rate of Events in Patients Stopping Antiplatelets Post-DES Implant

Around one in 10 patients prematurely discontinues antiplatelet therapy within the first year of drug-eluting-stent (DES) implantation, and this is strongly associated with increased cardiovascular events, including MI and death, a new study shows.

Results showed that 8.8% of patients had discontinued one or both antiplatelet agents within the first 12 months (early discontinuation) and 4.8% had discontinued aspirin after one year (late discontinuation). Patients with early discontinuation experienced a greater incidence of major adverse cardiac events (MACE), stent thrombosis, all-cause mortality, and cardiovascular death.

Patients with late discontinuation of aspirin showed a nonsignificant increase in MACEand stent thrombosis and a significantly greater incidence of MI and nonfatal stroke.Among patients with stent thrombosis, around one in four patients had prematurely withdrawn either aspirin or clopidogrel, but the risk of events did not seem relevant if the discontinuation duration was less than 5.5 days.

Clopidogrel use for more than six months was associated with a reduction in MACE. The authors point out that the optimal duration of dual antiplatelet therapy after DES implantation is unknown. While a recent study suggested no benefit of continuing after 12 months, larger trials are needed and are ongoing.

Early discontinuation of drug therapy in this study was predicted by in-hospital major bleeding, the use of oral anticoagulants at discharge, and the lack of a statin prescription, which the authors suggest may signify patients who have a lower compliance to medical therapy. Previous stroke was the only independent predictor of late discontinuation.

FDA Extends Clopidogrel Bisulfate Patent By Six Months.

Bristol-Myers Squibb and Sanofi-Aventis announced that the FDA granted the companies an extra six months to exclusively market Plavix [clopidogrel bisulfate] in the US. The FDA granted a pediatric exclusivity for the drug.  The FDA granted the extension "after the companies conducted extra studies of the drug in infants." The extension will help the two companies "delay the financial crunch hitting nearly all drugmakers, as patents on a wave of blockbuster drugs from the 1990s begin to expire." 

Platelet Transfusions in Trauma Patients Requiring Massive Blood Transfusions 

What is the role of platelet transfusion in patients who require massive blood transfusions? The authors reviewed transfusion records and mortality data from patients who required ≥ 10 packed red blood cell transfusions (n = 657) after trauma in a Level I trauma center. They divided patients into 4 groups on the basis of the platelet-to \-blood transfusion ratio: low (< 1:18), medium, high, and highest ratio (≥ 1:6). Mortality increased as the ratio of platelet to packed red blood cell transfusions decreased. Compared with patients who received the highest platelet transfusion ratios, patients in the lowest group had a 5.5-fold increased risk for death (P ≤ .001).

Viewpoint

Throughout the years, transfusion strategy has shifted from administering whole blood to providing appropriate component therapy. This report suggests that increasing the ratio of platelet infusions to packed red blood cell units dramatically lowers mortality in patients receiving 10 or more packed red blood cell transfusions. The results are based only upon the 2% of patients requiring massive amounts of blood, and the findings need to be confirmed in a properly designed prospective study. Nevertheless, the results from this large study imply that, in the select group of trauma patients requiring massive blood transfusions, giving platelets can have a significant impact on survival.

Ultrasound Plus Fibrinolysis Reduce Right Heart Dysfunction in Pulmonary-Embolism Patients 

Low-dose ultrasound energy administered in addition to thrombolytic therapy significantly reduces pulmonary clot burden and improves right heart function in patients with intermediate- and high-risk pulmonary embolism, new research shows Most of the patients that we treat have submassive pulmonary embolism, accounting for about 40% of all pulmonary-embolism patients, and they have a 90-day mortality of about 22%. These patients present as pretty stable--they're short of breath, of course, but their blood pressure is all right. The interesting thing is that these patients have right heart enlargement, and we know that patients die from having large right ventricles, so the goal is to get that down to normal size. We got to find a way to do that that's safe and effective, and that's the whole point of this therapy.

Ultrasound-accelerated thrombolysis is designed to use ultrasound energy to loosen and thin the fibrin strands of the pulmonary clot, exposing the plasminogen-receptor sites. This increases permeability and thrombolytic penetration when drug therapy is administered, which helps the drug work faster, clear the clot sooner, and use a lower dose of fibrinolytic therapy.  

Massive pulmonary embolisms, occur in 5% of all patients and are associated with a 58% mortality rate at 90 days. These patients often present in cardiogenic shock and have a high early mortality rate due to right ventricular failure. Treatment involves intravenous thrombolytics and surgical/endovascular embolectomy to remove the thrombus.

