Heparin

Heparin Fails to Stop Miscarriages in Women With Inherited Thrombophilia

Posted by

0


No difference in live birth rates with or without blood thinner

Daily injections of low-molecular-weight heparin (LMWH) failed to improve live birth rates for women with a history of recurrent miscarriages and inherited forms of thrombophilia, a randomized trial found.

In the 326-patient study, live birth rates were a similar 71.6% in women who received LMWH versus 70.9% with standard pregnancy care alone (adjusted OR 1.08, 95% CI 0.65-1.78, P=0.77), reported Saskia Middeldorp, MD, PhD, of the University of Amsterdam.

“The conclusions and take-home messages are pretty clear and … end a debate of decades,” Middeldorp said during a press briefing at the American Society of Hematologyopens in a new tab or window annual meeting.

But “we should not say this a negative study,” she added. “What we can do in our offices, in our practices, is reassure women with a history of recurrent pregnancy loss that they have a 70% chance of having a healthy baby.”

Side effects, while mostly minor, were significantly more frequent in the LMWH arm, with 43.9% experiencing one or more adverse events versus 26.5% in the control arm (OR 2.17, 95% CI 1.32-3.55). Common side effects included easy bruising, skin reactions at the injection site, and minor bleeding.

Middeldorp said the findings suggest that women with recurrent miscarriages should no longer be tested for inherited thrombophilia, pointing out that elimination of this testing could save an estimated $4,000, along with the additional $3,500 in savings for LMWH injections over the duration of a pregnancy.

In the U.S., “many women do get thrombophilia testing when they’ve had recurrent miscarriages, and there can be a lot of pressure of doing something versus doing nothing,” said press briefing moderator Cynthia Dunbar, MD, of the National Heart, Lung, and Blood Institute at the NIH.

“I had recurrent miscarriages myself and at the time read the literature and decided I wasn’t going to push for that and it didn’t make sense, but it was a hard decision,” she told MedPage Today. “Luckily, I also had two successful pregnancies after three miscarriages — so I have some personal experience with this.”

Dunbar said she hoped the findings would “settle the issue,” and that patients will stop getting very expensive panels that then label them as having a disease even if they have never had a clot.

“It’s not necessarily information that is helpful in any way, expect making you very anxious,” she said. “I was very happy about this trial — not happy about the results, I guess, but happy that at least it’s clear and it was a very well-performed trial.”

Past studies have shown an association between recurrent miscarriages and inherited thrombophilia, while other research has suggested that clots in the developing placenta could be a causal factor in miscarriages.

In a prior trialopens in a new tab or window from Middeldorp and colleagues in which anti-thrombotic therapy failed to increase live birth rates for women with unexplained recurrent miscarriages, there was a hint of potential benefit for the very small subgroup of women with inherited thrombophilia, leading to the current trial.

“For inherited thrombophilia, the curtains are closing in terms of aspirin and anticoagulants,” said Middeldorp, adding that the only group that benefits from aspirin and LMWH are women with acquired thrombophilia antiphospholipid syndrome.

ALIFE2 was an investigator-initiated trial that from 2012 to 2021 randomized 326 pregnant women with two or more miscarriages and inherited thrombophilia to standard care with or without LMWH (enoxaparin 40 mg, dalteparin 5,000 IU, tinzaparin 4,500 IU, or nadroparin 3,800 IU). Aspirin was also used in 11% of patients.

Participants had to be enrolled at gestational age of 7 weeks or earlier. Overall, more than 10,000 women were screened for inclusion over the 9-year study period at 41 centers in five countries (the Netherlands, U.S., U.K., Slovenia, and Belgium), with most women excluded for not having confirmed inherited thrombophilia.

The primary endpoint was live birth rate, with secondary endpoints including miscarriage and adverse obstetric outcomes. Safety outcomes included bleeding episodes, thrombocytopenia, skin reactions, and neonatal congenital malformations.

