What's New in Coagulation - June 2017

Want to be in the know? Check out our monthly compilation of the latest studies, guidelines, and discussions in coagulation.

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Celecoxib Superior to Naproxen for Reducing Risk of Recurrent GI Bleeding

There are at least seven national and international guidelines on the use of NSAIDs with very conflicting recommendations for patients for high GI bleeding risks requiring aspirin and NSAIDS due to cardiovascular risks. The CONCERN study tested whether the COX-2 selective NSAID celecoxib plus a PPI is superior to the non-selective NSAID naproxen plus a PPI for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous GI bleeding.

This study looked at 514 patients on NSAIDS with upper GI bleeding who required concomitant aspirin. After ulcer healing, patients were randomly allocated (1:1) to esomeprazole 20 mg once daily plus either celecoxib 100 mg twice daily or naproxen 500 mg twice daily. All patients resumed aspirin 80 mg once daily.

The primary outcome was recurrent GI bleeding within 18 months, and this occurred inf fewer patients on celecoxib versus naproxen. With a 5.6% recurrence rate of bleeding in the celecoxib versus 12.3% in the naproxen arm. Adverse events were similar for both groups (8% versus 7%), with no treatment related deaths.

Findings demonstrate that among high risk patients naproxen plus aspirin should be avoided despite co-therapy with a PPI. Instead, a combination of celecoxib, aspirin and PPI is the preferred treatment if pain cannot be relieved by simple analgesics.

Resuming Anticoagulants After ICH: A Cautious Nod?

A study published in Stroke looked at meta-analysis of observational studies of more than 5000 patients in whom anticoagulation was resumed in patients who had an intracranial hemorrhage and outcomes of their risk for a thromboembolic event. While is it well known that anticoagulant therapy is effective in reducing stroke and embolism in patients with AF and mechanical heart valves, it can place them at a risk for bleeding in particular ICH. It is difficult to make the decision to resume anticoagulation after an ICH. Resuming too soon can increase a recurrence, while a delay can increase thrombotic risk. There is an absence of evidence based guidelines and consensus on timing of reinstitution.

A meta-analysis of studies, included 5306 ICH patients. Results showed that re-initiation of anticoagulation was associated with a significantly lower risk for thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval [CI], 0.25 - 0.45) and no evidence of increased risk for ICH after reinstatement. Limitations of this analysis include non blinded, retrospective observation design of the included studies. This included lack of data on baseline hematoma, location and if the ICH was primary or recurrent as well as if there were additional complications that put some patients at a higher risk. Additionally, almost all studies used warfarin as the anticoagulant of choice. The DOACs have shown to have a lower ICH risk than warfarin and in patients who do present with an ICH on these drugs, have smaller hematomas and better functional outcomes.

In Stroke, a Major Reduction in Door-to-Needle Time

Two studies were reported at the American Academy of Neurology Annual Meeting in Boston.

Starting Stroke Management in the Ambulance

A study from Austria reported on their ability to give intravenous (IV) tissue plasminogen activator (tPA) with a door-to-needle time of only 10 minutes in a significant percentage of patients [with stroke]. When they looked at 361 patients who received tPA. Average time of administration was 25 minutes with some up to 50 minutes. They were able to reduce times to 10 minutes by obtaining storke history onset and other conditions during ambulance transport. By determining the patients weight they were able to pre mix the tPA prior to the person arriving in the ED. All of this meant upon arrival to the ED the patient only needed a cursory exam and a CT scan. Quicker intervention leads to better outcomes.

Stroke Codes: 24/7 Neurology Response

The second study out of North Carolina collected data on 535 stoke patients with a stroke scale score of 11.6. They changed their staffing paradigm so that neurologists and/or neuro-hospitalists were in the hospital 24 hours a day, 7 days a week. Response time was a neuro-hospitalist could be at the bedside within 2.5 minutes of a stroke code being called. The average door-to-needle time fell from 48 minutes, which is average, to 37 minutes, which is very good. Also up to 90% of ED cases were informed that patients were arriving. Outcomes showed that mortality fell by 3%. The only data that was not collected was functional outcomes. However both door to needle times and mortality resulted in good outcomes using this model.

