FDA Approves New 10 mg Dosing for Xarelto (rivaroxaban) to Reduce the Continued Risk of Venous Thromboembolism (VTE)

In continuation of my update on rivaroxaban

Janssen Pharmaceuticals, Inc. announced  the U.S. Food and Drug Administration (FDA) approved the 10 mg once-daily dose of Xarelto (rivaroxaban) for reducing the continued risk for recurrent venous thromboembolism (VTE) after completing at least six months of initial anticoagulation therapy. This approval follows a FDA Priority Review and is based on data from EINSTEIN CHOICE, the only clinical study to find that a Factor Xa inhibitor, specifically Xarelto, demonstrates superior efficacy in reducing the continued risk of recurrent VTE and with major bleeding rates similar to aspirin.

VTE includes deep vein thrombosis (DVT), a blood clot in a deep vein (often the legs), and pulmonary embolism (PE), a clot that travels to the lung. It is the third most common cause of cardiovascular death worldwide, after heart attack and stroke.

"We believe the availability of the 10 mg Xarelto dose will change clinical practice and the management of VTE recurrence," said Paul Burton, MD, PhD, FACC, Vice President, Medical Affairs, Janssen. "The landmark EINSTEIN program results yet again demonstrate Xarelto is a safe and highly effective option, not only for the initial treatment of a VTE, but also for the continued prevention of a recurrent event."

With this approval, the Xarelto prescribing information provides instructions for physicians to begin treatment with Xarelto 15 mg, dosed twice daily, for the first 21 days after a VTE occurrence. On day 22 through at least day 180, the daily dose decreases to Xarelto 20 mg once daily. After at least 180 days (6 months), physicians can prescribe Xarelto 10 mg once daily in patients at continued risk for DVT and/or PE.

"If anticoagulation therapy is stopped, up to 20 percent of patients will have a recurrent VTE within three years. To prevent this, physicians have long debated how best to extend anticoagulant use beyond the initial treatment window," said Jeffrey Weitz, MD, FRCP(C), FACP, Professor, Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, and Executive Director, Thrombosis & Atherosclerosis Research Institute. "The FDA’s approval of the 10 mg dose of Xarelto for preventing recurrent VTE, along with clinical evidence confirming the superiority of Xarelto over aspirin for extended VTE prevention, means we can finally put this debate to rest."

The FDA’s approval of the Xarelto 10 mg once-daily dose was based on the EINSTEIN CHOICE study results. The EINSTEIN CHOICE study evaluated patients with VTE who were already treated with six to 12 months of initial anticoagulation therapy and then received Xarelto 10 mg once daily, Xarelto 20 mg once daily or aspirin 100 mg once daily for up to an additional 12 months of treatment. Patients taking either Xarelto dose had significantly fewer recurrent VTE compared to those taking aspirin. Specifically, Xarelto 10 mg reduced the risk of recurrent VTE by 74 percent and Xarelto 20 mg by 66 percent. All three treatment groups had low rates of major bleeding (0.4 percent with Xarelto 10 mg, 0.5 percent with Xarelto 20 mg, 0.3 percent with aspirin).

In September 2017, Janssen’s development partner Bayer announced the Committee for Medicinal Products for Human Use of the European Medicines Agency granted a positive opinion to update the Xarelto label to include the 10 mg once-daily dose in the European Union; the European Commission granted approval on October 19, 2017.

FDA Approves New 10 mg Dosing for Xarelto (rivaroxaban) to Reduce the Continued Risk of Venous Thromboembolism (VTE)

Aspirin May No Longer Have Effect in Primary CVD Prevention

Aspirin may not be effective for primary prevention of cardiovascular disease and cancer mortality, according to research published online Nov. 21 in Family Practice.

Frank Moriarty, Ph.D., from the Royal College of Surgeons in Dublin, and Mark H. Ebell, M.D., from the University of Georgia in Athens, compared the benefits and harms of aspirin for primary prevention before (1978 to 2002) and after (2005 onward) widespread use of statins and screening for colorectal cancer.