Average patient age was 33-34 years, most were white, and 70% of the women in each arm had experienced three or more prior miscarriages. The most common thrombophilia types were heterozygosity for factor V Leiden (55-58%), prothrombin 20210A mutation (24-27%), and protein S deficiency (13-14%), while 3.6% had combined thrombophilia.

The OR for the primary endpoint adjusted for differences in baseline characteristics, including maternal age, number of miscarriages, type of center, and country.

Souce: medscape

Bridge Therapy Ups Bleeding Rates After Invasive Procedures

Posted by

0


Bridge therapy with heparin during warfarin interruption for invasive procedures is associated with increased bleeding rates in the 30 days that follow, according to a retrospective study.

Heparin is often used during warfarin interruption for patients at high risk of recurrent venous thromboembolism (VTE), but risk estimates of bleeding and VTE associated with this bridge therapy are lacking in real-world patients with VTE.

Thomas Delate, MS, PhD, from Kaiser Permanente Colorado (KPCO) in Aurora and colleagues reviewed data from KPCO’s electronic patient tracking tool and electronic medical records to compare real-world rates of clinically relevant bleeding and recurrent VTE among patients receiving warfarin for a prior VTE in whom treatment was interrupted for invasive procedures.

Out of 1812 procedures, bridge therapy was used in 555.

Bridge therapy was used for 28.7% of low-risk patients, 33.6% of moderate-risk patients, and 63.2% of high-risk patients, according to the May 26th JAMA Internal Medicine online report.

The 30-day rate of clinically relevant bleeding was much higher in the bridge therapy group than in the non-bridge therapy group (15 events, 2.7%, vs 2 events, 0.2%; hazard ratio, 17.2).

Clinically relevant bleeding rates did not differ significantly between those receiving a therapeutic or a prophylactic dose of a bridge anticoagulant. More than half the bleeding events were procedure complications, and one-third were related directly to bridging agent injections.

Major bleeding was also significantly more common with versus without bridge therapy (2.2% vs 0.2%; P<0.001).

Recurrent VTE rates did not differ between the bridge and non-bridge therapy groups, and there were no deaths in either group.

“Thus, the risk of bleeding associated with bridge therapy appeared to outweigh the potential benefits in our study population,” the researchers conclude. “Our results highlight the need for further research to identify patient- or procedure-related characteristics that predict a high risk of VTE recurrence during interruption of warfarin therapy.”

Daniel J. Brotman, MD, from Johns Hopkins University in Baltimore, Maryland, who coauthored a commentary on the report, told Reuters Health by email, “I would put patients in a high-risk group only if they (1) have had recurrent thromboses, particularly in the setting of brief anticoagulation cessation, (2) thrombosis in the prior 4-6 weeks, and (3) some instances of catastrophic thrombosis from hypercoagulable conditions (e.g., massive pulmonary embolism or fulminant liver failure from Budd-Chiari syndrome in the context of antiphospholipid antibodies or JAK-2 mutations). Other patients should be generally categorized as low-to-intermediate risk. In these patients, bridging anticoagulation should be restricted to prophylactic dose anticoagulants, rather than full (therapeutic) doses.”

“Of course there may be exceptions to this approach, but the vast majority of patients with prior VTE should not receive bridging anticoagulation with full-dose heparin products, particularly post-procedurally,” Brotman said.

“Before a thrombus stabilizes (in the first few weeks of treatment), there is a very high rate of embolization when anticoagulation is stopped, but beyond that time period, the risk is appreciably lower,” Brotman continued. “Patients who develop recurrent thromboses promptly upon anticoagulation cessation constitute a very challenging, but fortunately small, population. These patients are better identified based on their prior history than based on laboratory tests, although many of them will have laboratory detected thrombophilias (particularly antiphospholipid antibodies).”

Ramez Nairooz, MD, from the University of Arkansas for Medical Sciences in Little Rock recently reported on major bleeding rates with and without bridge therapy in patients with atrial fibrillation. He told Reuters Health by email, “These results are important to the medical community; however they are not surprising. Patients at low risk of recurrent VTE mostly should not be bridged for most procedures and this study confirms that.”

