Stroke prevention drug combo shows promise, study says

In continuation of my update on clopidogrel  and aspirin

If you've had a minor stroke or a transient ischemic stroke (TIA), taking the clot-preventing drug clopidogrel along with aspirin may lower your risk of having a major stroke within the next 90 days, according to new research published in The New England Journal of Medicine.

An international study of 4,881 adults in 10 countries who either had a minor stroke or a TIA showed that people who took clopidogrel plus aspirin had a 25 percent lower risk of a major stroke, heart attack or death from blood clots within the three months after the first incident, compared with those who took aspirin alone.

clopidogrel          aspirin

"The study gives us solid evidence that we can use this drug combination to prevent strokes in the highest-risk people, but not without some risk of bleeding," said lead author Clay Johnston, M.D., Ph.D., dean and professor of neurology at Dell Medical School at The University of Texas at Austin.

Both minor stroke and TIA are warning signs that a person has a 3 to 15 percent chance of having a more severe stroke within the next three months. Minor stroke is one that results in mild, nondisabling symptoms. TIA, often called a warning stroke or mini-stroke, is caused by a temporary blockage in a blood vessel to the brain that often dissolves or dislodges on its own to stop symptoms. More than a third of U.S. adults have had TIA symptoms, according to the American Stroke Association.

The study also showed a small increase in the risk of hemorrhage in the clopidogrel-aspirin group compared with the aspirin alone group. For every 1,000 patients treated with the combination, an extra five major bleeds would be expected but with 15 fewer strokes and other major ischemic events. Because the bleeding events are generally reversible, the overall benefit outweighs the risk for most patients, Johnston said.

"Of the 33 major hemorrhages that occurred in these 4,881 patients, more than half involved the gastrointestinal tract, and none of them was fatal. These largely preventable or treatable bleeding complications of the treatment have to be balanced against the benefit of avoiding disabling strokes," said co-author J. Donald Easton, M.D., professor of neurology at the University of California, San Francisco School of Medicine.

One previous trial in this area showed that clopidogrel plus aspirin was effective in lowering risks but did not find the risk of hemorrhage.

"The results of this large international trial, when added to the results of previous research, provide evidence to support the use of clopidogrel plus aspirin for 90 days among patients with minor ischemic stroke and high-risk TIA treated within 12 hours," said Ralph Sacco, M.D., M.S., professor of neurology at Miller School of Medicine at the University of Miami. "This trial is likely to change practice since most clinicians and patients are usually willing to accept the increased risk of hemorrhage to offset the disabling impact of a stroke."

The research was part of the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trial—a randomized, double-blind, placebo-controlled trial conducted between May 2010 and December 2017. It included patient information from 269 sites in 10 countries throughout North America, Europe and Australia. Patients were included if they had a minor stroke or a transient ischemic stroke and were at high risk of having a major stroke.

"It's likely we will see more patients who have had a TIA or a minor stroke receiving the combination of clopidogrel and aspirin in the future," Johnston said. "If you've suffered from a minor stroke or TIA, it's important to see a physician immediately, even in the emergency room, to ensure you're taking steps to avoid a potentially debilitating stroke later on," he said. "There are several tests that need to be done right away to determine the cause of the event and to make sure the best treatments are started as soon as possible."

Clopidogrel, known by the brand name Plavix, is a platelet inhibitor commonly prescribed to people who have peripheral artery disease or who have had a recent heart attack or stroke to prevent future cardiac or stroke events.

Ref : https://www.nejm.org/doi/full/10.1056/NEJMoa1800410

Ticagrelor drug may reduce risk of dying following heart attack

In continuation of my update on ticagrelor 

Scientists from the University of Sheffield have discovered ground breaking clues as to how the pioneering heart drug ticagrelor might reduce the risk of dying following a heart attack, in comparison to previous standard treatments.

The new findings, published in Platelets, show that ticagrelor (see left structure above) may reduce the risk of dying as a result of a lung infection after suffering a heart attack compared to patients treated with the drug clopidogrel (see right structure below).

The analysis, which was led by researchers from the University of Sheffield and Uppsala University Sweden, is the latest to come from the PLATO study which originally included over 18,000 patients worldwide. 

In the initial PLATO study, the annual mortality rate for patients treated with clopidogrel was 5.9 per cent and this rate was significantly reduced to 4.5 per cent for patients treated with ticagrelor.

The extent of this reduced risk was unexpected, as previous similar trials had not been so successful in reducing mortality risk - prompting speculation as to the possible mechanisms for this benefit.

Professor Robert Storey said: "We have now shown that there were fewer deaths due to overwhelming bacterial infection (sepsis) in patients treated with ticagrelor, with lung infection accounting for the source of this sepsis in many cases.

"This is a surprising finding but does seem to provide a potential lead in explaining why ticagrelor saved so many lives in comparison to clopidogrel treatment.

"Ticagrelor not only has greater anticlotting activity compared to clopidogrel, which easily explains its greater effectiveness in preventing further heart attacks, but also has another property not possessed by clopidogrel that allows it to prevent adenosine from being cleared from the blood stream.