The researchers found that for older versus newer studies, the relative risks for vascular outcomes were 0.89 (95 percent confidence interval [CI], 0.83 to 0.95) versus 0.93 (0.86 to 0.99) for major adverse cardiovascular events; 1.73 (1.11 to 2.72) versus 1.06 (0.66 to 1.70) for fatal hemorrhagic stroke; 0.86 (0.74 to 1.00) versus 0.86 (0.75 to 0.98) for any ischemic stroke; 0.84 (0.77 to 0.92) versus 0.88 (0.77 to 1.00) for any myocardial infarction; and 0.79 (0.71 to 0.88) versus 0.94 (0.83 to 1.08) for nonfatal myocardial infarction. In newer studies, there was no significant decrease observed for cancer mortality (relative risk, 1.11; 95 percent CI, 0.92 to 1.34). Significant increases were seen in major hemorrhage (older studies, relative risk, 1.48 [95 percent CI, 1.25 to 1.76] versus newer studies, relative risk, 1.37 [95 percent CI, 1.24 to 1.53]).

"In a modern era characterized by widespread statin use and population-wide cancer screening, aspirin no longer reduces the absolute risk of cancer death or myocardial infarction when given as primary prevention," the authors write.

https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmz080/5637484

Experimental Drug-apixaban (Eliquis) : Might Beat Aspirin in Preventing Repeat Strokes: Study

An investigational drug called apixaban (Eliquis) appears to be better than aspirin at preventing blood clots in certain patients who have already suffered a stroke or so-called "mini-stroke" due to an abnormal heart rhythm, according to the results of a new study.

For patients with the dangerous irregular heart rhythm known as atrial fibrillation who can't tolerate the standard drug treatment, daily apixaban seems to be more effective at warding off a stroke or blood clot than aspirin, the study found.

More....

Ancient anti-inflammatory drug salicylic acid has cancer-fighting properties: Diflunisal -- a cousin of aspirin -- blocks a key protein that causes tumor formation in leukemia

In a study published in eLife, the researchers found that both salicylic acid and diflunisal suppress two key proteins that help control gene expression throughout the body. These sister proteins, p300 and CREB-binding protein (CBP), are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth. By inhibiting p300 and CBP, salicylic acid and diflunisal block the activation of these proteins and prevent cellular damage caused by inflammation. This study provides the first concrete demonstration that both p300 and CBP can be targeted by drugs and may have important clinical implications.

"Salicylic acid is one of the oldest drugs on the planet, dating back to the Egyptians and the Greeks, but we're still discovering new things about it," said senior author Eric Verdin, MD, associate director of the Gladstone Institute of Virology and Immunology. "Uncovering this pathway of inflammation that salicylic acid acts upon opens up a host of new clinical possibilities for these drugs."

Earlier research conducted in the laboratory of co-author Stephen D. Nimer, MD, director of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and a collaborator of Verdin's, established a link between p300 and the leukemia-promoting protein AML1-ETO. In the current study, scientists at Gladstone and Sylvester worked together to test whether suppressing p300 with diflunisal would suppress leukemia growth in mice. As predicted, diflunisal stopped cancer progression and shrunk the tumors in the mouse model of leukemia.

"The ability to repurpose drugs that are already FDA-approved to be part of novel therapies for cancer patients is incredibly exciting," said Nimer. "We have conducted a clinical trial of salicylic acid in patients with hematologic cancers and found it to be safe. Thus, this collaborative effort to develop novel epigenetic therapies is an important next step in our journey to find more effective treatment for leukemia patients."

The scientists are now pursuing a clinical trial that will test the ability of salicylic acid to treat patients with leukemia as part of novel combination therapies. Other possible clinical applications for salicylic acid include other forms of cancer, type 2 diabetes, inflammatory diseases, and even neurodegenerative disorders, such as Alzheimer's disease. Prior Gladstone research showed that another drug containing salicylic acid prevented the accumulation of tau in neurons and protected against cognitive decline in a mouse model of dementia.

Aspirin May Fight Cancer by Slowing DNA Damage

Researchers hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. Researchers  evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two researchers detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett's cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs. More...

Aspirin May Fight Cancer by Slowing DNA Damage | ucsf.edu

Silver nano particles as antiplatelet agent?

We know common side effects of anti-thrombotic agents [aspirin & Reo Pro (abciximab) ] like dangerous bleeding and ulcerogenecity (of aspirin) so there is an urgent need to have more safer antiplatelet agents. Now thanx to Debabrata Dash and colleagues of Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi for their innovative findings that is., now silver nano particles can be used as antiplatelet agent.

