Stroke

Young people, stroke and a hole in the heart (PFO)

September 28, 2017 By Dr John

(This post introduces my latest column on TheHeart.org | Medscape Cardiology. It’s about stroke in young people.)Â

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We define stroke as the death of brain cells. The typical cause is a blocked blood vessel in the brain. Stroke usually occurs in older people who have established blood vessel disease. Stroke is bad; it may be the worst outcome in all of medicine. That’s because stroke can permanently remove basic functions of being human, things such as speech, thought, personality, movement, swallowing, and many others.

Stroke is not supposed to happen in young people. But sometimes it does. And in some of these cases, the cause may be due to a hole in the heart or patent foramen ovale (PFO). This membrane of sorts can allow blood to flow across the right and left atrium.

From AHA

What experts think happens in PFO-related stroke is that a clot from the venous system (say, from prolonged sitting or some other reason) travels from the right atrium across the PFO into the left atrium. That’s bad because LA clot goes to the left ventricle and gets pumped out into the body to lodge somewhere. (Since it is a straight shot from heart to brain, clots in the heart usually lodge in the brain.)

But get this: about one in four humans have a PFO. Please read that again. One in four. So it’s completely normal to have a PFO. I see this all the time when doing AF ablations. Sometimes the catheter goes right across the membrane without help from the needle.

The tricky question, therefore, is what to do about a young person–with a PFO–who presents with a stroke and no other obvious cause is found. No vascular disease; no AF, no evidence of abnormally thick blood. Nothing. Just the PFO.

Was the PFO the cause of the stroke or was it incidental–remember, PFO occurs in one in four people.

One idea for treatment is to place a device used to plug much larger holes in the heart (called atrial septal defects) to plug the PFO. Then if the connection is blocked no clots could get from the veins to the arterial side.

The other way to prevent venous clots from causing strokes is to use clot-blocking drugs, such as aspirin or warfarin or the new anticoagulant drugs called NOACs.

These are two different strategies: one is mechanical blockage and the other is medical inhibition of clots forming in the first place.

Three recent studies published in the NEJM compared PFO-closure to clot-blocking drugs in young people with stroke of unknown cause. All three studies showed favorable results for PFO closure. This was a reversal of sorts, as three previous studies on this question had been negative.

The title of my column isÂ Positive Results for PFO Closure Come With Caveats. (You need to give an email to read this.)

In this piece, which is written for a medical audience, I introduce the background, summarize the three NEJM papers, compare the new PFO studies to the old ones, and then offer comments on how to translate this evidence to the care of younger people with stroke.

The take home is this:

If a person with a stroke has a large PFO that can shunt blood from right to left (often, this can be seen during an echo) and a thorough search for other causes of stroke comes up negative, then it’s reasonable to discuss closure.

But … even though the trials were positive, this is a hard decision. Why?

Two reasons are that the differences between PFO closure and drug therapy were tiny–in the range of a few percent or less. Â AndÂ the procedure comes with the risk of serious harm, about 2-6%.

The biggest uncertainty, however, was the comparison to aspirin. Yes, in the three trials, the closure device was better than aspirin, but everyone knows aspirin is lousy therapy for clots in the venous system. When people have venous clots (sometimes called DVT or deep venous thrombosis or VTE, ie venous thromboembolism), doctors choose drugs that block coagulation, such as warfarin or the NOACs.

In the end, I don’t know the right answer. I often think: what would I do if it were me? Would I have a foreign body put in my heart, or, would I take an anticoagulant drug? I am not sure.

The key here will be slow decision-making. Patients will need doctors to go over the nuances of both choices. It’s not a simple call.

JMM

New Data Increase Caution on Left Atrial Appendage Occlusion

June 27, 2017 By Dr John

I remain concerned about the irrational exuberance among some of my colleagues toward left atrial appendage occlusion devices for the prevention of stroke in patients with atrial fibrillation.

In short, these devices are plugs that doctors place into the left atrial appendage. The idea is to stop clots from forming or escaping from the left atrial appendage. It was a good theory because the appendage can be a place that harbors clots.

One of the barriers to overcome with these plugs is prevention of clots on the device. The plug sits in the left atrium exposed to the low flow of blood in that chamber.

Foreign bodies exposed to blood leads to clotting; it’s exactly why metal stents used in coronary arteries render the person dependent on potent clot-blocking drugs.Â The appendage plug, too, needs drugs to prevent clots from forming on it.

