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Newer Blood Thinners, Warfarin, Anticoagulation                                                              

 August 13, 2015

Sanjay Singh MD

Sanjay Singh, M.D., FACC

 

This article is being written to help our patients understand the risks and benefits of blood thinning agents used to treat atrial fibrillation, and the variety of therapies that are currently available. The issue has been brought to a head by a recent article in The Milwaukee Journal Sentinel causing significant concern in the medical community. We have received calls from patients very upset about the article.

The Facts:

Atrial fibrillation is a condition in which the top chamber of the heart or atrium starts fibrillating. The word “fibrillation” comes from the Latin “fibrillaire”, which literally means to “shake in the wind like a leaf.”  Normally, the top chamber of the heart (atrium) and the lower chamber (ventricle) both beat fairly regularly between 60-100 times per minute. The atrium beats just before the ventricle. The two, therefore, behave as if they were pumps in series.

The atrium fills the ventricle which then does the majority of the work in terms of pushing blood out. This happens approximately 70-80 times per minute or about 100,000 times per day. In certain conditions, the atrium tries to beat at such a rapid heart rate, for example at 400 beats per minute that it is physically impossible for the atrium to perform as a pump if it is beating that quickly.

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If you think of a heart rate of 60 beats per minute, the heart is beating once every second, pushing or expelling blood out.  Within that period of time it is also relaxing to receive the blood from the previous beat. Both of these activities take approximately the same amount of time. The heart will expel blood in about one-half second and receive blood for about one-half second with a resting heart rate of 60 beats per minute. When the heart rate goes up to 120 beats per minute, the time now available to receive blood from the previous beat is one-fourth of a second.  When it beats at 240 beats per minute, the time is one-eighth of a second.

It is not possible to have a mechanical pumping action when the heartbeat becomes very rapid. Electrically, that rhythm can be recorded.  Therefore, the end result of atrial fibrillation is basically two-fold:

  1. Due to the lack of atrial contraction on a regular basis, the atrium now becomes a passive conduit of blood rather than an active pumper of blood. This leads to stasis. To use a common analogy, if you look at a running stream very few deposits or sedimentation occurs. If however, you look at a pool in which the water is not moving, much more sedimentation tends to occur. When the atrium becomes a passive conduit, more sedimentation occurs, leading to the formation of blood clots.

Blood clots are potentially disastrous because if they break off and circulate around the body they can cause a stroke.  Interestingly, about 80-90% of them end up in the brain.  Clots can create heart attacks if they go down a heart artery.   They can cause kidney damage if they go to a kidney artery, or gangrene of the leg if they end up in a leg artery.

Atrial fibrillation, because of clot formation, puts patients at higher risk for events like this. These are called embolic events. Embolic events occur when a blood clot breaks off from the heart and goes to another location.

  1. When the pumping function of the smaller chamber (atrium) is lost, the amount of blood being pumped by the heart is reduced. We physicians commonly refer to this as atrial transport mechanism.   This contributes about 15-30% to cardiac output and will vary depending on the underlying condition.  This leads to a reduction in the total amount of blood being pumped, creating symptoms such as shortness of breath, dizziness, and fatigue. Some patients may remain totally asymptomatic though they remain in atrial fibrillation.

 

Atrial fibrillation can be caused by a variety of different conditions affecting the heart including: high blood pressure (hypertension), coronary artery disease, or blockages in the heart arteries.  It can also be caused by cardiomyopathy, or changes in the heart muscle function, congestive heart failure, or valvular heart disease affecting the major valves of the heart.  Certain other extra cardiac conditions such as hormonal changes related to excessive thyroid function or thyrotoxicosis can also cause atrial fibrillation.

Treatment with Warfarin:

Treatment of atrial fibrillation with Warfarin has been the gold standard for many years. Warfarin, interestingly, was discovered at the University of Wisconsin-Madison by Dr. Link from the School of Veterinary Medicine. The word “warfarin” refers to Wisconsin Alumni Research Foundation. This drug has been available as a generic for many years. Warfarin has been shown, in multiple studies, to be extremely effective in reducing the risk of stroke that occurred in patients with atrial fibrillation.