The scientists describe development and lab testing of silver nanoparticles that seem to keep platelets in an inactive state. Low levels of the nanosilver, injected into mice, reduced the ability of platelets to clump together by as much as 40 percent with no apparent harmful side effects. The nanoparticles "hold immense potential to be promoted as an antiplatelet agent," the researchers note. Nanosilver appears to possess dual significant properties critically helpful to the health of mankind — antibacterial and antiplatelet — which together can have unique utilities, for example in coronary stents. One more "Nano" to the drug discovery kitty. Congrats Dash and group for this achievement. More...

Naproxen and omeprazole combination effective in preventing bladder cancer

The anti-inflammatory class of drugs NSAIDs have shown great promise in preventing cancers including colon, esophagus and skin. However, they can increase the risks of heart attacks, ulcers and rare but potentially life-threatening bleeds.

A new study suggests there may be ways to reduce these dangerous side effects. Collaborators from the University of Michigan, the National Cancer Institute and the University of Alabama looked at naproxen, which is known to have a lower cardiovascular risk than other NSAIDs. Naproxen, like most NSAIDs and aspirin, does increase the risk for gastric ulcers or bleeding. Here, the researchers used the proton pump inhibitor omeprazole, a commonly used acid inhibitor, in combination with naproxen and tested its effects on cancer prevention in a rat model of bladder cancer.

They found that naproxen reduced the incidence of bladder cancer by 75 percent in rats. Omeprazole by itself did not affect the development of cancer but it also did not interfere with the effect of naproxen at preventing tumors. The rats who received naproxen alone or naproxen with omeprazole developed cancer at similarly low rates, while all rats receiving omeprazole alone or no treatment developed bladder cancer.

Clinical data in humans has previously shown combining omeprazole plus naproxen reduced gastric toxicity roughly 70 percent.

The authors also found that intermittent dosing with naproxen (three weeks on the drugs, followed by three weeks off) was highly effective and likely to reduce gastric toxicity. However, it does not have the clear clinical data supporting reduced gastric toxicity associated with naproxen and omeprazole.

"Our study shows that naproxen works just as well with a proton pump inhibitor as without. This provides proof of principle that this could be a valuable cancer prevention strategy and one hopes it can advance quickly to a clinical trial for those at high risk of colon, esophageal, squamous cell skin cancer or potentially other cancers," says lead study author Ronald A. Lubet, Ph.D., a scientist with the Chemopreventive Agent Development Research Group at the National Cancer Institute.

Naproxen and omeprazole combination effective in preventing bladder cancer

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

Beta blocker use linked to NSCLC patient survival

Analysis shows that the 155 NSCLC patients given incidental beta blockers had significant better distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival than the 567 patients who were not given the agents.

However, beta blocker use had no impact on locoregional progression-free survival (LRPFS), leading the researchers to suggest that "the drugs may be affecting the tumor metastatic cascade rather than affecting the primary tumor."

The team investigated the impact of beta blockers on newly diagnosed NSCLC patients at the MD Anderson Cancer Center between 1998 and 2010 following reports that norepinephrine may stimulate tumor cell migration - a process could be targeted via the beta-adrenergic receptor.

Beta blocker use significantly predicted longer DMFS (hazard ratio [HR]=0.67), DFS (HR=0.74), and OS (HR=0.78), after adjusting for confounders including age, cancer stage, histology, tumor volume, Karnofsky performance score, use of concurrent chemotherapy, and radiation dose. Other factors including presence of hypertension or chronic obstructive pulmonary disease, and use of aspirin were also considered in the multivariate analysis.

The researchers note that 68% of patients were given beta blockers for hypertension. The remaining patients were given beta blockers for nonhypertensive disorders such as coronary heart disease.

Most patients were given selective (β1) beta blockers such as metoprolol (n=89)(left structure) and atenolol (above right structure)(n=43). Just 21 of the patients were given nonselective agents, such as carvedilol.

Beta blocker use linked to NSCLC patient survival

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?'"

Ginger Supplements Might Ease Inflammation Linked to Colon Cancer..