Here’s the problem: many of the patients getting these devices are getting them because they have had major bleeding events while taking anticoagulants like warfarin or NOACs.They are deemed ineligible to take drugs that block the body’s clotting system.

But anti-platelet drugs, e.g. aspirin, can cause bleeding–especially in the elderly. See the BAFTA trial.(Ref below).

Two studies chosen as featured presentations at the European Heart Rhythm Meeting did not deliver any reassurance of these devices.

Both studies looked at real-world data on how the device performs when used by regular doctors outside the clinical trial.Â Real-world observational studies are important because a therapy (drug or device) may not deliver the same outcomes when used outside the protective confines of a trial.

A French study took data from numerous centers in an effort to study the presence of clots on the device, and the influence of anti-clotting drugs to prevent these clots.

A German study, sponsored by industry, also looked at the presence of clots as well as overall complications from the procedure. This study took data from more than 61 centers across the world.

The details of the studies are included in my column:Â Real-World Data on Left Atrial Appendage Closure Does Not Reassure

The gist of these studies was that clots on the device are not rare; potent clot-protecting drugs are likely required to prevent clots (at least for a period of weeks-months); the presence of clots increase the risk of stroke, and finally, major procedural complications are in the range of 4%.

These findings bolster my already cautions approach to this procedure.

Remember, left atrial appendage closure is a preventive procedure. Its benefit is a probabilistic one in the future. If you start with a 3-4% major complication rate, future risk reductions have to be higher than that to deliver a net gain. Thus far, the data from the randomized controlled trials don’t show that it is.

Why my colleagues are speeding ahead with this risky procedure is hard for me to understand. The conclusion of my analysis of these two most recent studies is that we need a head-to-head comparison of the device versus no therapy in patients who cannot take clot-blocking drugs. My prediction is that the device will be no better or worse than no therapy.

JMM

Reference:

Mant J, Hobbs FDR, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. The Lancet.370:493-503.

(Note, I do not use the term blood-thinner. Anticoagulants (warfarin and NOACs) and anti-platelet (aspirin and clopidogrel) drugs do not thin the blood; they inhibit parts of the normal clotting system.)

How important are short AF episodes?

May 25, 2017 By Dr John

A study presented at the recent Heart Rhythm Society meeting in Chicago has added more uncertainty about the significance of short-duration AF episodes.

Before I tell you about the study, I need to clarify what I mean by short-duration AF episodes, sometimes called subclinical AF (SCAF).

SCAF is AF on a monitor that is often not felt by the patient. Doctors are seeing more of this because patients are increasingly being monitored–with pacemakers, ICDs, long-term event recorders and implantable cardiac monitors. These devices can pick up minute-long or hour-long AF episodes.

In the past, AF could only be picked up when there were symptoms that prompted an office visit or the AF lasted long enough to be recorded on a standard ECG. We call this clinical AF. And, importantly, patients with this type of AF were enrolled in clinical trials that showed benefits from taking anticoagulants (warfarin and NOACs).

In 2017, there is no clinical trial evidence that treating short-duration AF (SCAF) with anticoagulants confers benefits. These studies are ongoing.

Now to the new study. It’s called the REVEAL-AF study. This Medtronic-funded study was simple. They took about 400 older patients who had no known AF but risk-factors for getting AF and stroke (high-blood pressure, diabetes, obesity, age > 65, etc) and put Medtronic-branded internal cardiac monitors in them. (The tiny and expensive monitors can be injected under the skin in minutes under local anesthetic.)

Get this:

In patients with no known history of AF, REVEAL AF researchers discovered â‰¥ 6-minute episodes of AF in 30% of these patients over 18 months. Over 30 months, 40% of this group had short-duration AF. Remember, these were people without known AF.

This revelation is disruptive to the status quo because that is nearly exactly the incidence of short-duration AF that we find in patients who have just suffered a stroke of unknown causes.

Three-years ago, the CRYSTAL AF study launched the widespread use of expensive internal monitors by finding short-duration AF in about 30% of older patients who had just had a stroke of unknown cause. The thinking in 2014 went–we have to look for AF in these patients who just had a stroke because if we find AF, then we can prevent another stroke by giving anticoagulant drugs.

Well, hold on.

There are problems with this thinking. First is the REVEAL AF study that I just told you about. REVEAL AF says the average old person with risk factors (millions of these people) will have short-duration AF. That’s the same incidence of those with stroke.

