Trials & Fibrillations: Major Matters Of The Heart

Two years on from my frenetic spate of consultations, cardiac scans and scores, diagnoses, drugs and interventions, I review the state of play with Atrial Fibrillation. I get some some heart-stopping shocks and some welcome frankness from an ‘honest broker’. I’ll be sleeping better now.

All By Myself

“How does it feel to be on your own, with no direction home, like a complete unknown – like a rolling stone?” – Bob Dylan

That’s exactly how I feel, but how did I get here – with a heart condition that can’t be fixed, a script for a drug with a success rate akin to Russian Roulette, and no cardiologist to talk to? And that’s despite spending much time and money on cardiologists and related specialists, on scans and angiograms and on attempts to reverse Atrial Fibrillation. 

It’s a couple of years since the dust settled, and I’m sitting here wondering if any of the guys I saw will ever get back to me.

You know, send me an email asking how I’m going, or invite me to come in for a chat and a check-up. Maybe even check if I’m still alive. No such luck. Not even the GP who referred me to the first cardiologist who alerted me to the ‘cardiac conveyor belt‘ (see below). Modern medicine; appalling after sales service.   

Coronary artery scans are the newest tool and stress labs run days and weekends. Stress tests are like fuel for cath labs. Positive stress tests lead to coronary angiograms, which then lead to stents and bypass surgery. Patients feel fixed. Doctors and hospitals make money. All is in balance.

John Mandrola, Electrophysiologist

Recap

In a previous post, I talked about The ‘Cardiac Conveyor Belt’: My Experience.

To recap, I have AFib (non-valvular Atrial Fibrillation), which is a common arrhythmia (abnormal heartbeat). AFib raises the risk of stroke 3- to 5-fold and doubles the risk of death. Anticoagulants reduce that risk. Here’s a primer on AFib with more details.

The GP subscribed Xarelto (rivaroxaban) to reduce the risk of stroke, and the first cardiologist I saw could barely disguise his enthusiasm for this drug. It belongs to a class of drugs called ‘Factor Xa inhibitors’ or ‘Direct Oral Anti-Coagulants’ (DOACs).

Adverse effects of these drugs include bleeding in the intestine and brain (intracranial hemorrhage) which is life-threatening. The reversal agent Andexxa, approved in 2018, comes with serious adverse effects of its own. The challenge for cardiologists is getting the knife-edge balance right between the blood clotting or flowing freely.

Yet none of the doctors I talked to, nor the 2 pharmacists who filled the scripts, warned me of Xarelto’s dark side. Hard to believe, I know.

I decided to stay on my Omega-3 optimised diet and grape seed extract since they both act as blood thinners. Now there is a voice in the back of my head asking, ‘Are you mad? Do you really think you’re smarter than all these cardiologists?’

No Safety in Numbers

Thinking about how to silence that voice, I realised I didn’t really know enough about AFib or the drugs prescribed for it.

The GP said ‘You’ve got AFib, you must take this drug to reduce your risk of stroke.’ The other docs I saw later always asked me if I was taking Xarelto; it seemed it was all they wanted to know.

Some serious digging reveals that Xarelto (rivaroxaban) has the worst safety profile among the DOACs. In 2015, it accounted for the highest number of serious injury reports received by the FDA’s Adverse Events Reporting System.

Its makers (Johnson & Johnson and Bayer) settled some 30,000 lawsuits in the US for nearly $775 million in 2019. There are also big questions about the ROCKET AF trial, on which the FDA based its approval of Xarelto, according to Medscape. In addition, the approval was given ‘despite the objections of the primary FDA scientists assigned to study its safety and effectiveness.’ (POGO – Project On Government Oversight).

One of the issues with ROCKET AF was that ‘the warfarin comparator arm stacked the deck in favor of rivaroxaban.’ The other was that patients in the warfarin arm had their INRs (tests monitoring that the correct dose is taken) adjusted using a point-of-care device that was under a class I FDA recall. (Medscape). In other words, the results were not as reliable as you may think.

An Honest Broker

When I can’t get a clear picture out of complex material in a specialised field, I look for specialists in that field who have sharp critical faculties, speak in plain English and and aren’t afraid to speak their minds.

That’s how I found John Mandrola, a cardiac electrophysiologist who is the chief cardiology correspondent for Medscape. His speciality is treating AFib, including with ablation, one of the interventions suggested for me two years ago. He attends cardiology conferences around the world, presents at many of them and reports on other presentations there.

John was a bike racer until he had a couple of crashes and concussions. He also lived with AFib for a time, which was induced by over-training. You could say he has hands-on experience.

Over My Head

John’s posts on Sensible Medicine and Medscape provided the inside knowledge I needed to decide whether I could trust him or my own inexpert but passionate thoughts. He signs his post JMM, so I’ll use that monicker for him, from here on.