All NSAIDs Linked to Increased MI Risk

An meta-analysis of NSAID use has showed an increased risk of MI as early as the first week of use, with a greater risk when using higher doses. However the timing of the risk, the effect of dose and treatment duration along with the comparative risks between different drugs are poorly understood.

The pooled data in this case included 61,460 cases of MI and 385,303 controls for a total of 446,763 individuals. The studies included celecoxib, diclofenac, ibuprofen, naproxen and rofecoxib. The increased risk was found to be 20-50% with all traditional NSAIDs, with a rapid onset in the first week. Longer duration or use doesn't seem to increase the risk, but it doesn't go away.

The elevated MI risk linked to NSAIDs is thought to be related to the selective inhibition of the COX-2 enzyme, which may increase blood pressure.

Preventing Dangerous Blood Clot Formation Without Blood Loss From Wounds

From Thomas Jefferson University, scientists provide an alternative to traditional blood-thinning drugs - like aspirin - that only interfere with clot formation at the cost of necessary blood loss prevention. This is based on a protein called C1B1 which could have all of the thrombus-preventing abilities but presents no danger to blood loss. Mice lacking the gene coding for this protein were less likely to form a thrombus but could easily still form a platelet plug, indicating that CIB1 could prevent dangerous blood clots without interfering with healthy clotting.

Based on this theory, they probed molecules interacting with CIB1 after activation of human platelets and found that CIB1 indeed does not bind and interact with platelet molecular machinery until after platelets begin to link together to form a platelet plug. They also identified specific molecules involved with CIB1 activity during outside-in signaling and thrombus formation. This can indicate that C1B1 could be an anti-thrombotic drug target. If it can halt thrombus formation without interfering with platelet plug formation it could play a role in the reduction of risk of heart attack and stroke, while minimizing the risk of bleeding.

No Symptoms, but Raised Platelets - Red Flag for Cancer?

Patients with thrombocytosis are at an increased risk for being diagnosed with cancer within a year, in particular if they have a second raised platelet count within 6 months. The study showed 11% of men and 6% of women were diagnosed with cancer within the following year. One third of patients were asymptomatic but diagnosed with lung or colorectal cancer. Up to now thrombocytosis has not been considered a risk factor for cancer. People could have their cancer diagnosed up to three months earlier.

The study looked at a prospective cohort study of electronic primary data of 40000 patients >/= 40 years of age between the years of 2000-2013 with platelet counts > 400 x 109/L. The final comparison cohort comprised 7969 individuals, with a median age of 68.3 years; 67.4% were female. When compared to individuals with normal platelet count the incidence of cancer was 4.1% in men and 2.2% in women.

The theory behind this is that a tumor releases chemicals that increase platelet counts. Another theory is that the rise in platelet counts occurs independently of the cancer, but promotes the spread and development of cancer.

New Strategy Cuts Hospital-Acquired VTEs

A new quality improvement protocol along with a risk assessment tool and prevention strategy reduced hospital acquired VTE rates by 22% in both medical and surgical patients, with a greater reduction seen in medical patients. The assessment tool places patients in a low, medium or high risk category. This is in accordance with guidelines which included protocols of pharmacologic and mechanical venous thromboembolism. This is a three bucket assessment that can be used quickly as opposed to longer scoring systems. Measurevention or real time monitoring of the intervention was a key part.

There is a lack of consensus about VTE prophylaxis and many clinicians feel the risk is low in medical patient and doesn’t warrant the evaluation. The study decreased the rate from 5/1000 to 4/1000.

Post-TAVR Bleeding Unaffected by Valve Type in BRAVO 3

The BRAVO 3 Trial looked at the comparison of bivalirudin with unfractionated heparin in transcatheter aortic valve replacement. This was compared in balloon expandable versus non balloon expandable valve type. There was no significant difference in the risk of 30 day major bleeding events. The study was underpowered to show if one valve was more thrombogenic, but not underpowered to look for bleeding avoidance using bivalirudin.