The second problem with the search for short-duration AF comes from a recent analysis of the ASSERT study. In the original ASSERT study, published in 2012, researchers found short-duration AF recorded in cardiac devices (pacers and ICDs) increased the odds of a stroke by 2.5-fold.

But the new look at the ASSERT study found that only AF episodes lasting â‰¥ 24-hours associated with stroke events. Other studies confirm these findings–namely that only longer-duration AF increases the risk of stroke.

As I concluded in my column posted on theHeart.org | Medscape Cardiology,

“The more we learn about stroke prediction, the less valuable short-duration AF looks as a surrogate marker. Perhaps we should be looking deeperâ€”at the reasons why the atria fibrillate or other systemic/genetic factors.”

Finally, I want to copy part of a comment on my article from Dr. Paul Dorian, a thoughtful Canadian cardiologist who “warned about relentless seeking of information when we do not know how to deal with the data the screening tests provide, especially since there is likely harm from a diagnosis of SCAF ( anxiety, possible therapy adverse effects, insurability, a label of illness, cost, etc.)”

The title of my column is REVEAL AF Dampens Excitement for the Search for Short-Duration AF

JMM

The column over on theHeart.org | Medscape Cardiology has 11 references.

Less is more in atrial fibrillation stroke prevention — please, drop the aspirin

September 30, 2014 By Dr John

A recent study in the Journal of the American College of Cardiology shed more light on the commonly used drug combination of aspirin and a vitamin-K antagonist (such as warfarin).Â It was a small registry study from one region of France but I believe it offered confirmatory evidence against this dangerous practice.

Investigators followed patients with stable coronary artery disease (no recent events) for 2 years to assess the incidence and outcomes of major bleeding episodes. They found that overall rates of major bleeding were less than 1%, but those patients on the combination of aspirin and an anticoagulant drug were almost five times more likely to suffer major bleeds. In fact, the combination was the major predictor of bleeding–more than two-fold greater than diabetes.

The reason why I point you to this study is that the practice of combining clot-preventing drugs in patients with AF is one I see so frequently. And I’m not an outlier, registry studies suggest up to 40% of AF patients are taking the combination.

This is a bad idea. It needs to stop.

The French study aligns well with prior evidence on combining drugs. In March of 2013, I published this review of the existing data on theHeart.org. My conclusion was that, in the great majority of patients, there was no evidence for added stroke protection but there was a compelling signal of higher bleeding. Only three subgroups of patients fell out of this general statement. The ratio of benefit to harm may be positive in patients with AF and mechanical heart valves, AF and recent stents or AF and recent acute coronary syndrome. That’s it.

The vast majority of AF patients taking this combination likely should not be.

I do a lot of deprescribing these days. Aspirin, when used in AF patients who are on anticoagulant drugs, is perhaps the most common drug I deprescribe.

Look at the data yourself and see if you come to a different conclusion. My article on theHeart.org has references.

JMM

Is it safe to take aspirin and warfarin together?

March 7, 2013 By Dr John

The ultimate goal in medicine: protect the patient from stroke. Even a heart doctor has to admit the dominance of the human brain.

Always think about preventing stroke. It’s one of the worst outcomes that can happen to a person. Life as a ‘normal’ human requires a healthy brain. A stroke irreversibly kills off part of the brain. Stuff you take for granted can go away: swallowing, speaking, understanding language, sight, movement of a limb, not drooling, and the list goes on.

The most common cause of stroke is ischemic–meaning a blocked blood vessel leading to the brain or in the brain itself. A common cause of ischemic stroke is embolic–or when a clot breaks off from somewhere else and travels north to the brain, lodging in an artery.

Aside from living a healthy lifestyle from the get-go, one of the best ways to prevent these catastrophes is to use drugs that inhibit clotting. Aspirin and clopidogrel (and others now) inhibit platelets from sticking together. We call them antiplatelet drugs. Warfarin, dabigatran (Pradaxa), rivaroxaban (Xarelto) and apixaban (Eliquis) block parts of the coagulation cascade and we call them anticoagulants. (The term â€œblood-thinnersâ€ is also used for these drugs, but itâ€™s not really accurate, because they do not change blood viscosity.)

The problem in giving these drugsâ€”like any drugsâ€”is the tradeoff. On the one hand, the benefit is prevention of clots and strokes, but on the other is the risk of bleeding. The key is finding the right balance, picking the right patient and then discussing risk-tolerance with the patient. Remember, we donâ€™t use the word â€˜need.â€™ We talk about balancing benefits and risks and then we share the decision.