"Adenosine has many different effects in the body including influencing the activity of white blood cells that are involved in tackling pneumonia and other infections."

Ticagrelor drug may reduce risk of dying following heart attack

Brilinta (Ticagrelor) better than Plavix. ?.......

W knew that, Astra-Zeneca,  in its PLATO clinical trial in mid-2009,  found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had slightly greater chances of major bleeding which was non-significant (11.6 vs. 11.2, p=0.4). Like clopidogrel and ticlopidine, ticagrelor blocks ADP receptors of subtype P2Y₁₂. In contrast to the other antiplatelet drugs, the blockage is reversible. Moreover, it does not need hepatic activation, which could reduce the risk of drug interactions-which makes it special.

Now this has been further substantiated by Dr. Chris. Cannon, who claims that  clot-busting drug Ticagrelor (Brilinta), may soon take the place of Clopidogrel (Plavix) in treating patients with acute coronary syndrome, which includes angina and heart attack.

In a new trial (by Dr. Christopher Cannon, a cardiologist with Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School, both in Boston), the upstart drug ticagrelor (Brilinta) reduced the risk of second heart attacks and death without raising the risk of bleeding, as clopidogrel (Plavix) can do and the authors claim  that this is pretty compelling evidence from this trial that ticagrelor is better without any increased risk of bleeding. 

In this study (funded by AstraZeneca) of more than 13,000 patients with acute coronary syndrome, Brilinta, appears to be more potent than Plavix and has  emerged with several advantages over the old standby  claims the researchers.

Brilinta is s processed as soon as it's swallowed (meaning it doesn't have to go through the liver), and kicks in faster than Plavix, where as Plavix (usually in combination with aspirin) has its share of problems, namely a lag time between when it is administered and when it takes effect, and variability in how different individuals respond to it. And because of an increased risk of bleeding, Plavix must be discontinued before surgery. Overall the researchers, claim that Brilinta has a more reliable level of anti-clotting effect. There's less variability. At the dose, it has about twice the level of anti-clotting effect and hence the  benefit in preventing heart attacks and stent thrombosis. The authors attribute the reason for the superiority of the drug to its quicker reversblity (than Plavix) and patients could have surgery with a lower risk of bleeding. FDA is expected to approve the drug late this year and  hope the patients with thrombosis, angina and acute coronary syndrome will breathe a sigh of relief...

Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2962191-7/fulltext

Mylan receives final FDA approval for Clopidogrel Tablets ANDA

Mylan receives final FDA approval for Clopidogrel Tablets ANDA: Mylan Inc.  announced that its subsidiary Mylan Pharmaceuticals Inc. has received final approval from the U.S. Food and Drug Administration (FDA) for its Abbreviated New Drug Application (ANDA) for Clopidogrel Tablets USP, 75 mg and 300 mg.

Flavonoid Compound Found in Foods and Supplements May Prevent the Formation of Blood Clots, Study Suggests...

A compound called  rutin (see structure - a quercetin derivative), commonly found in fruits and vegetables and sold over the counter a dietary supplement, has been shown to inhibit the formation of blood clots in an animal model of thrombosis.

 As per the researchers claim,

"Approximately half of all morbidity and mortality in the United States can be attributed to heart attack or stroke."..

The study focused on protein disulfide isomerase (PDI) which is found in all cells. Investigators in BIDMC's Division of Hemostasis and Thrombosis had previously shown that PDI is rapidly secreted from both platelets and endothelial cells during thrombosis, when a clot forms in a blood vessel, and that inhibition of PDI could block thrombosis in a mouse model.

"This was a transformative and unanticipated finding because it identified, for the first time, that PDI is secreted from cells in a live animal and is a potential target for preventing thrombosis," says Flaumenhaft. However, because intracellular PDI is necessary for the proper synthesis of proteins, the scientists had to identify a specific compound that could block the thrombosis-causing extracellular PDI -- without inhibiting the intracellular PDI.

They began by conducting a high-throughput screen of a wide array of compounds to identify PDI inhibitors. Among the more than 5,000 compounds that were screened, quercetin-3-rutinoside (rutin) emerged as the most potent agent. "Rutin was essentially the champion compound," says Flaumenhaft.

A bioflavonoid that is naturally found in many fruits, vegetables and teas including onions, apples and citrus fruits, rutin is also sold as an herbal supplement, having received a special designation for safety from the U.S. Food and Drug Administration (FDA). Surprisingly, studies of the rutin molecule demonstrated that the same part of the molecule that provides rutin with its ability to inhibit PDI also prevents the compound from entering cells."That finding explained how this compound can be both a potent inhibitor of PDI and a safe food supplement," says Flaumenhaft. "Our next questions were, 'Is this compound anti-thrombotic? Can it prevent blood clots?'"

New drug more effective than standard treatment to prevent heart-attack deaths

In continuation of my update on ticagrelor .....

Robert Storey, Professor of Cardiology at the University of Sheffield's Department of Cardiovascular Science, presented findings today that confirm one in five deaths in the year following a heart attack could be prevented if a new drug, ticagrelor (see structure), was used instead of the standard treatment, clopidogrel...

More...