Patients with submassive pulmonary embolism, on the other hand, are treated less aggressively, with guidelines recommending only that physicians consider intravenous therapy. Aggressively treating submassive pulmonary embolisms makes sense because systemic thrombolysis can reverse right ventricular dilatation, which in turn lowers the risk of recurrent pulmonary embolism and chronic pulmonary hypertension. An improvement in the right-ventricle/left-ventricle ratio is also associated with a lower risk of mortality.

In CT follow-up, taken at three months after treatment with ultrasound-accelerated thrombolysis, most patients have no evidence of clot, which is expected because the body's own fibrinolytic system kicks in to further break down the thrombus. In follow-up in one patient, however, seen three weeks after treatment, the clot was also completely gone, which is too soon for endogenous fibrinolysis to work.

AstraZeneca Replies to FDA Queries on Ticagrelor

AstraZeneca announced today that it has replied to the US FDA queries about its new antiplatelet agent, ticagrelor (Brilinta), and says it "remains confident" that the drug will gain US approval.Ticagrelor was recommended for approval by an FDA advisory panel last July, but last month, the FDA said it was delaying approving the drug and in a "complete response letter" requested further analyses of clinical trial data.

The company says the additional analyses of the PLATO trial requested by the FDA focused primarily on interactions between ticagrelor and high-dose aspirin. Aspirin is typically given in higher doses in the US than in Europe in ACS, and there was a trend toward poorer outcomes in North America.  AstraZeneca says it believes "these supplementary analyses support the hypothesis that the apparent difference in treatment effect observed in the US and non-US patient subsets in PLATO is most likely a reflection of an underlying interaction between ticagrelor and higher doses of aspirin." But it adds that the difference could also be a play of chance.

Berger said he was more concerned about the impact of administering a twice-a-day, reversible drug to a noncompliant population. "It may be that the superior drug in clinical trials [ticagrelor] is associated with less efficacy when administered to a nonadherent population. Clinical-trial populations are always more adherent to study drugs than randomly selected patients are to prescribed medications. That may require physicians to ensure that the patient can afford the drug and actually take it before choosing ticagrelor over clopidogrel, even though clopidogrel was outperformed in the trial."

Risk for Death After Trauma Higher in Patients Using Warfarin

The risk for death after trauma is significantly higher in patients using warfarin, according to the results of a retrospective cohort study. Warfarin is a commonly used anticoagulant for the long-term management and prevention of thromboembolic events associated with atrial fibrillation, mechanical heart valves, deep venous thrombosis, pulmonary embolism, the antiphospholipid syndrome and occasionally, myocardial infarction."

The goals of the study were to assess the prevalence of preinjury warfarin use in a large national sample of trauma patients enrolled in the National Trauma Databank and to examine the association between preinjury warfarin use and mortality. The main study endpoints were the prevalence of warfarin use and all-cause in-hospital mortality. The investigators estimated the odds ratio (ORs) for mortality associated with warfarin use before the injury using multivariate logistic regression.

Of 1,230,422 patients admitted to 402 eligible trauma centers during the study period and eligible for analysis, 36,270 were warfarin users. In 2002, just 2.3% of all patients used warfarin, and this percentage increased to 4.0% in 2006 (P < .001). Among patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (P < .001).Mortality rate was 9.3% in warfarin users and 4.8% in nonusers (OR, 2.02; 95% confidence interval [CI], 1.95 - 2.10; P < .001). Warfarin use was associated with increased mortality risk among all patients (OR, 1.72; 95% CI, 1.63 - 1.81; P < .001) and among patients at least 65 years old (OR, 1.38; 95% CI, 1.30 - 1.47; P < .001).

Compared with those not treated with warfarin, users of this drug had more severe injuries and a higher prevalence of intracranial hemorrhage. Also, they were more likely to have blunt mechanism injuries (87% vs 96%) and to be injured at home or in residential institutions. Among all individuals admitted with intracranial hemorrhage, warfarin users had a significantly increased risk for death vs nonusers (22% vs 18%), but there was no difference in the risk for death between the 2 groups among those at least 65 years old.

"Warfarin use is common among injured patients and its prevalence has increased each year since 2002," the study authors write. "Its use is a powerful marker of mortality risk, and even after adjusting for confounding comorbidities, it is associated with a significant increase in death."

Limitations of this study include possible selection bias, inability to classify users of other antiplatelet and anticoagulant agents, and inability to assess the degree of anticoagulation or compliance with outpatient warfarin treatment.