It turns out, rightly I think, that most medical doctors lean heavily towards stroke prevention. They know how awful strokes can be. And this thinking has led to combining these two classes of drugs.

Intuitively, the combination makes sense. The oral anticoagulant (OAC) takes care of “red clot” (cardioembolic) that occurs in low-flow states like atrial fibrillation and venous thromboembolism, and the antiplatelet drug treats the “white clot” associated with atherosclerosis. Cover the bases. Protect the patient.

Call this the ‘more is better’ approach. But these days, as many of you know, the new movement favors a ‘less is more’ approach. I spent a couple of weeks looking into the matter of combining aspirin and another anticoagulant. I figured that since the combination was so commonly used, there must be an extensive evidence base in support.

Here is what I have come up with. It was surprising.

You can read my survey over at theHeart.org: A dangerous cocktail: Aspirin and anticoagulants

JMM

Apixaban (Eliquis) gets FDA approval

December 29, 2012 By Dr John

Yesterday afternoon, the FDA finally approved apixaban (Eliquis) for the prevention of stroke in patients with non-valvular atrial fibrillation. I use the words ‘finally approved’ because the markedly positive ARISTOTLE trial was published 15 months ago in the New England Journal of Medicine. The long delay was mysterious.

On paper, apixaban looks to be the strongest of the three warfarin-replacement agents (dabigatran (Pradaxa) and rivaroxaban (Xarelto) being the other two). Here is an old post of mine that generally outlines the three.

In the ARISTOTLE trial, (nicely covered here on theHeart.org) apixaban at a dose of 5 mg twice daily was compared to warfarin in 18,000 patients. Apixaban statistically bested warfarin in three major categories:

Lower rates of stroke*
Lower rates of overall bleeding, with much less intracranial bleeding.
Improved mortality.

The asterisk on stroke reduction is the major criticism of apixaban. Let me explain: Apixaban did indeed lower the overall rate of stroke, but the reduction was driven by fewer hemorrhagic strokes. Ischemic strokes–those caused by clots or blocked blood vessels–were similar in both groups.

This phenomenon may be specific to Factor-Xa inhibitors, as it was also seen with rivaroxaban in ROCKET-AF. Dabigtran, on the other hand, reduced both types of strokes.

Critics of novel anticoagulants will view this subtle finding as a knock against Factor-Xa inhibitors. They say an anticoagulant should work by reducing clot-related strokes. And no doubt, Boerhinger-Ingelheim (makers of dabigatran) will use this as a talking point to favor dabigatran.

Of course, for you or me, as a patient, what matters most is not the mechanism of brain injury; it’s simply not having one. Overall stroke reduction seems to be the most important measure.

My take home:

This is a big development. Apixaban looks strong. It’s the only drug of three that statistically lowered mortality–the ultimate metric.

Novel anticoagulants really started to take off in 2012. Most of the growth was with rivaroxaban. The once-daily drug is well-tolerated. Unlike dabigatran, rivaroxaban does not cause GI symptoms. This difference doesn’t seem like much in the pages of the NEJM, but in the real world, it’s huge. The other tailwind for rivaroxaban was the “bad drug” commercials knocking dabigatran. Patients see these ads, and they have had an effect.

Assuming apixaban is priced competitively, I see it moving in immediately and being a major player. Its displacement effect on the other two agents is hard to predict. On the one hand, you could argue that doctors will choose apixaban over dabigatran because of its lack of GI side effects and over rivaroxaban because of its superior data. But on the other hand, another warfarin-replacement agent will surely grow the pie larger.

A final issue: One area that comes up a lot is what to do with anti-coagulants in the time before and after AF procedures, like cardioversion and ablation. Here, we have tons of data with warfarin, a little with dabigatran and essentially none with rivaroxaban and apixaban. Given that many AF patients get started on these drugs with an eye towards rhythm-control, this is an important topic to pay attention to. I look forward to hearing more about the peri-procedural safety of the Factor Xa inhibitors.

It’s an exciting time in the treatment of atrial fibrillation.

JMM

New Trials and Fibrillations post up: Thoughts on left atrial appendage occlusion to prevent stroke in AF

August 27, 2012 By Dr John

There was a lively debate on this topic at ESC 2012.

One of the strategies proposed to reduce stroke in AF involves occlusion of the sack-like structure called the left atrial appendage. Two devices are being evaluated and nearing consideration for approval. There is a great deal of debate on these devices.

Here is my recap yesterday’s session.