The study aimed to compare 30-day outcomes by type of valve—balloon expandable and non–balloon expandable—and anticoagulation—bivalirudin or heparin—in patients in BRAVO 3. The balloon-expandable valves that were used were Sapien valves (Edward's Lifesciences), mainly the third-generation Sapien XT valve or the newer Sapien 3 valve. The non–balloon-expandable valves were mainly the self-expanding Medtronic valves (83%), including the third-generation CoreValve and new Evolut R (Medtronic), and less often Portico, Lotus, Symetis Acurate Neo, and Direct Flow valves. The study's co–primary outcomes were major bleeding (defined as Bleeding Academic Research Consortium [BARC] ≥3b) at 30 days, and a composite of major adverse cardiovascular events (MACE; all-cause mortality, MI, or stroke) or major bleeding at 30 days.

There were significant differences between patients who received the two valve types. Compared with other patients, those who received non–balloon-expandable valves were older and weighed less versus patients who received non–balloon-expandable valves. These patients were less likely to have local anesthesia or require valvuloplasty. Almost all (90%) had a sheath size of at least 18 French and most had valves that were 29 mm or greater.

In contrast, close to 50% of patients who had a balloon-expandable valve had a sheath size of less than 18 French, and 70% had a 23-mm or 26-mm valve and were more likely to be receiving a P2Y12 inhibitor versus an anticoagulant.At 30 days, patients who had received a non–balloon-expandable valve had nonsignificant increased adjusted odds of all-cause mortality and major vascular complications.

AEIOU Advances Uninterrupted NOAC Strategy in AF Ablation

Apixaban has demonstrated associated with rates of major and minor bleeding (<2%) similar to uninterrupted warfarin in patients who underwent ablation for atrial fibrillation. In addition, no strokes and systemic embolism occurred among the strategies. Additionally the RE-CIRCUIT study showed dabigatran was superior to warfarin on major bleeding (1.6% vs 6.9%) in AF ablation patients.

The primary safety end point of clinically significant bleeding (BARC score >2) occurred in 11.3% of uninterrupted-apixaban patients, 9.7% of those with the morning apixaban dose withheld, and 9.8% of warfarin-treated patients. Rates of major bleeding (BARC >3) were also not statistically significantly different between groups at 1.3%, 2.1%, and 1.4%, respectively. One patient in each of the apixaban groups and two in the warfarin group experienced a transient ischemic attack. No deaths occurred.

In the AEIOU study 300 patients were prospectively enrolled and given uninterrupted apixaban versus morning apixaban withheld the day of catheter ablation. These were matched by sex, age and AF pattern to 295 retrospective warfarin patients with a target INR of 2-3. There were procedural differences between groups. Prior AF ablation, use of transesophageal echo within 48 hours of ablation, and a double-transseptal puncture were significantly more common in the warfarin group, while use of force-sensing radiofrequency, pulmonary vein isolation, and robotic catheter navigation were significantly more common in the apixaban groups.

Rivaroxaban Better Than Warfarin for Preventing Recurrent VTE

Rivaroxaban has been found to be better than warfarin in reducing the risk for recurrent VTE. A Danish registry has demonstrated the safety and effectiveness in 5004 first episode patients. There was a 25% lower rate of recurrence 3 months post event and 26% lower post 6 months. Bleeding rates and mortality rates were similar.

The results of this study confirm the observations from large clinical trials that treatment with rivaroxaban is an effective and safe alternative to warfarin in oral anticoagulation-naive patients with incident unprovoked deep vein thrombosis and pulmonary embolism.

Removing Blood Clots More Than Six Hours After Stroke is Still Effective

Current guidelines recommend that brain clots should be removed within six hours of a stroke as well as the administrate of a tissue plasminogen activator given within three to four hours of a stroke. A new study suggests that the procedure may be effective up to 24 hours post stroke. These findings could increase the treatment of a mechanical thrombectomy which uses a stent retriever to physically remove the clot from the brain.

In a study at the University of Pittsburgh a randomized control trial looked at the current guideline window of six hours and patient who arrived outside that window. Patients were randomized to receive thrombectomy or standard of care- that is drug dissolving clots.

In patients 90 days post treatment, those who received thrombectomy recovered well about 50% versus 13% of those who just received drugs. The initial study was to enroll 500 participants, however the data clearly showed that patients benefited getting the thrombectomy outside of the six hour window so the study was stopped to allow all patients to have that opportunity. Stroke treatment should be given as soon as possible, however this study showed that even being treated outside the window greatly improved recovery and reduced disability.