“This study contains a small number of high risk patients and no conclusive evidence can be withdrawn from that but expert opinion and conventional wisdom goes with bridging high risk patients,” Nairooz said.

Nairooz cautioned, “The study lacks information on the anticoagulant used for bridging — unfractionated heparin, fondaparinux or enoxaparin. These anticoagulants are known to have different effects on bleeding outcomes.” He also pointed out, “This study lacks analysis based on procedural risk which should be taken in account when deciding on peri-procedural anticoagulant management.”

Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation.

Posted by

0


BACKGROUND

Many patients requiring pacemaker or implantable cardioverter–defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach.

METHODS

We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation).

RESULTS

The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group.

CONCLUSIONS

As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma.

Source: NEJM

 

Burning Bridges: Must Warfarin Be Stopped for Device Implantation?

Posted by

0


In a randomized trial, heparin bridging for implantation of a pacemaker or implantable cardioverter-defibrillator was associated with an increase in device-pocket hematoma.

Warfarin increases the risk for bleeding. Surgery is associated with bleeding. The intuitive inference that patients should discontinue chronic warfarin therapy before undergoing surgery, combined with concern about the ensuing thromboembolic risk, has led to the standard use of intravenous heparin or subcutaneous low-molecular-weight heparin as an anticoagulation “bridge” during warfarin washout. However, some practitioners question the benefits of this practice.

In a multicenter trial, 681 warfarin recipients undergoing permanent pacemaker or implantable cardioverter-defibrillator implantation were randomized to continue warfarin or to discontinue warfarin with a heparin bridge for 5 days before surgery. All patients had an estimated annual risk for thromboembolism of 

≥5% (mean CHADS2 score, 3.4). The trial was stopped early because of a strongly significant increase in the rate of device-pocket hematoma in the heparin-bridging group compared with the warfarin-continuation group (16.0% vs. 3.5%). Two patients in the warfarin-continuation group experienced stroke or transient ischemic attack (compared with none in the heparin-bridging group); however, both had subtherapeutic international normalized ratios at the time of surgery.

Comment: These data confirm what many surgeons and electrophysiologists observe on a daily basis — heparin bridging during warfarin interruption increases bleeding risk even more than continuing warfarin does. The findings are important for patients with atrial fibrillation and a high annual risk for thromboembolism. Whether warfarin can be withheldwithout bridging in individuals at low risk for thromboembolism remains unstudied. For such patients, an effective strategy might be to stop warfarin 1 or 2 days — rather than the traditional 5 days — before surgery.

 

Source:Journal Watch Cardiology

 

 

 

Continued Warfarin Better Approach to Cardiac Device Surgery.

Posted by

0


Higher-risk patients undergoing cardiac device surgery are better off continuing warfarin than switching to heparin as guidelines recommend, according to a New England Journal of Medicine study.

The study included nearly 700 patients at moderate-to-high risk for thromboembolic events who were taking warfarin and required nonemergency pacemaker or implantable cardioverter-defibrillator surgery. Patients were randomized to either continue warfarin (target INR: 3.0 or less; 3.5 or less for patients with mechanical valves) or receive bridging therapy with heparin as recommended by the American College of Chest Physicians.

The study was stopped early after an interim analysis found that the primary outcome — device-pocket hematoma — had occurred four times as often with heparin as with warfarin (16% vs. 3.5%). Continued warfarin didn’t increase major perioperative bleeding.

One explanation for the “counterintuitive” finding, the authors write, “is the concept of an ‘anticoagulant stress test.’ That is, if patients undergo surgery while receiving full-dose anticoagulation therapy, any excessive bleeding will be detectable and appropriately managed while the wound is still open. In contrast, if bridging therapy with heparin is used, such bleeding may be apparent only when full-dose anticoagulation therapy is resumed postoperatively.”

Source: NEJM