ESC 2012: Left atrial appendage closure is NOT the therapy of choice for many patients with AF?

JMM

What’s the best blood thinner for AF ablation?

February 2, 2012 By Dr John

Letâ€™s get off cell biology and back to something I really know.

Atrial fibrillation, AF ablation and blood thinners.

There was an important study published today in the Journal of the American College of Cardiology concerning the use of the new blood thinner, dabigatran (Pradaxa), around the time of AF ablation. A very concise overview, including a quote from a blogger, can be found on Cardiobrief.

Basically, Dr Nataleâ€™s group reported that patients who underwent AF ablation while taking dabigatran did less well than a group managed in the usual way with warfarin. The most concerning finding was that dabigatran-treated patients had a higher risk of stroke after ablation.

The increased popularity of non-warfarin blood thinners has injected yet another challenge to AF ablation: how best to prevent the most-feared complication of AF ablation, stroke.

Before there were alternatives to warfarin, AF ablation-ists all had a plan for protecting the 50 or so scabs in the left atrium from forming clots and then stroke. This is the issue with ablation; to electrically wall off areas of the atria, we make burns. Burns must heal, and healing means scabs are exposed to blood.

Most AF centers ablate AF without interrupting warfarin. (Notably, this protocol originated from Nataleâ€™s group.) Other centers favor bridging with IV heparin or subcutaneous low-molecular weight heparin. The point was: we all had a protocol that worked.

Now, the new blood thinners have jostled the AF ablation world. AF patients get started on dabigatran, and most recently, rivaroxaban and soon, apixaban. These drugs are blood thinners; they have solid evidence to support their efficacy, safety and perhaps superiority to warfarin in AF. Butâ€¦there are important issues pertaining to AF ablation.

One is the issue of adequate blood thinning in the weeks before the procedure. With warfarin-treated patients, we can check a weekly INR test to confirm that the drug has indeed thinned the blood. The doctor doing the burns knows the status of the blood. With the new blood thinners, however, this confirmation isnâ€™t possible. Only the patient knows. Some AF doctors arenâ€™t comfortable with trusting that their patients have taken the pills exactly as directed. This uncertainty leads these doctors to recommend a trans-esophageal echo (TEE) before the ablation. I hate this idea because it means doing another procedureâ€”one that entails sticking a thick probe down the throat and esophagusâ€”before the ablation. One that wasnâ€™t needed with the warfarin protocol.

Another procedure-related issue with the new blood thinners stems from their lack of an antidote. If the heart is perforated during the procedure, bleeding in the chest could be worse. Moreover, how does one get catheters out of the leg veins while the blood is fully thinned on dabigatran? These concerns have been answered with warfarin. Good studies and years of experience have taught us that ablating with warfarin is both safe and effective.

Finally, many experts posit that the increase in procedure-related strokes with dabigatran described in Dr Nataleâ€™s study occurred because of a short window after ablation where the blood was not thin. Maybe. But maybe it was just chance? Or maybe the patients missed some doses?

Enough about the minutia.

What are the larger messages of this seemingly focused issue?

Let me offer three that I find compelling:

Non-warfarin blood thinners are marketed as simpler and easier to use than warfarin. Maybe so in patients with AF that never need anything done to them. In the other 90%, the situation is different. These agentsâ€™ lack of an antidote, un-measurability of effect and dependency on patient compliance belie the notion that they are simple. In other words, the real world use of these drugs looks a little tricky.
Secondly. Is it bad that I like the idea that experts donâ€™t know what to recommend for peri-procedural blood thinners? In an editorial accompanying Dr Nataleâ€™s study, Dr Bradley Knight proposed 7 possible regimens. If there are 7 possibilities, this means no expert consensus or mandates are likely to emerge in the near-term. We doctors must think and judge. Thank goodness for that. Love judgment.
Finally, concerning my quote on Cardiobrief. The issue of protecting AF patients from stroke is our most pressing concern, whether it is around the time of ablation or not. I like simple. For now, in patients that I feel sure are taking dabigatran correctly, or in those at low risk of procedural stroke, I donâ€™t feel that a 290 patient study with only 3 events in the dabigatran arm should close the book on non-warfarin blood thinners around the time of ablation.

Before concluding, a comment on rivaroxaban: I know of no data on using rivaroxaban in the peri-ablation period. Since the prevailing thoughts of most AF doctors (rightly or wrongly) are that once-daily rivaroxaban isnâ€™t quite ideal, Iâ€™d be very uneasy about burning the left atrium with only rivaroxaban therapy. (Please note: these thoughts represent pure blogger speculation.)