A small, preliminary study finds that ginger root supplements seem to reduce inflammation in the intestines  a potential sign that the pills might reduce the risk of colon cancer. Previous research in animals has suggested that ginger can reduce inflammation but isn't potentially toxic to the stomach like aspirin, Zick noted. And scientists have linked chronic inflammation in the gut to colon cancer, suggesting that easing this inflammation could reduce the risk of the disease.

In the new study, Zick's team randomly assigned 30 people to take pills containing 2 grams of ground ginger root extract or a "dummy" placebo pill each day for 28 days. They measured the level of inflammation in the participants' intestines before and after the test period. The researchers found that the level of inflammation in the subjects who took the ginger pills fell by an average of 28 percent, while staying about the same in those who took the placebo.

Ref : http://cancerpreventionresearch.aacrjournals.org/content/early/2011/10/07/1940-6207.CAPR-11-0224.abstract

Are Omega-3s Linked to Lower Risk for Fatal Heart Attack?

In continuation of my updates on omega-3 fatty acids

Regularly eating fish and other foods rich in omega-3 fatty acids may lower your risk of fatal heart disease, a new research review suggests.

"Our results lend support to the importance of fish and omega-3 consumption as part of a healthy diet," said senior study author Dr. Dariush Mozaffarian, dean of the Friedman School of Nutrition Science and Policy at Tufts University, in Boston.

"At a time when some but not other trials of fish oil supplementation have shown benefits, there is uncertainty about cardiovascular effects of omega-3s," Mozaffarian said in a university news release.

Fish are the main dietary sources of omega-3 fatty acids. Fatty fish, such as salmon, trout, anchovies, sardines and herring, are the richest source of these nutrients.

Walnuts, flaxseed oil, canola oil and some other seeds and nuts contain the plant-based omega-3 known as alpha-linolenic acid, according to the U.S. Department of Agriculture.

For the study, the researchers analyzed 19 studies from 16 countries that involved nearly 46,000 people. Of these people, nearly 8,000 suffered a first heart attack over time, which resulted in 2,781 deaths.

Plant-based and seafood-based omega-3s were not associated with a lower risk of non-fatal heart attacks. But they were linked with a roughly 10 percent lower risk of fatal heart attacks, although the study can't prove a direct cause-and-effect relationship.

"These new results, including many studies which previously had not reported their findings, provide the most comprehensive picture to date of how omega-3s may influence heart disease," said study leader Liana Del Gobbo, a postdoctoral research fellow at Stanford University School of Medicine. "Across these diverse studies, findings were also consistent by age, sex, race, presence or absence of diabetes, and use of aspirin or cholesterol-lowering medications."

Are Omega-3s Linked to Lower Risk for Fatal Heart Attack?  

New anti-inflammatory drug shows promise for treating inflammatory disorders

In one of my earlier blog, I  did mention about the antiinflammatory activity of H₂S gas. Now interestingly John Wallace, a pharmacologist and director of the Farncombe Family Digestive Health Research Institute at McMaster University, compared naproxen, a commonly used NSAID, to a novel anti-inflammatory drug, ATB-346 (ATB-346 is a derivative of naproxen which releases hydrogen sulfide), which he developed in collaboration with a team of Italian chemists and is now commercializing through his company, Antibe Therapeutics Inc. The basis for this research is by the fact that hydrogen sulphide is an important mediator of gastric mucosal defence. As we all know the ulcerogenecity associated with NSAIDs, there is a need to have NSAIDs with least or no ulcerogenecity.

As per the claim by the researchers, ATB-346, [above, structure : 2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester] acts by inhibiting cyclooxygenase-1 and 2 and  reduces inflammation (in vivo). More interesting out come from their research is  that ATB-346 suppressed gastric prostaglandin E₂ synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. 

ATB-346 did not cause significant damage, where as naproxen rendered significant  gastric mucosa damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K_IR6.x channels). Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity, but with substantially reduced gastrointestinal toxicity (100 times safer than naproxen). Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats.

The researchers concluded that H2S-releasing NSAIDs appear to represent a promising alternative to existing therapies for the treatment of inflammation and pain. Future research will focus on the potential cardiovascular benefits of these drugs. .....

Ref : John L Wallace et. al., British Journal of Pharmacology, 159(6),  1236 - 1246