"These data support other reports that suggest that patients who undergo pre-injury anticoagulation with warfarin are at increased risk of death after trauma," the study authors conclude. "Warfarin prescribers should consider these data in the overall risk-benefit analysis when opting to prescribe warfarin, and these data provide further rationale for discontinuing warfarin when the clinical evidence no longer supports its use.... Centers should also develop and implement protocols for reversing warfarin after injury in a way that minimizes morbidity, mortality, and costs."

Arch Surg. Published online January 17, 2011. Abstract

Addition of rt-PA Superior to Heparin Alone as Catheter Locking Solution

Substituting recombinant tissue plasminogen activator (rt-PA) for heparin once a week as a locking solution in the central venous catheters of patients receiving hemodialysis significantly reduces the incidence of catheter malfunction and bacteremia compared with the standard heparin-only regimen, a new study shows. Compared with patients receiving rt-PA, the risk for catheter malfunction — the study's primary outcome — was nearly twice as high in the heparin-only group, and the incidence of catheter-related bacteremia — the secondary outcome — was almost 3 times higher.

Up to 50% of catheters fail within 1 year, and two thirds of those failures are caused by thrombosis. In an effort to reduce the thrombosis rate, technicians instill an antithrombotic, or locking, solution into the catheter at the end of each dialysis session and leave it there until the next session. The locking solution is also thought to reduce the risk for infection. Heparin traditionally has been the locking solution of choice, but the evidence supporting its use over other agents is slim. rt-PA had been shown in 1 small study to be superior to heparin, but given rt-PA's high cost and hemorrhagic potential, these authors felt a larger trial was in order.

In this controlled, blinded, multicenter trial, 225 patients were randomly assigned to receive either the standard regimen of 5000 U/mL heparin instilled to full luminal volume after each dialysis session, or 1 mg rt-PA in each lumen instead of heparin after the midweek session and the usual heparin solutions at other times. Of the 225 participants, 110 were assigned to the rt-PA group, and 115 to the heparin-only group.

The planned follow-up time was 6 months, but 56 patients in the heparin group (48.7%) and 58 in the rt-PA group (52.7%) discontinued the study medication early. Median follow-up times, therefore, were 89 days for the heparin group and 115.5 days for the rt-PA group, with no patients lost to follow-up.

Catheter malfunction occurred in 40 patients (34.8%) in the heparin-only group and 22 (20%) in the rt-PA group (hazard ratio with heparin vs rt-PA, 1.91; 95% confidence interval [CI], 1.13 - 3.22; P = .02). Fifteen patients receiving heparin only (13%) developed catheter-related bacteremia compared with 5 (4.5%) who received rt-PA (hazard ratio with heparin, 3.30; 95% CI, 1.18 - 9.22; P = .02). "The findings were consistent between patients for whom this was the first use of a catheter and those who had had previous catheters," the authors write.

Serious adverse events were reported in 34 patients (29.6%) in the heparin group and in 23 of those who received rt-PA (20.9%; P = .14).

Possible study limitations included a primary outcome that was actually a surrogate outcome because it was defined according to blood flow, but "ongoing evidence of catheter malfunction after the primary outcome provides support for the validity of this definition," the investigators say. Other limitations included early discontinuation of enrollment, the inability to perform analyses on certain potentially important subgroups, and the high number of patients who discontinued the study medication, usually because they were hospitalized or switched to arteriovenous access..

N Engl J Med. 2011;364:303-312, 372-374. 

No PPI Attenuation of Clopidogrel Antiplatelet Effects: MI Registry Analysis 

No significant sign of excess cardiovascular events, including death, MI, or stroke in-hospital or at one year, were seen in patients who received proton-pump inhibitors (PPIs), especially omeprazole, along with clopidogrel in a French MI registry.That was seen regardless of whether patients carried a gene variant known to interfere with clopidogrel's antiplatelet action, according to investigators in a report published online January 24, 2010 in Circulation."The study reported here represents new information, not only because it uses real-life data from clinical practice but also because individual PPI treatments and the presence of CYP2C19 polymorphisms were taken into consideration, and propensity-matching was performed to compensate for confounding factors and baseline differences..

The findings from 3670 participants support a large body of observational, largely retrospective data--but also at least one prospective clinical trial--suggesting that PPIs can be safely given with clopidogrel in patients at increased gastric bleeding risk.  