Hope this helps.

JMM

Thanks to my friend and ace heart news journalist, Larry Husten (@Cardiobrief) for the prominent mention.

Female gender and stroke risk in atrial fibrillation: Know your CHA2DS2-VASc Score

October 25, 2011 By Dr John

You don't want this...

When it comes to the risk of stroke in atrial fibrillation, it pays to be a boy. Sorry, ladies.

An important question came up on my recent post on AF and stroke.

Why does being female give you an automatic point on CHADS2-VASc?Â I keep seeing it, but I donâ€™t see why that is.

It doesn’t seem intuitive that female AF patients should have more strokes. Why? AF should equal AF.

But it does matter. When it comes to AF and stroke, women are very different.

Here are three references that support the fact that female gender increases the risk of stroke in AF.

–First: This Italian study of 780 AF patients on blood-thinners, published in the British blood journal, Thrombosis Haemostasis, reported three main findings:

Female gender did not increase the risk of bleeding.
Female genderâ€”even when correcting for age–doubled the risk of stroke.
Females had more disabling strokes, including a three-fold greater risk of fatal stroke.

–Second: From the British Medical Journal (January 2011): This registry-based look-back Danish study of more than 70,000 AF patients between 1997-2006 showed that female gender alone increased the risk of stroke. Additionally, adding female gender with other moderate risk factors (high blood pressure, age > 65 and vascular disease) greatly accentuated stroke risk. It was a strong study due to the huge number of subjects.

–Third: The strongest study to date on gender-related differences in the risk of stroke in AF comes from the ATRIA study, published in 2005 in Circulation. Researchers form California and Boston looked back at more than 13,000 AF patients. They found that females had a 60% greater risk of stroke. The enhanced risk occurred at all ages and held up after correction for confounding diseases. Reassuringly, they also found that warfarin reduced stroke risk equally in females and males.

Data like this is why European AF specialists believe that female gender warrants a point on the CHA2DS2-VASc score.

AF patients and treating docs have to remember that stroke represents a devastating complication from AF. There exists many situations where one can live reasonably well with partially damaged organs; the brain is often not one of these. Sight, memory, speech, cognition, ambulation, and continence are all brain-controlled functions that directly relate to quality living. Stroke is to be avoided. And another thing to think about: though bleeding is a risk of blood thinners, bleeds rarely leave permanent damage. Bleeds can be treated and often are impermanent–unlike stroke.

Here are the pertinent risk factors for stroke:

C: Congestive Heart Failure (or a weak heart muscle; low ejection fraction)

H: High Blood pressure

A*: Age above 75

D: Diabetes

S*: Previous stroke or TIA (or clot)

V: Vascular disease (CAD, PAD, Aortic plaque)

A: Age between 65-74

Sc: Female gender

The data is clear; if one or more of these risk factors are present, the evidence strongly suggests thinning the blood with either warfarin or dabigatran protects one from stroke.

Hope this helps.

JMM

* – Represents very strong risks and warrant two points on the CHADS-VASc scoring system.

The new blood thinners and personal accountability

July 19, 2011 By Dr John

I recently came across a very important blog post on the use of the novel new blood-thinner, dabigatran (Pradaxa).

Fellow Kentucky cardiologist, and frequent TheHeart.org contributor, Dr. Melissa Walton-Shirley wrote this very detailed case presentation involving a cantankerous non-compliant rural patient with AF (atrial fibrillation) that sustained a stroke while â€œtakingâ€ dabigatran.

Dr. Walton-Shirley details the very commonly done procedure of cardioversion (shock) for AF. As she clearly points out, the most important safety feature of shocking AF back to regular rhythm entails adequate blood thinning before and after the procedure. Thin blood prevents the possibility of clots dislodging after restoring normal contraction to the top chambers of the heart (atria).

Herein lies the rub with dabigatran, and the two soon-to-be-approved non-warfarin blood-thinning agents, apixaban and rivaroxaban. In the past, with warfarin, the doctor was responsible for confirming a patientâ€™s compliance. This task was easy on the doctor: patients come in for weekly INRs before and after the shock. If an inadequate INR was found, the procedure was postponed. Responsibility was squarely on the doctor.

