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Long-term clopidogrel confers less MACCE, bleeding events vs. aspirin after PCI

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Wang HY, et al. Featured Clinical Research: Part 2. Presented at: Society for Cardiovascular Angiography and Interventions Scientific Sessions; May 19-22, 2022; Atlanta.

Wang reports receiving grant and/or research support from the Chinese Academy of Medical Sciences and Peking Union Medical College.

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ATLANTA — Clopidogrel monotherapy after 12 months of event free post-PCI dual antiplatelet therapy was associated with fewer MACCE and bleeding events vs. aspirin monotherapy in high bleeding risk patients, a speaker reported.

Data presented at the Society for Cardiovascular Angiography and Interventions Scientific Sessions, showed that, at 30 months post-PCI, patients taking the P2Y12 inhibitor clopidogrel, as monotherapy experienced nearly half the risk for all-cause death, MI, definite/probable stent thrombosis, stroke or Bleeding Academic Research Consortium type 2, 3 or 5 bleeding compared with those taking aspirin monotherapy.

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“Trials of early aspirin cessation were not designed to evaluate the effects of these strategies on the endpoints the medications are intended to influence, such as myocardial infarction, stent thrombosis and stroke, and that scarce information is available beyond 1 year,” Hao-Yu Wang, MD, of Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, said during a presentation. “

Prior studies, such as HOST-EXAM, evaluated the use of clopidogrel or aspirin monotherapy after 6 to 18 months of dual antiplatelet therapy following PCI.

As Healio previously reported, the HOST-EXAM primary endpoint of all-cause death, nonfatal MI, ischemic stroke, readmission for ACS or Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater at 24 months was less frequent among patients taking clopidogrel compared with aspirin.

However, Wang said, “Optimal antiplatelet monotherapy during the chronic maintenance period beyond 12 months after PCI with drug-eluting stents in high-risk patients in real-world settings remains unclear.”

Utilizing the Fuwai PCI Registry, researchers identified 5,664 high-risk patients (mean age, 58 years; 76% men; 65% who had PCI for ACS; 17% at high bleeding risk) who were event-free during the initial 12 months of DAPT following PCI and were subsequently switched to either aspirin monotherapy (n = 3,690) or clopidogrel (n = 1,974).

The primary endpoint was a composite of all-cause death, MI, definite/probable stent thrombosis, stroke, or BARC bleeding type 2, 3 or 5, from 12 to 30 months. Secondary endpoints included MACCE, defined as all-cause death, MI, definite/probable stent thrombosis or stroke; and BARC bleeding type 2, 3 or 5.

At 30 months post-PCI, Wang and colleagues observed that 5% of patients taking aspirin monotherapy during the maintenance period experienced the primary composite endpoint compared with 2.5% of the clopidogrel cohort (HR = 0.557; 95% CI, 0.397-0.781; log-rank P = .001).

Over the same period, 3.1% of patients taking aspirin monotherapy experienced the secondary composite endpoint of MACCE compared with 1% of those taking clopidogrel (HR = 0.442; 95% CI, 0.275-0.71; log-rank P = .001).

BARC bleeding type 2, 3 or 5 occurred in 2.1% of the aspirin group at 30 months compared with 1.5% of the clopidogrel arm (HR = 0.732; 95% CI, 0.454-1.181; log-rank P = .199).

Multivariable adjustment did not change the results, and the results did not vary according to prespecified subgroups.

“In this real-world study, clopidogrel monotherapy has effects on all-cause and cardiovascular mortality, as well as stroke, compared with aspirin monotherapy,” Wang said during the presentation. “Therefore, this strategy might be an effective alternative to aspirin for secondary prevention of cardiovascular disease.”

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Clopidogrel monotherapy linked with reduced risk of net adverse clinical events, study finds

Clopidogrel monotherapy linked with reduced risk of net adverse clinical events, study finds

Results from a real-world study investigating safety and effectiveness of clopidogrel versus aspirin monotherapy beyond 12 months after PCI in high-risk patients during the chronic maintenance period. This study found that clopidogrel monotherapy was associated with reduced risk of net adverse clinical events (NACE; all-cause death, MI, stent thrombosis, stroke, or BARC type 2, 3, or 5 bleeding) and MACCE (death, MI, stent thrombosis, stroke), and a numerical decrease in major or clinically relevant nonmajor bleeding (BARC type 2, 3, or 5 bleeding), compared with aspirin monotherapy. The findings were presented today as late-breaking clinical research at the Society for Cardiovascular Angiography & Interventions (SCAI) 2022 Scientific Sessions.

