Tag Archives: xarelto

Subclinical Atrial Fibrillation-Seek And Ye Shall Find, But What Then?

For those of us over age 55 years there is a lifetime risk of developing atrial fibrillation (AF) of 37%. and with AF comes a 5 fold risk of stroke which can be reduced by oral anticoagulant therapy.

Because up to 25% of AF is asymptomatic investigators have recognized a need to screen for AF in high risk individuals with the goal of reducing stroke. When AF is found in individuals without symptoms by screening or from monitoring a patient’s pacemaker it is termed subclinical atrial fibrillation (SCAF.)

Surprisingly, there is no consensus on 1)  whether we should screen for SCAF 2) if we should screen for SCAF, how should we do it 3) whether individuals with SCAF  found  by screening should be treated with oral anticoagulants just as we treat clinical AF patients.

Two presentations at the 2018 American College of Cardiology Meeting in Orlando shed some light on the problem of SCAF.

The mHealth Screening To Prevent Strokes (mSTOPS) study took a novel  approach to identifying and enrolling patients. Working with Aetna, invitations were sent by email or snail mail to over a 100,000 Aetna members who did not have a diagnosis of AF and who were over age 74 year or younger but with CHADS2 risk factors.

The members were directed to a website for information on the the trial and were guided through an enrollment process for informed consent. Half were randomized to early monitoring and half delayed monitoring at 4 months.

Immediate monitoring involved the patient being mailed a 14 day patch type monitor (Zio Patch, iRhythm Technologies Inc.) within 2 weeks of consenting to the trial. Patients in the delayed monitoring group received the patch 4 months after consent.

The primary endpoint was a new diagnosis of AF at 4 months,  defined as greater than 30 seconds of AF by ECG or a new diagnosis listed on Aetna claims data.

Patients in the immediate or early monitoring group were 9 times more likely to have AF diagnosed than those in the delayed group (prior to them wearing the Zio)).

Diagnosis of AF in these participants were then compared to 5,310 observational controls matched for age, sex and CHADS-VASc score who did not undergo screening.

At the end of one year 6.3% of the monitored group had been diagnosed with AF versus 2.8% in the observational controls, a highly significant 3 fold increase in AF detection.

More patients in the monitoring group were started on therapy and had more testing done (at the discretion of their physicians who were informed of the results at the patient’s discretion).

There was no difference in stroke, MI or systemic thromboembolism at one year between the two groups but clearly this study was underpowered and nonrandomized so differences would have been unlikely and if present hard to interpret.

Does Manner of Detection of AF Matter

AF detected by screening and AF detected only by implanted devices share many similarities. For both, if we seek them we shall find them (one study showed in patients with no history of AF undergoing new pacemaker implantation during a mean follow-up period of 596 ± 344 days, 77 (29%) patients had at least one AF episode lasting ≥ 5 min.

At another session at ACC18 two EP doctors debated whether  a high stroke risk individual with 9 minutes of an atrial high rate episode (AHRE) of presumed AF detected by pacemaker should receive anticoagulation.

I ended up agreeing with the CON side of this debate for most patients because

-device detected AF has a lower stroke risk (precisely how much unclear and related to CHADSVAS score (but I’m going with 1/3) than clinically detected AF

-The ASSERT study only showed increased risk for >24 hours duration of device detected AF (DDAF)

-Unlike clinical AF we have no randomized controlled trial data supporting treatment with oral anticoagulants for DDAF.

(Of note, funding for many studies in this area comes from either makers of monitor devices like the Zio patch (iRhythm) used in mStops or the Medtronic loop recorder used in LOOP which detect SCAF or makers of the blood thinners doctors would be prescribing if SCAF is detected (like Janssen the maker of Xarelto.))

I haven’t learned the answer to the 3 key questions I posed at the beginning of this post since 2018 but more information continues to emerge.

For example, the ongoing Danish LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring) study is a randomized, controlled trial, randomizing subjects who are ≥70 years of age and have ≥1 of the following stroke risk factors: hypertension (HTN), diabetes, heart failure, or previous stroke, in a 1:3 ratio to receive an implanted loop recorder (ILR) (Reveal LINQ; Medtronic, Dublin, Ireland) with continuous electrocardiographic monitoring via the CareLink Network, or to standard of care.

The early results published late last year are fascinating and worthy of more detailed discussion. Briefly, 35% of participants had SCAF lasting>6 minutes. However, the AF burden was low, and progression was limited. In addition, symptoms were scarce, and the heart rate was only modestly elevated during SCAF.

This graph shows the time course of AF (blue bars) before and after a first AF episode >24 hours. Contrary to the idea that AF gets progressively more frequent with longer episodes, the natural history of AF in these patients varied wildly. Many had no prolonged episodes for  months before or after the first prolonged AF episode.

The final results of this study will tell us if seeking SCAF is worthwhile in reducing cardiovascular morbidity and mortality.