But the irony of the new blood-thinning drugs is that their most attractive feature, convenience of not needing frequent blood tests, shifts the burden of responsibility to the patient. Because these new blood-thinners do not reliably affect any measurable blood tests, the doctor cannot know whether the patient has had an adequate period of blood thinning before (or after) shocking the AF back to rhythm. Only the patient can know. In a RE-LY sub-study, cardioversion with dabigatran was found to be safe, but these were study patients, not cantankerous patients that â€œa secretary had to deploy the National Guard to locate.â€

In Dr. Walton-Shirleyâ€™s case, she took the patient at his word: that he was taking dabigatran before the shock. But after he suffered a stroke less than 24 hours later, both circumstantial and real evidence suggests that he was non-compliant with his regimen of dabigatran. Fortunately, the patient recovered well from his stroke, albeit with a rocky course.

Dr. Walton-Shirley goes on to dissect the case. She writes about three lessons that could be learned in this case. It’s an important discussion.

Role of TEE (trans-esophageal echo) before the case:

She mentions the possibility of searching for a clot inside the heart by doing a TEE before the shock. The problem here is that doing a TEE means sedating a patient and sticking a very large rigid black tube into the esophagus. This far from non-invasive procedure is not needed in patients who have adequate blood thinning before the shock. In her case, the patient ended up with a severe complication from a TEE at an outside institution. She rightly concludes that TEEs are not the answer to confirming patient compliance.

Role of measuring the PTT (a common measure of blood-thinning) pre-shock:

Though it is true that patients that have taken dabigatran the day before the procedure have elevated PTTs, it does not in anyway confirm that the patient was taking the drug for the prior 3 weeks. Nor does it imply the patient will take the drug after the shock, which is of equal significance.

The general concept of using dabigatran in patients non-compliant with warfarin:

After this case, Dr. Walton-Shirley writes, “I will never utilize dabigatran in a patient with a history of poor or marginal compliance, because even if their PTT is adequate at the time of cardioversion, there is no guarantee they will be taking it regularly in the future or that they’ve been compliant with it consistently.”
Few could disagree with that statement.

I commend Dr. Walton-Shirley for writing such an important case report.

My comments on the case are as follows:

The new paradigm that these novel blood-thinning drugs have created represents a seismic shift for doctors and patients. For doctors, we have to decide, no, call it judge, perhaps even trust, that our patients will comply with taking an expensive drug that makes them feel no differently.

Doctors vary in the degree that they mother patients. Some will send the National Guard to locate a patient to get them into the office for their care, while others are of the ilk that think a patient needs to accept at least enough responsibility to get to the doctorâ€™s office for routine care. They take the view, if a person can afford 12$ per day for cigarettes, they can afford a ride to clinic. This notion of mothering will have a lot to do with how a doctor uses these new drugs. Do they want the responsibility (of confirming INRs), or is it okay for the patient to be responsible (for taking the drug as directed)?

Ultimately, preventing strokes with potent drugs that patients must take as directed, and doctors cannot confirm that they have done so, highlight three important criteria for good outcomes with any medical treatment:

The critical role of patient responsibility for their own health. Non-warfarin blood thinners place the onus on the patient. The conveniences of these drugs come with a hefty price: personal accountability.
The ever-important communication skills of the doctor in explaining the concepts of these novel drugs.
The requirement that doctors exercise sound judgment in deciding whether a patients can garner benefits from this very new paradigm of therapy.

Itâ€™s an exciting time to be an AF doctor.

Thanks to Dr. Walton-Shirley for sharing such an important case.

JMM

Rivaroxaban: The next non-warfarin oral blood thinner

July 5, 2011 By Dr John

The unrelenting epidemic of inactivity and excessive eating wreaks havoc on more than just the heart and blood vessels. Lugging around extra weight also breaks down the joints and back. For evidence, look no further than the waiting room of any orthopedist; the people waiting for joint replacements look the same as those waiting to see the heart doctor.

Bone doctors and heart doctors must deal with the problem of stasis (pooling) of blood in low-flow parts of the circulation. After joint replacements, blood can clot in the veins of the immobile lower extremities, and in atrial fibrillation (AF), clots may form in the non-contracting left atrium. Using blood-thinning drugs helps prevent complications in both scenarios. Until 2010, having thin blood meant enduring a sharp needle, or taking warfarin.

The good news for both patients and doctors is that the number of oral-blood-thinners in the US recently expanded from two (warfarin and dabigatran) to three possibilities.

Last week, the FDA approved once-daily rivaroxaban (Bayer and Johnson & Johnson call it Xarelto) for the prevention of venous blood clotsâ€”VTE or venous thrombo-embolism–in the setting of hip or knee-replacement surgery.