P2Y12 inhibitor monotherapy reduces bleeding risk without increasing the risk of ischemic events compared with dual antiplatelet therapy (DAPT), especially in the first 12 months following percutaneous coronary intervention (PCI). Recent research showed that among patients who were event free for six to 18 months post-PCI and successfully received the intended duration of DAPT, clopidogrel monotherapy was superior compared with aspirin monotherapy in terms of NACE. However, optimal antiplatelet monotherapy during the chronic maintenance period beyond 12 months after PCI with drug-eluting stents in high-risk patients in real-world settings is previously unknown.

In total, 8,377 consecutive patients at high risk for both bleeding and thrombosis were identified from the prospective Fuwai PCI Registry if they satisfied one clinical and one angiographic criterion. Patients who received antiplatelet (aspirin or clopidogrel) monotherapy longer than 12 months and were free from ischemic and bleeding events at 12-month post-PCI without extended duration of DAPT were included. The primary endpoint was net adverse clinical events (NACE) from 12 to 30 months. The key secondary endpoints were major adverse cardiac or cerebral events (MACCE) and major or clinically relevant nonmajor bleeding (BARC type 2, 3 or 5).

“These findings show for the first time clopidogrel monotherapy is associated with reduced risk of long-term NACE and MACCE,” said Hao-Yu Wang, Cardiometabolic Medicine Center, Coronary Heart Disease Center, Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. “Our results may have important practical implications for determining the optimal treatment for patients requiring a single antiplatelet drug, either aspirin or clopidogrel, for secondary prevention of ischemic events in high-risk PCI population.”

Of 7,392 high-risk patients that were event-free after the first year and adherent to DAPT, 5,664 patients who received antiplatelet monotherapy (clopidogrel monotherapy: n=1,974 and aspirin monotherapy: n=3690) were included in the present analysis. Researchers found that between 12 and 30 months, the net adverse clinical events were lower with clopidogrel monotherapy compared to aspirin monotherapy (Kaplan-Meier estimate: 2.5% vs. 5.0%; adjusted HR:0.566, 95% CI: 0.403-0.795). Clopidogrel monotherapy was associated with lower risk for MACCE (Kaplan-Meier estimate: 1.0% vs. 3.1%, log-rank p = 0.001 ), as well as lower incidence rates of all-cause death, MI, and stroke. The difference in risk between the groups was statistically similar for major or clinically relevant nonmajor bleeding (Kaplan-Meier estimate: 1.5% vs. 2.1%, log-rank p = 0.199).

Researchers recommended that their findings should be further investigated through a randomized clinical trial.

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Leakage after left atrial appendage occlusion associated with higher risk of adverse events

Leakage after left atrial appendage occlusion associated with higher risk of adverse events

Patients who had leakage to the left atrial appendage due to incomplete device sealing after left atrial appendage occlusion (LAAO) experienced more clotting and bleeding events within a year following their procedure compared with patients who had no leaking, according to a study presented at the American College of Cardiology’s 71st Annual Scientific Session.

The study, which included data from more than 50,000 patients, is by far the largest to date to assess how leaking after LAAO affects the likelihood of adverse health outcomes. The results suggest that even small leaks are associated with a 10%-15% higher risk of adverse events.

Our study shows that any leak matters, and we should find ways to optimize the procedure to minimize the proportion of patients who end up with leaks. Because this is a preventative procedure, it is important to find ways to master this and prevent leaks from happening. Fortunately, there are indications that leaking might be less common with newer devices and improved techniques.”

Mohamad Alkhouli, MD, professor of medicine at Mayo Clinic and study’s lead author

Stroke is a major concern in patients with atrial fibrillation (AFib), the most common heart rhythm disorder. Blood thinners are the primary medical option for reducing the risk of strokes, which are caused when a blood clot blocks an artery in the brain; however, blood thinners are not suitable for many patients due to drug interactions, bleeding complications, cost, frequent blood checks with warfarin or other reasons. The WATCHMAN device, approved by the U.S. Food and Drug Administration in 2015, is designed to help prevent strokes by sealing off the heart’s left atrial appendage where blood can pool and clot. It is now widely used to reduce the risk of stroke in patients with AFib who cannot tolerate long-term use of blood thinners.

For the study, researchers analyzed data from 51,333 patients who underwent LAAO procedures with the WATCHMAN device between 2016-2019 as recorded in the ACC’s LAAO Registry, a database that includes nearly all LAAO procedures conducted in the U.S. and is part of the College’s NCDR registries. Echocardiograms were used to classify the size of any leaks around the device an average of 45 days after a LAAO procedure, a standard part of the clinical follow-up for this procedure. Registry data also included information about subsequent adverse health events occurring in the years after the procedure.