I see patients daily with brief episodes of AF detected by their pacemaker of which they are completely unaware. Currently, after a discussion with the patient about the risks and benefits of anticoagulation in this situation I will offer the option of anticoagulation if episodes >24 hours are noted, recognizing the lack of scientific studies to guide us.

Ideally, patients with <24 hours of DDAF will be enrolled in ongoing randomized trials which will give us the correct answer to these difficult questions. Similarly, we desperately need randomized studies on the effects of screening for AF on long term outcomes.

Skeptically Yours,

-ACP

 

Why Does The TV Tell Me Xarelto is a BAD DRUG?

One of my patients called the office today concerned about a medication she was taking because she was “seeing about 4-5 commercials a day about how bad Xarelto is”.

She is the latest of many of my patients who have been inundated with ads like these which state in very strident tones that a drug is bad and that if “you or a loved one has had a serious bleeding problem” contact 1-800-BAD DRUG and see if you are eligible for compensation.

These drugs are not bad and the only reason these advertisements are being played is that tort lawyers sense an opportunity to make money.

To understand why they are flooding the TV market now I will have to give you some background on atrial fibrillation , stroke and the drugs available to reduce stroke risk.

Preventing Stroke Associated With Atrial Fibrillation

Patients with atrial fibrillation are at increased risk of stroke and since the 1950s the only drug available for doctors to reduce clot formation in the heart and susbsequent strokes was warfarin (brand name Coumadin). Warfarin is only effective and safe within a narrow window and its effects are strongly influenced by Vitamin K in the diet and most medications. Thus, frequent blood testing is needed, and close monitoring of diet and changes in medications. Even with this close monitoring, serious and sometimes fatal bleeding occurs frequently with warfarin.

Novel Anticoagulants

In recent years, three new drugs for reducing strokes in patients with atrial fibrillation which are much less influenced by diet and medications have gained approval from the FDA. These are generally referred to as “novel anticoagulants” reflecting their newness, different effects from warfarin or aspirin, and their blood thinning properties.  The first  (brand name Pradaxa) was released to much excitement and fanfare in October, 2010.  The press release for this approval read as follows:

PRADAXA, an oral direct thrombin inhibitor2 that was discovered and developed by Boehringer Ingelheim, is the first new oral anticoagulant approved in the U.S. in more than 50 years. As demonstrated in the RE-LY® trial, PRADAXA 150mg taken twice daily has been shown to significantly reduce stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin, the current standard of care for patients with non-valvular atrial fibrillation. PRADAXA 150mg taken twice daily significantly reduced both ischemic and hemorrhagic strokes compared to warfarin

Differences Between Warfarin and the Novel Anticoagulants

What was very clear from the study with Pradaxa  and stated very clearly in all publications and patient and doctor  information sources was that just like warfarin, patients could have severe bleeding complications, sometimes fatal. Overall serious bleeding complications were about the same (the rate of major bleeding in patients Pradaxa  in the RE-LY trial was 3.1% versus 3.4% in the warfarin group) but Pradaxa had about 50% more bleeding from the gastrointestinal tract and warfarin about 50% more bleeding into the brain.

Another big difference between the novel anticoagulants and warfarin is that we have antidotes (Vitamin K, fresh frozen plasma) that can reverse the anticoagulation state rapidly for warfarin but none for the newer drugs. This information also was made very clear to all doctors prescribing the medications in the package insert and educational talks. Despite this, in the major trials comparing these newer agents to warfarin, the newer agents were as safe or safer than warfarin.

The Pradaxa Bad Drug Ads

Beginning about a  year after Pradaxa was released advertisements paid for by law firms seeking “victims” of Pradaxa  identical to the ones we are now seeing for Xarelto began to appear.

The Pradaxa ads went away in mid 2014 when these lawsuits were settled and almost immediately the lawyers began paying for Xarelto ads. Xarelto was the second “novel anticoagulant) to be approved by the FDA and, similar to Pradaxa, was proven to as effective as warfarin in preventing strokes with a similar rate of serious bleeding complications.

As the Wall Street Journal noted (with the catchy title “The Clot Thickens” and opening line “Is a blood thinner causing lawyers to smell blood?”)

“Spending (on Xarelto ads)  jumped to $1.2 million in July from just $8,000 in June, according to The Silverstein Group Mass Tort Ad Watch, which noted the number of ads that ran in July exceeded 1,800. …

The spending increased shortly after Boehringer Ingelheim, which sells a rival blood thinner called Pradaxa, last May agreed to pay $650 million to settle about 4,000 lawsuits over claims the drug caused serious bleeding episodes. The settlement likely emboldened attorneys to turn their sights toward Xarelto which, like Pradaxa, is one of a relatively new batch of blood thinners.”