This highly specific indication gets the 10mg dose of rivaroxaban on the market.

But whatâ€™s far more anticipated is the (likely) approval of the 20mg once-daily dose of rivaroxaban for the prevention of stroke in patients with non-valvular AF. Larry Husten (@Cardiobrief) re-tweeted today that the FDA will meet in September to consider approving rivaroxaban for this purpose.

I see little reason to believe that the higher dose of rivaroxaban will not be approved.

The stroke prevention data on rivaroxaban are quite strong. The ROCKET-AF trial randomized (in a blinded fashion) more than 14,000 high-risk AF patients to either a single daily dose (20mg) of rivaroxaban or warfarin. The results were clear: AF patients that took rivaroxaban had fewer strokes and far fewer serious brain bleeds. (Very nice additional coverage of the Rocket-AF trial can be viewed on these posts at TheHeart.org or Cardiobrief.)

As the second non-warfarin blood thinner approved, Rivaroxaban shares many similarities to dabigatran:

Neither need INR monitoring;
Neither have means to measure the degree of blood-thinning–Doctors cannot confirm that patients are taking the drug as instructed, only the patient knows;
Neither requires patients to eat a special diet;
Both require lower dosages in patients with impaired kidney function;
Both have a short duration of action, and rapid onset of actionâ€”which has important implications for pre-andÂ post-surgical patients;
Neither have an antidote–but both have less risk of bleeding than warfarin.

And the differences…

Rivaroxaban is once daily, while dabigatran is twice daily–this may have important implications for compliance;
The metabolism of rivaroxaban may cause potential interactions with other medicines;
Rivaroxaban thins the blood differently–As a Factor Xa inhibitor, it blocks the coagulation cascade one step before the direct-thrombin inhibition of dabigatran.

And here are a few caveats and questions that come to mind:

–The Rocket-AF trial has yet to be published in a peer-reviewed journal. The data was presented in abstract form at last year’s AHA meeting. Look for a major publication soon.

–Will the slightly different manner in which Rivaroxaban thins the blood prove significant? So far, the two Factor Xa inhibitors, rivaroxaban and apixaban, were found ‘non-inferior’ to warfarin, while the direct thrombin inhibitor, dabigatran, was shown to be ‘superior.’ Is this related to trial designs, or, are they real differences?

–Rocket-AF randomized very high risk AF patients. More than half had a previous history of stroke (or transient stroke), and the average CHADS scoreâ€”a 6-point measure of stroke risk–was 3.5. As the current debate goes with dabigatran, it’s hard to know whether lower-risk patients doing well on warfarin should switch to rivaroxaban. Clinical judgement will play a large role here, so will patient choice.

–After approval of rivaroxaban, this question will naturally arise: Which is the best blood thinner? Watch for Bayer/Johnson & Johnson to posture the once-daily dosing of rivaroxaban as a major advantage to dabigatran. At the same time, Boehringer-Ingelheim will counter that dabigatran was shown superior to warfarin, rather than non-inferior. The intricacies of the two trials (RE-LY versus Rocket-AF) will provide infinite ways to compare the two drugs, but without a head-to-head comparison, we simply will not be able to declare a winner.

–It will not be long before the fourth oral blood-thinner is approved. Preliminary reports show that Apixaban, another Factor Xa-inhibitor, appears effective in reducing strokes in AF patients. Bristol-Myers Squibb and Pfizer recently announced (in a press release) that the 18,000-patient-strong Aristotle trial showed apixaban to be non-inferior to warfarin. An official presentation of the data awaits.

–Dabigatran has practical limitations: (1) Cost. Many patients simply cannot (or will not) pay for a drug that promises statistical benefits in the future. (2) The issue of compliance is both real and unmeasurable. I make judgements (often uneasy ones) every day on whether I think a patient can comply with taking the drug every 12 hours. Can, or did, the patient understand my instructions? (3) Dabigatran causes significant GI side effects–at minimum 10% of the time. The company says these are minor “nuisance” side effects. Maybe so, but I will tell you that sifting through symptoms of AF patients is hard enough, without adding a new pill to the mix. Is the AF patient feeling badly because of AF, or because of this new pill?

For now, AF patients at risk for stroke have a choice between dabigatran and warfarin. But there will soon be other choices.

Perhaps in my career, warfarin will be one of those treatments that doctors remember with words like this:

“…remember when we treated people with that ****”

JMM