Friday, 12 April 2019

Reversing the effects of the new anti-clotting drugs

Pediatricians and child behavior specialists who work with teens know that adolescence is an incredibly important time for social growth. Yet these years can be fraught with anxiety for the parents of teens. How will you know if your moody teen is hanging out with the right people? Which friends might be a bad influence? How can you help your son or daughter develop healthy relationships?

Recent research has addressed some aspects of these questions. One study entitled “Spreading of healthy mood in adolescent social networks,” published this year in the Proceedings of the Royal Society of London, investigated whether a teen whose friends have a healthy mood is less likely to be depressed. It also looked at how emotionally healthy friends affected a teen’s recovery from depression. Basically, the researchers wanted to find out: is a good mood contagious?

The study involved roughly 3,000 teens. Each study volunteer completed two surveys, six months apart, in which he or she listed up to five male and five female friends. Each teen was then followed over time, to see how his or her mood changed.

One of the interesting things about this study is that these researchers defined depression as a behavior, not necessarily as a disease that someone could get. This allowed them to do their statistical analysis a little differently from previous studies looking at the same subject matter, and it uncovered the potential power of positively minded friends.

The investigators found that having a social network made up of friends with a healthy mood cut a teenager’s probability of developing depression in half over a 6- to 12-month period. It also significantly improved the chances of recovering from depression for teens who already suffered from it. While the data don’t show a direct cause and effect, this study does suggest that having friends with a healthy mood may reduce the risk of depression and make it a little easier to recover from depression should it occur.
Surprising findings on from social networking research

This study is a nice example of a recent trend in epidemiology — using data about an individual’s social network to learn things about that person. This type of research has led to numerous interesting findings, and has really shaped an entire new area of inquiry. A study published in 2007 in The New England Journal of Medicine was one of the first of this kind. It showed that people who had obese friends and family were themselves more likely to be obese. Since then, additional research has looked at how social networks influence an individual’s risk of developing (or sidestepping) specific health conditions, such as obesity, smoking, and depression.

Results of these studies have been, at times, surprising, thus giving the medical community valuable new information. For example, I myself led a study in 2011 called “The influence of social networks on patients’ attitudes toward type II diabetes.” When I started this research, I supposed that patients would be less concerned about having diabetes if more of their friends and family members had diabetes. I had guessed that these patients might have become so used to the idea of diabetes that the disease would seem common and almost normal. But in fact, my team found the opposite! Patients with a higher prevalence of diabetes within their social networks expressed greater concern about their illness. This unexpected result gave me information that helped me to better take care of my patients.
Using social network data to improve your teen’s mental health

This type of research is not only helpful to doctors, but it also provides important information for anyone trying to improve his or her own health, or the health of one’s family. The study on positive mood in teens’ social networks suggests that parents may be able to reduce their teen’s chances of developing depression — or improve her or his mood if she does have depression — simply by promoting and supporting friendships with emotionally healthy peers. With much controversy about using antidepressants in teens, results such as these can give parents a simple way to promote emotional health and well-being in their adolescent children — with no medications involved. The oral anticoagulant warfarin (Coumadin) became available for prescription in 1954. This anti-clotting drug commanded national attention when President Dwight Eisenhower received the drug as part of his treatment following a heart attack. No other oral anticoagulant was successfully developed and marketed in the United States until 2010.

Warfarin is a dangerous drug. Along with insulin, it is responsible for the most emergency hospitalizations due to adverse drug reactions. Whereas insulin causes low blood sugar, warfarin is notorious for the complication of major bleeding. Warfarin is plagued by hundreds of drug-drug and drug-food interactions. The optimal dose is determined by monitoring the level of anticoagulant in the blood. Standard-intensity anticoagulation with warfarin is usually targeted to achieve prothrombin blood test results, expressed as international normalized ratio (INR), within a range of 2.0 to 3.0. If the INR is greater than 3.0, the warfarin dose is decreased to prevent excessive bleeding. If the INR is lower than 2.0, the warfarin dose is increased to prevent excessive blood clotting. This approach is slow, cumbersome, and frustrating. Even when the INR tests within the desired range, catastrophic bleeding complications, such as bleeding into the brain, can still occur.

Patients and health care providers complain about the difficulties and inconveniences of trying to use warfarin properly. Multiple algorithms and even genetic testing have been undertaken with the hope of deriving an easy-to-follow dosing scheme, but these efforts were disappointing overall.
Enter the new anticoagulants

In a remarkable five years spanning 2010 through 2014, four novel oral anticoagulants underwent pivotal trials for stroke prevention in atrial fibrillation, as well as treatment of pulmonary embolism and deep vein thrombosis. The four new drugs have better safety profiles than warfarin, and some are more effective than warfarin for stroke prevention in people with atrial fibrillation. All four were rapidly approved by the Food and Drug Administration to treat these thrombotic conditions. One, dabigatran (Pradaxa), is a direct thrombin inhibitor — that is, it inactivates clotting factor II (thrombin). The other three — rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) — inactivate clotting factor X. None of these target-specific novel anticoagulants requires regular laboratory monitoring. They are administered in fixed doses. There are virtually no restrictions on foods such as green leafy vegetables, as there are with warfarin. And there are only about a dozen important drug-drug interactions.