Unfortunately, Warfarin carries some risks itself. It is well known that patients who take Warfarin carry the risk of a stroke at approximately 1-2% per year.  Despite the best expectations and best practices, the levels of Warfarin may fluctuate from time to time and bleeding may occur. Bleeding inside the brain can, itself, cause strokes and this is a potentially very serious, perhaps, even fatal complication of Warfarin therapy. This has been well recognized by the medical community for many years and a test is available, called the INR, to monitor this.

Physicians frequently order this test once per month or more often to regulate the level of Warfarin and effect of blood thinning.  If your blood is thinning too low on the test, you are not getting the proper effect.  If it is too high, there is a risk of bleeding which can include bleeding inside the brain. This is the major pitfall of using Warfarin.

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The advantages of using Warfarin:

  1. It is a well-known drug in use for many years.
  2. It is relatively inexpensive. In many pharmacies it is available for as little as $4 per month.
  3. The drug can be monitored using a blood test called the INR, though this does require occasional trips to the hospital or clinic to have this blood level checked.
  4. It has been shown effective in many studies at reducing the risk of strokes in patients who have had atrial fibrillation.
  5. Your cardiologist decides which patients with atrial fibrillation need anticoagulation or blood thinning with Warfarin.

The downfalls of using Warfarin:

  1. The levels of Warfarin fluctuate from time to time.  They may fluctuate as a result of changes in dietary habit.  For example, consumption of certain leafy green vegetables increase the level of Vitamin K in the body which can make Warfarin less effective.
  2. Consumption of alcohol can also influence the drug in an adverse fashion and can increase the blood thinning effect.
  3. Many other drugs interact with Warfarin. Common antibiotics used for minor infections can raise the blood thinning level and lead to bleeding.
  4. Many interactions can occur with other medications that are used commonly over the counter. Ibuprofen, Naprosyn, and Advil can also potentiate the bleeding effect of Warfarin.
  5. Warfarin requires a blood test to monitor levels which means time, energy, and money in terms of having to go back and forth to get blood levels checked. Results need to be called from the doctor’s office, or a visit may be necessary if the dose of Warfarin must be adjusted.
  6. Despite adequate utilization of Warfarin blood levels and monitoring, there still remains an approximate 1-2% risk of excessive bleeding at different sites. One of these sites can be the brain which can lead to significant hemorrhage or bleeding, which can often be fatal. This is the most dreaded side effect of Warfarin. If Warfarin blood thinning is too much, a medication is available called Vitamin K, which can be administered to patients to reverse the thinning effect. Blood transfusions and/or surgery may also be required in some cases of bleeding.
  7. Patients with liver problems or with less than optimal liver function also do not tolerate Warfarin well and may be at higher risk of bleeding. Patients who are taking medications that affect the liver will also require particularly aggressive monitoring. Patients who have had heart stents placed are placed on drugs that help prevent blood clots in these stents; these drugs often interact with Warfarin and need to be treated with great caution by the treating physician/cardiologist.

It is extremely important to realize that virtually all decisions in medicine are made on the basis of looking at risk and benefit.  As with the old saying, “there is no free lunch”, there is virtually no medication or procedure in medicine which is completely free of risk and is completely beneficial to the patient. One must, on a constant basis, assess the risk and the benefit.

From a physician’s perspective, one would want the risk to be low and the benefit to be high. In other words, the risk-benefit window should be in favor of the patient, as that is when the best decisions are made. Even when such risk assessment has been carried out, there are circumstances beyond a physician’s and beyond the patient’s control which can adversely influence matters.