The third drug to be approved for preventing strokes in atrial fibrillation was Eliquis. Data from the large, randomized study comparing it to warfarin suggest that it is more effective at preventing stroke than warfarin and significantly less likely to have bleeding complications. However, I predict that within the year (especially if the Xarelto lawsuits also are settled by its manufacturer) we will start to see lots of TV ads telling us that Eliquis is a BAD DRUG.

It’s important to remember that all drugs have benefits and side effects. Seemingly harmless antibiotics can increase your risk of dying suddenly (see here), rupturing your achilles tendon or developing a life-threatening colitis.

Xarelto is not a BAD DRUG. When prescribed to appropriate patients with atrial fibrillation with  appropriate precautions it prevents strokes which are potentially life-threatening or disabling. All blood thinners are two-edged swords: they stop good clots and bad clots.

Ignore The Ads

Patients are better off ignoring both positive, direct to consumer, advertisements, promoting these newer anticoagulants and negative, greedy-lawyer sponsored advertisements, soliciting “victims”.

Hopefully when your doctor discusses the choices of blood thinners with you he will present to you a balanced discussion of the pros and cons both of whether or not to take  a blood thinner and whether to take the old standby warfarin or one of the newer agents. An interactive discussion should follow in which your particular issues and concerns factor into the final decision.

 

Two Spades or Two Diamonds, Two Ladies and Two Studies

I saw two delightful eighty-something ladies recently whose cases highlight some important points about atrial fibrillation, stroke and long term heart monitors.

Ms. M was playing bridge and found that she had 7 spades solid (solid, Mrs M informed me, means you have 7 of the suit with all of the honors (ace, king, queen, jack). Instead of bidding 2 spades which she meant to do, she bid 2 diamonds, and her partner responded by bidding 5 diamonds. This miscommunication resulted in a disastrous hand for the pair.

Ms. K  told me she had had an episode of “mass confusion” two weeks earlier during which for 15 seconds her “thinking process was not working properly.”

These cases illustrate the subtlety and brevity with which transient ischemic attacks (TIAs) or mini strokes can manifest. In contrast to the normal forgetfulness that is associated with aging, these women recognized  a sudden, transient and disturbing major alteration in their baseline mental processing.

TIAs are basically strokes that resolve quickly, generally within 24 hours, and leave no residual symptoms. They are often a warning that larger, more permanent strokes will follow.

In both of these cases, when I first saw the patients, they were in normal or sinus rhythm but subsequent monitoring revealed atrial fibrillation (AF).

Cryptogenic Strokes

A quarter of the 500,000 strokes occurring annually in America are unexplained (the medical literature tends to use the exotic and Halloween-appropriate term, cryptogenic for unexplained strokes). This means that imaging of the brain and arteries to the brain finds no abnormalities that would cause a stroke and that the patient has no history of AF. Since there is such a strong association between atrial fibrillation, clot formation in the heart, and stroke, (see my post on AF here) doctors assume that an otherwise unexplained stroke in a patient with AF is due to a clot leaving the heart and landing in an artery to the brain. These patients benefit from medications which reduce the risk of clot formation (either warfarin or one of the newer anticoagulants everyone has been hearing about either from negative TV ads from lawyers or positive direct-to-patient drug company ads).

New evidence suggests that if we monitor the heart rhythm for 30 days of patients who have had unexplained strokes a significant percentage will manifest atrial fibrillation.

A Canadian study of 572 men over the age of 55 who had had a cryptogenic stroke or TIA found that atrial fibrillation lasting 30 seconds or longer was detected in 45 of 280 patients (16.1%) in those who underwent 30 day monitoring, as compared with 9 of 277 (3.2%) in those who were only monitored for 24 hours.

Another study evaluated 441 patients following cryptogenic stroke with half randomized to receiving an insertable cardiac monitor (we call these implantable loop recorders (ILR) in the US). The ILR is a small device that can be inserted under the skin in the left chest region and allows continuous monitoring of the heart rhythm. After 6 months, atrial fibrillation had been detected in 8.9% of patients in the ILR group, versus 1.4% of patients in the control group. At 12 months it was 12.4% versus 2%.

Neither of my two ladies felt palpitations (a sense of the heart beating irregularly) that would have suggested a problem with the heart. About half of my patients with AF will feel their heart fluttering or “flip-flopping” or racing when the heart goes out of rhythm but the rest of my patients feel nothing. Thus, AF can be silent and I have many patients whose first symptom was a TIA or stroke.

These two ladies and two studies have taught (or reinforced for) me the following:

TIAs can be very subtle. Patients need to be aware of transient episodes of significant confusion or speech difficulties and report them to their doctors. We doctors need to pay close attention when patients report such episodes.

The patient who has had a cryptogenic stroke or TIA should undergo long term cardiac rhythm monitoring looking for AF. My take on the literature at this point is that we don’t need to do the more expensive and invasive ILR. I think a 30 day monitoring device that is capable of automatically identifying AF is sufficient.