As this wave of new oral anticoagulants came to market, there were predictions (which turned out to be false) that warfarin would rapidly become an infrequently used anticoagulant. At Harvard-affiliated Brigham and Women’s Hospital, we have about 3,500 patients in our Anticoagulation Management Service who still receive warfarin. So, why were the initial predictions wrong? And why does warfarin continue to command more of the “market share” than these target-specific designer-drug anticoagulants?

The biggest concern is that the novel oral anticoagulants have not, until now, had specific antidotes to counteract major bleeding. Warfarin is a vitamin K antagonist, so a dose of vitamin K is an antidote to warfarin — though one that works slowly and unreliably. But the fear with the novel oral anticoagulants has been that the rare episode of major bleeding might not be controllable or rapidly reversed.
New antidotes pave the way for greater use of the new anticoagulants

The landscape changed drastically in October 2015, when the FDA approved a dabigatran antibody as an antidote to dabigatran. After a rapid intravenous injection of the antidote, dabigatran is attracted to its own antibody at least 300 times more strongly than to thrombin (clotting factor II). When dabigatran and its antibody bond, thrombin is liberated from dabigatran and can do what clotting factors do best—stop the bleeding. In an ongoing clinical trial, laboratory evidence of anticoagulation from dabigatran was reversed within minutes of injecting the dabigatran antibody antidote. Hospitals across the United States now have the dabigatran antibody available for emergency use.

Though catastrophic bleeding from the novel oral anticoagulants is extremely rare, the availability of antidotes reassures health care providers, patients, and their families. It changes the psychology of prescribing and tilts the balance more strongly toward the novel agents.

As for rivaroxaban, apixaban, and edoxaban, a universal antidote is in late and successful stages of clinical development. This antidote is not an antibody, but it is an attractive “decoy” for these three anticoagulants, all of which target clotting factor X. The antidote is more attractive to the anticoagulants than factor X is, even though it is only slightly modified from the structure of factor X. The decoy, which is inert, “fools” these three anticoagulants. They then detach from clotting factor X and bind to the decoy instead, liberating the unbound clotting factor X to stop the bleeding.

In summary, these two antidotes are important “backups” to our arsenal of novel anticoagulants. They permit us to prescribe the new agents with increased confidence. Regular exercise is one of the cornerstones for maintaining good health. Regular physical activity helps to prevent heart and blood vessel disease, diabetes, dementia, and even some types of cancer. But while the health benefits of exercise are indisputable, there is still a question about exactly how much exercise is needed to promote optimal health.

According to a recent article in The Journal of the American Medical Association by Thijs Eijsvogels and Paul Thompson, the answer may be “not as much as you might think.”
Every little bit of exercise counts

Drs. Eijsvogels and Thompson reviewed several published studies and concluded that as little as 15 minutes a day of moderate-intensity exercise — and only 8 minutes a day of vigorous-intensity exercise — reduced the risk of death. They referred to this as the “lowest effective dose.” This means that even a small amount of exercise may have substantial health benefits compared with being sedentary, and even people who are “too busy to exercise” can find this amount of time.

Exercising beyond the lowest effective dose had further health benefits. For every additional 15 minutes of moderate-intensity exercise, there was a further 4% reduction in the risk of death. The greatest benefit was seen in people who exercised for an average of 63 to 88 minutes a day, and vigorous-intensity exercise was better than moderate-intensity exercise.

Another new study, published in JAMA Internal Medicine, found that young adults who were physically fit (as measured by endurance testing on a treadmill) had a lower risk of developing heart and blood vessel disease over the next three decades. For each additional minute a person was able to stay on the treadmill, there was a 15% reduction in the risk of death and a 12% reduction in the risk of heart and blood vessel disease.
Putting the “lowest effective dose” of exercise to work for you

Taken together, these two new studies further underscore a single conclusion: you don’t have to be a triathlete to achieve health benefits from physical activity. Even small amounts of exercise and modest increases in fitness can make a clear difference, and some exercise is always better than no exercise.

If you need to increase your level of physical activity, it may be a good idea to start by counting your daily steps using a Fitbit or similar device (there are also free apps for your phone or tablet that can count your steps). Gradually increase your daily goal, and before you know it, you will be on track towards having a longer and healthier life.

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