If a patient is on a blood thinner and is in a car accident, they may bleed much more. This is an outside factor that can influence side effects and complications which cannot be accounted for in the normal risk-benefit analysis.   Also, probability only allows an assessment of what the risks are. Reality may be very different.  It is easy to say that the risk of mortality for a certain surgical procedure is only 1%. One out of 100 sounds fairly safe. Of course 99% of the patients will do very well but for that one patient who dies as a result of the procedure, the risk is 100% for that particular individual. This also must also be taken into account.

PradaxaII

The First New Agent, Dabigatran Etexilate or Pradaxa:

Circa year 2000, the first new challenger to Warfarin appeared on the scene. This is nowadays marketed as Pradaxa. In a famous trial called the RELY Trial, it was demonstrated that for the first time in the history of medicine there was a new medication that competed effectively with Warfarin. This medication had the following advantages over Warfarin:

  1. It reduced the risk of ischemic stroke or a clot causing a stroke in the brain after traveling from the heart a further 24% over patients treated with Warfarin. In other words, there was a drug superior to Warfarin, which had been the gold standard until then, in appropriately preselected cases, for reducing the risks of ischemic stroke.
  2. The risk of overall bleeding, which was a side effect of Warfarin, also occurred with Pradaxa at about the same rate as with Warfarin. There were, however, salient differences. The most dreaded complication of bleeding inside the brain was reduced in comparison with Warfarin by 74%. In addition, there was a higher risk of bleeding from the gastrointestinal (stomach/intestines). The risk of GI bleeding in the study was in 1.6% of patients treated with Pradaxa versus 1.1% in those treated with Warfarin. The risk increase was significant.
  3. Patients who were placed on Pradaxa did not require monitoring of INR. In a very large study of approximately 18,000 patients, which were randomized to Warfarin and different doses of Pradaxa, it was demonstrated that treating these patients led to a result in which, without any monitoring, patients treated with Dabigatran did better than with Warfarin. Remember, Warfarin levels fluctuate, varying from population to population and from individual to individual. These levels were monitored very carefully in this study.

Approximately 64% of the patients had a level of blood thinning reported as optimal.  This means that approximately 64% of the time patients taking Warfarin in this trial and being watched very closely had a level of blood thinning neither too low nor too high. This actually compares very favorably with other trials of Warfarin, which despite the best use by patients and physicians, the level of TTR has been closer to 40-50%. In other words, in the RELY Trial, the patients taking Warfarin were doing better in terms of keeping their levels optimally blood thinned as compared to historical controls.

Despite this, there was risk of bleeding.  Pradaxa reduced the risk of intracranial hemorrhage, a potentially fatal complication, by 74%. There was also a movement towards some reduction in vascular death in patients who received Pradaxa rather than Warfarin. This effect was small and estimated at approximately 15%.

One unfortunate effect that was noted was that there was a slightly higher incidence of heart attack or myocardial infarction in patients taking Pradaxa as compared to Warfarin. This was approximately 0.7% in the Pradaxa patients versus 0.6% in the Warfarin patients.

Not particularly significant, this was an unexplained event and was pointed out to physicians.   Physicians were expected to point this out to their patients and to keep this in account when prescribing this drug.

Pradaxa falls into a class of drugs called Direct Thrombin Inhibitors which affect blood thinning in a directly simpler fashion than does Warfarin.  Pradaxa is not indicated for patients who have artificial heart valves or severe valvular heart disease which is felt to be hemodynamically significant by their physicians.   This drug was also approved for use for blood clots in the leg known as deep venous thrombosis and for clots in the lungs that move from the legs called pulmonary embolus.

Other Factor Xa Inhibitors:

The introduction of Pradaxa was soon followed by a group of three other drugs which are respectively called the following: Xarelto or Rivaroxaban, Eliquis or Apixaban, and Savaysa or Edoxaban. These are all Factor Xa Inhibitors which again act very uniquely on a single part of the coagulation cascade. In general, these drugs offer the following advantages:

  1. Lack of monitoring just like with Pradaxa.
  2. Roughly equivalent bleeding rates though slightly higher rates of bleeding from the gastrointestinal tract.
  3. Dramatic reductions of bleeding inside the brain.
  4. Equality or non-inferiority with Warfarin in preventing ischemic stroke.
  5. Some of the drugs may be taken on a once-a-day basis rather than twice-a-day basis as with Pradaxa. Many of these drugs are also approved for deep venous thrombosis and pulmonary embolus.