Overall, researchers found that 73.4% of patients had no leaks, 25.8% had small leaks (greater than zero but less than 5 millimeters across) and 0.7% had large leaks (greater than 5 millimeters)—proportions similar to those reported in previous registry studies and clinical trials.

While relatively few patients—roughly 2%-3%—experienced adverse events in the year following their LAAO procedure, the researchers found that the relative risk of these events varied significantly between patients with and without leaks. Compared to patients who had no leaking, those with small leaks had a 10% higher relative risk of suffering any major adverse events, an 11% higher relative risk of major bleeding complications, and a 15% higher relative risk of clotting-related events, including stroke, systemic embolization and transient ischemic attacks.

The study revealed no significant differences in the rate of adverse events between patients with large leaks and those with small or no leaks, which Alkhouli said is likely due to the use of anticoagulants in these patients. Instructions for the WATCHMAN device indicate that patients who have residual leaks greater than 5 millimeters across should be considered to have a failed procedure, and they are generally treated with anticoagulants.

Alkhouli said leaking is relatively common with LAAO procedures because the size and shape of the left atrial appendage varies widely from person to person, which can make it difficult for operators to position the device in a way that completely seals off the appendage. He noted that the shape of the appendage portion where the leaked blood flows into could affect the associated risks. More recent technologies, such as the use of CT scans to image the appendage and software that allows users to practice the procedure virtually before operating on a patient, could help operators place the WATCHMAN device in a more optimal position. Alkhouli said newer generation WATCHMAN device designs, which were introduced in 2021, could also help to reduce the risk in some patients.

The study was based on registry data reflecting real-world practices, meaning variations in the measurement of leaks could exist and may impact the results of the study, Alkhouli said. He added that future studies could help clarify whether using blood thinners in some patients with leaks smaller than 5 millimeters would be helpful in reducing stroke risk.

This study was simultaneously published online in the JACC: Clinical Electrophysiology at the time of presentation. The study was funded by Boston Scientific, maker of the WATCHMAN device.

Alkhouli will present the study, “Residual Leaks Post Left Atrial Appendage Occlusion,” on Sunday, April 3, at 12:15 p.m. ET / 16:15 UTC in the Main Tent, Hall D.

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Reduced kidney function caused by antithrombotic therapy can influence bleeding events

Reduced kidney function caused by antithrombotic therapy can influence bleeding events

Antithrombotic therapy is prescribed to prevent thrombotic (blood clotting inside a blood vessel) events but the treatment also increases the likelihood of experiencing a bleeding event, which can be extremely serious if it occurs in a vital organ. Aging societies tend to have an increased number of patients undergoing antithrombotic therapy, and the drugs used in this treatment can affect kidney function. In particular, reduced kidney function caused by antithrombotic medications can significantly influence bleeding events. It is highly recommended that patients, especially those with decreased kidney function, have a detailed discussion with their doctor about the possible risks and benefits of proceeding with antithrombotic therapy.

Patients with heart arrythmia (atrial fibrillation) have a high risk for thrombotic events in blood vessels that could lead to permanent organ damage-;such as cerebral infarction-;and are prescribed antithrombotic therapy to lower their risk of developing blood clots. However, the risk of bleeding events simultaneously increases due to the nature of these medications. The severity of these bleeding events is highly variable, ranging from epistaxis (nosebleeds) to fatal brain hemorrhage.

While kidney function is known to be related to bleeding event risk, researchers at Kumamoto, Miyazaki, and Tohoku Universities in Japan conducted a post-hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial to determine the impact of kidney function on the risk of recurrent bleeding events during antithrombotic therapy. Their analysis revealed that the effect of kidney function on recurrent bleeding risk events was quite large for patients undergoing this treatment. They also found that the bleeding risk decreased with time for patients with healthy kidney function but remained high for patients with decreased kidney function. Clearly, the decision to use such a therapy should be balanced between the expected antithrombotic effects and bleeding risks.

In most cases, it is considered better to continue antithrombotic therapies even after bleeding events as long as the event was not severe. However, it is not surprising that both patients and physicians hesitate to continue the therapy after any bleeding event. To assess for drug safety and efficacy, these drugs are usually measured by the numbers of bleeding and thrombotic events. Unfortunately, in the assessment of antithrombotic therapy, most studies only consider the first event in their analyses even though patients could experience multiple events throughout their lifetime. This study revealed that the impact of kidney function on bleeding risk during antithrombotic therapy is larger than estimated in previous studies. Furthermore, patients with healthy kidney function appear to have a decreased risk of experiencing a bleeding event over time, but the risk for patients with reduced kidney function remains high as time continues.

A detailed discussion between patients and physicians based on all current scientific evidence about the risks and benefits of antithrombotic therapy is highly recommended. Our analysis should be quite useful in facilitating this type of discussion.”