But they are also at odds with other clinical evidence and ex vivo testing of platelet reactivity suggesting that PPIs may attenuate clopidogrel's protection against ischemic events. As such, they continue a long-burning controversy over whether the drugs should routinely be given to patients on clopidogrel.

Among the two-thirds of clopidogrel-naive FAST-MI patients who received clopidogrel and contributed DNA, the odds ratio (OR) for major in-hospital events for PPI vs no PPI therapy were 0.29 (95% CI 0.06–1.44) for patients with one variant CYP2C19 allele and 1.70 (95% CI 0.10–30.3) for patients with two variant alleles in propensity-adjusted analyses. The OR was 0.70 (95% CI 0.35–1.40) in such patients with wild-type CYP2C19 alleles.In the propensity-matched cohort analysis of patients discharged on clopidogrel, PPI therapy was seen to pose no significant increased clinical risk. The hazard ratio (HR) for one-year stroke, MI, or death was 1.24 (95% CI 0.87–1.78, p=0.24) and for one-year mortality was 1.15 (95% CI 0.73–1.83, p=0.54).

Given that "well-conducted pharmacodynamic studies" suggest that some PPIs can attenuate clopidogrel's antiplatelet effects, O'Donoghue noted, "why does this not appear to translate into a higher risk of CV events?   It is plausible that the pharmacodynamic interaction between clopidogrel and PPIs is too weak to translate into CV harm." Or, "it is plausible that platelet reactivity needs to be pushed above a certain threshold before patients are placed at increased risk," she said.

"Until the relationship between platelet reactivity and CV events is better understood, caution should be used when clinical decisions are being based on a surrogate end points rather than clinical outcomes."

Screening Tool for Bleeding Disorders in Women With Menorrhagia Performs Well 

A short eight-question screening tool, coupled with either a serum ferritin level and/or the pictorial blood assessment chart (PBAC) score, can help gynecologists and primary care providers identify women with menorrhagia who should be evaluated for a possible bleeding disorder, a new study finds.Undiagnosed bleeding disorders, such as von Willebrand disease and platelet function defects, are common in women with menorrhagia and may impact women's lives adversely because of bleeding complications after childbirth and surgery, blood transfusions, and chronic iron deficiency anemia," the study team notes in the January 19th online issue of the American Journal of Obstetrics and Gynecology.

Some gynecologists and primary care physicians may not recognize menorrhagia as a symptom of a bleeding disorder. There is also no simple laboratory test to screen for hemostatic abnormalities in these women.

Its eight questions fall into four categories: (1) severity of menorrhagia, defined by a duration of menses of 7 days or more and either flooding or bleeding through a tampon or napkin in 2 hours or less; (2) family history of a diagnosed bleeding disorder; (3) personal history of excessive bleeding after specific challenges such as delivery, miscarriage, surgery, tooth extraction; and (4) history of treatment for anemia.

In initial testing in 146 women with unexplained menorrhagia, the screening tool performed well, which led it to be tested it in a larger prospective study at six centers across the US.There were 217 women ages 18 to 50 in the study, including 169 white and 35 black women. All of the women had menorrhagia identified by a pictorial blood assessment chart (PBAC) score of 100 or more. The mean hemoglobin level was 12.1 g/dL; more than half of the women were anemic (56%) with a hemoglobin level of less than 12 g/dL. The mean serum ferritin level, obtained in 155 women, was 20.6 ng/mL.

On laboratory testing, 154 of 217 women (71%) had one or more hemostatic abnormalities; 120 (55%) had a platelet function defect, 11 (5%) had low von Willebrand factor, and 11 (5%) had coagulation factor deficiencies.For hemostatic abnormalities, the screening tool had a sensitivity of 89% and a positive predictive value of 72%.. When the screening tool was combined with a PBAC score greater than 185, sensitivity for hemostatic abnormalities increased to 95% and the positive predictive value remained unchanged.

There was a similar increase in sensitivity (93%) and no change in positive predictive value when the screening tool was combined with a low serum ferritin level (20 ng/mL or less).The utility of the serum ferritin level as an adjunct to screening for hemostatic abnormalities has not been demonstrated previously and may provide a similarly effective, but clinically more feasible, supplement to the screening tool than the PBAC score.Serum ferritin may be less cost-efficient than the PBAC, but it may facilitate a quicker decision about whether to refer as it precludes waiting for a menstrual cycle for a prospectively completed PBAC score.

This study, the researchers conclude, confirms the usefulness of this screening tool for stratifying women with unexplained menorrhagia for hemostatic evaluation.

Am J Obstet Gynecol. Published online January 19, 2011.

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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