Choice of Agent for Blood Thinning:

Physicians decide, in consultation with their patients, which is the best drug for providing blood thinning.  A patient that has been on Warfarin, is well controlled, has not had any bleeding problems, and is on a stable dosage regimen the patient understands well, likely does not need to be switched from Warfarin.

Persuasive arguments can be made that in other drugs one may be able to get more efficacy than Warfarin in preventing ischemic stroke.   Monitoring problems are eliminated. There is equivalent risk of bleeding with the exception of bleeding from the gastrointestinal tract, but dramatic reduction of bleeding inside the brain.  All of these are effects that physicians need to consider when prescribing an agent.  Patient’s individual conditions, other drugs, and drug interactions often influence this decision making.

It should be noted that the newer drugs are much more expensive than the older ones.   They may cost anywhere from $100-$300 per month depending on insurance coverage or lack thereof, the insurance plan, and which drug is being prescribed. The older drug, Warfarin, is available at much lower cost.

The decision as to which drug to use in the setting of atrial fibrillation is not an easy one.   Cardiologists and/or physicians taking care of their patients need to make a careful decision looking at the risk and benefit ratio for each individual patient to see who would do best on which drug regimen. The risk-benefit analysis is a unique one and needs to be carried out on an individual basis and in an individual patient may change over a period of time.

None of these drugs currently has a reversal agent such as Warfarin.  The half-life of the drugs is relatively short and stopping them leads to a cessation of the effect of bleeding. This is also well highlighted and well understand by physicians utilizing these drugs.

Reporting Mechanism/Reporting Requirements:

In cases of mortality, physicians fill out a death certificate. The certificate also asks for other comorbid conditions which may have led to mortality. For new approved medications, there is also a self-reporting mechanism in which drugs that have been known to cause bleeding and/or mortality are reported to Federal Authorities.

Older drugs, such as Warfarin, are infrequently reported as contributing to mortality because physicians know that this drug is associated with the risk of bleeding and mortality. There is a natural tendency to over report all the newer medications and under report all the older medications such as Warfarin. This reporting bias needs to be taken into account before looking at data that suggests that the mortality and bleeding rate of the newer drugs is higher than Warfarin.

Medicare did a retrospective trial of approximately 120,000 patients who had received the new anticoagulant drug, Pradaxa.  It found that there was really no significant difference in risk of bleeding versus Warfarin as far as Pradaxa was concerned and it was concluded that:

  1. Pradaxa further reduced risk of ischemic stroke as compared to Warfarin as had been shown in the RELY Trial.
  2. The risk of all bleeding was virtually similar to that of Warfarin.
  3. The risk of bleeding inside the brain, the catastrophic intracranial hemorrhage, was significantly and substantially reduced.
  4. There was a higher risk of bleeding in the gastrointestinal system when patients took Pradaxa rather than Warfarin.
  5. Most interestingly, the small difference in heart attacks, 0.7% for Pradaxa and 0.6% for Warfarin, that had been shown in the RELY Trial was no longer present and this larger group of patients, 120,000, demonstrated no difference in risk of heart attack between Pradaxa and Warfarin.

 

This data suggests that the conclusions drawn by the Milwaukee Journal Sentinel, though interesting, should not panic patients. The importance is to provide the public with a balanced view.

Recommendations:

We strongly recommend that patients do not stop their blood thinning agent without consulting their physicians.  Most patients will find this article, which is perhaps a more balanced view, reassuring and should have a conversation with their physician regarding this.  Any of our patients who wish to have a further conversation, please feel free to call our office and schedule an appointment.

 

 

Sanjay Singh, MD