Dr. Kunihiko Matsui, Study Leader, Kumamoto University Hospital’s Department of General Medicine and Primary Care


Journal reference:

Matsui, K., et al. (2022) The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial. BMC Medicine.

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Hemophilia A Gene Therapy Reduced Bleeding Events, Need for Clotting Factors

Hemophilia A Gene Therapy Reduced Bleeding Events, Need for Clotting Factors

The phase 3 trial of valoctocogene roxaparvovec for severe hemophilia A showed it reduced bleeding events as well as the use of factor VIII concentrates.

A phase 3 trial of valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, showed it reduced bleeding events as well as the use of factor VIII concentrates and increased endogenous production of clotting factors.

Severe hemophilia A, defined as a factor VIII level of 1 IU/dL or lower, carries the highest risk of spontaneous and traumatic bleeding, resulting in loss of limbs, chronic pain, decreased quality of life, and higher risk of mortality. About 1 in 5000 males is born with the rare disease, and about 60% have the most severe form, according to the National Organization for Rare Disorders.

Outcomes for individuals with hemophilia A, caused by a deficient F8 gene, have improved with factor VIII concentrates that are used prophylactically, but bleeding events are not eliminated.

If approved by the FDA, the adeno-associated virus (AAV) vector gene therapy would be sold as Roctavian by BioMarin, which funded the study. The FDA has granted valoctocogene roxaparvovec Regenerative Medicine Advanced Therapy and Breakthrough Therapy designations; according to press reports, it could be priced as high as $3 million, making it the most expensive therapy to date.

Writing in The New England Journal of Medicine, the authors said the gene therapy enables steady production of factor VIII without additional prophylactic measures. However, the authors also said, “The expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”1

Participants in the trial (GENEr8-1) were 134 adult men 18 years or older who had previously been treated with clotting-factor prophylaxis for at least 1 year, 2 of whom were living with HIV. At baseline, 61.9% of the participants were receiving factor VIII prophylaxis with standard half-life products, 27.6% with extended half-life products, and 17.9% with plasma-derived products. None of the participants were receiving emicizumab (Helimbra), a humanized bispecific monoclonal antibody that joins both factor IXa and X, which are proteins necessary to activate the natural coagulation cascade and restore the blood clotting process.

Exclusion criteria for the open-label, single-group, multicenter, phase 3 study included those who had preexisting anti-AAV5 antibodies, factor VIII inhibitors, or significant liver disease.

Patients received a single infusion of valoctocogene roxaparvovec at a dose of 6×1013 vector genomes per kilogram of body weight, and investigators examined the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion.

Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates.

Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. The analysis included data from 132 HIV-negative participants, including 112 participants enrolled from a prospective noninterventional study.

Results showed:

  • A decline in annualized rates of factor VIII use of 98.6% and treated bleeding of 83.8% (P <.001 for both comparisons)
  • A median factor VIII activity level of 5 IU/dL or higher in 88.1% of participants

As for safety, all participants had at least 1 adverse event (AE); 22 of 134 (16.4%) reported serious AEs.

Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with glucocorticoids. The other most common AEs were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%).

There were no deaths in the trial or withdrawals due to AEs, and there was no thrombosis or development of factor VIII inhibitors.

The investigators wrote that “intra- and interindividual variability in factor VIII activity after gene transfer were notable.” Seven participants had a median factor VIII activity level of greater than 150 IU/dL; 12 participants had a median factor VIII activity level of less than 3 IU/dL, measured by chromogenic assay; and 2 participants, measured by a 1-stage assay, had a factor VIII activity level of less than 1 IU/dL.

The causes of the variability are not fully known; the authors said biologic variables and molecular events related to gene transfer and expression may impact endogenous factor VIII production.

There were a few limitations to the study. The 2 participants with HIV were excluded from the primary analysis, and so generalizing the results to that population may be constrained. In addition, direct comparisons to emicizumab cannot be made because the participants had previously been using factor VIII concentrates, but the authors said “the annualized rates of treated bleeding here were similar to those reported with long-term emicizumab prophylaxis.”

In an accompanying editorial, the author called valoctocogene roxaparvovec “a new choice for care that could be truly transformative and liberating for eligible men with hemophilia” and called on payers, policymakers, and others to get ready for its entrance.2


1. Ozelo MC, Mahlangu J, Pasi KJ, et al; GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386:1013-1025. doi:10.1056/NEJMoa2113708

2. Thornberg CD. Prepare the way for hemophilia A gene therapy. N Engl J Med. 2022;386:1081-1082. doi:10.1056/NEJMe2200878