Here is what I found from JMM; most was news to me:

• AFib ablation (reversal) has a success rate of 1 in 2 (50%) at best;
• The older you are, the lower your chances of success;
• There’s no evidence that AFib ablation reduces rates of stroke or death;
• There’s no evidence that ablation will add years to your life;
• Low-dose aspirin treatment for primary prevention in seniors raises the risk of hemorrhage but doesn’t lower the risk of strokes or heart attacks.
• There is an AF Stroke Risk calculator called CHA₂DS₂-VASc (see pic below). Until your score exceeds 4, the use of DOACs must be weighed against the risk of bleeding;
• HAS-BLED is another calculator to assess your risk of bleeding.

These risk calculators really got me thinking, particularly as the desired score is 4 or under and my score was 3.

What intrigued me was that 2 of my 3 points were due to my age being over 75. Similarly, women would get an extra point just because of gender. Oddly, diabetes history would add the same single point, despite being by far the highest risk factor for strokes and heart attacks.

These are pretty crude calculators; there are more detailed ones here.

Hallelujah

JMM is a straight shooter.

This is from an article headed: How do Dubious Norms Get Established? ‘Coronary artery scans are the newest tool,’ he writes, ‘and stress labs run days and weekends. Stress tests are like fuel for cath labs. Positive stress tests lead to coronary angiograms, which then lead to stents and bypass surgery. Patients feel fixed. Doctors and hospitals make money. All is in balance.’

As I mentioned, JMM is a cardiac electrophysiologist who specialises in AFib ablation, where some of the faulty electrical wiring on the outside of the heart is either burnt off by Thermal Ablation or by Pulsed Field Ablation, which uses electrical pulses instead.

If you’re contemplating ablation, this article from JMM explains the options. He also makes the point that our choice of lifestyle has a lot of impact on our risk of strokes, AFib or no AFib.

His 4 key lifestyle factors to lower risk are surprisingly simple:

• Healthy diet;
• Regular exercise;
• Optimum weight;
• Enough good sleep.

Rule 3-30

Professor Enrique Sánchez-Delgado is another straight shooter.

He wrote to the BMJ, arguing that many recent drugs don’t confer real benefits. He writes that ‘Most of the practice-changing drugs in the last 2 decades follow the RULE 3-30.’

He explains the rule this way, ‘Their relative risk reduction (RRR) is 30% or more (not less than 20 pc), the absolute risk reduction is 3% or more (not less than 2 %) and the number needed to treat for benefit (NNT) is 30 or less, up to 50.’

And here is the crunch: Sánchez-Delgado highlights that the NNH for mortality for rivaroxaban is much lower than NNT; that is, more patients are harmed by the drug than gain benefit from it. It should be the opposite. He also stresses that the long-term safety of DOACs need to be investigated.

Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo.

Monash University Study

Staying Alive

When a Medicine Works but Overall Benefit is Minimal is JMM’s take on the ANNEXA-I study, which compared Andexxa (Andexanet alpha, the drug designed to counteract the side effects of rivaroxiban) with a prothrombin complex concentrate (PCC), a mixture of blood products used to do the same thing.

Andexxa was 13% more effective at stopping bleeds than PCC but caused more clotting events, strokes and heart attacks. JMM doesn’t cite the number of deaths, nor does the trial report. What we do know is that Andexxa caused almost double the number of blood clots, and more than 4 times the number of strokes than PCC.

I found the numbers of deaths in an analysis on emergency medicine site the bottomline.org.uk. Its detailed table lists 73 deaths in the drug group and 68 in the PCC group, that’s 141 deaths in a total of 452 treated patients – almost one in three.

So, almost one third patients died from trying to counteract the side effects of another drug designed to reduce risk of stroke. Mmm. Is that why this number was so hard to find? I’m struggling for a clear perspective here – do people realize that a drug designed to reduce their risk of stroke might land them in a place where 1 in 3 won’t leave alive?

The next question is this: How often do anticoagulants cause serious bleeding events?

In a study we discuss below, it is 1.61/100 person-years for Xarelto (rivaroxaban) and 1.34/100 person-years) for Eliquis (apixaban). That’s 1 in 62 events for Xarelto, and 1 in 75 for Eliquis in just the first year and, mostly, these drugs are prescribed for life. By the way, Andexxa only works for these two drugs.  

Everybody’s Talkin’

I checked the drugmaker’s website to get its side of the story, and there I found this astonishing admission: ‘Remember, all blood thinners come with a risk of bleeding. Around 3% of people taking XARELTO in combination with low-dose aspirin experienced a major bleeding event, such as bleeding into the brain, compared to around 2% of people taking low-dose aspirin alone.’

Let’s be clear: Xarelto is not a blood thinner and aspirin is not an anticoagulant. The daily baby aspirin is still popular in America for preventing heart troubles, despite many studies finding it does more harm than good. The Europeans changed their guidelines many years ago to reflect this reality.

It took until 2019 before the American Heart Association (AHA) finally changed the guidelines to reflect recent research, such as this 2018 study which found that ‘Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo.’

‘Taking a daily low-dose aspirin is, at best, a waste of money for healthy older adults,’ CNN summed up. ‘At worst, it may raise their risk of internal bleeding and early death.’ That risk is higher in people of boomer age.

The ASPREE trial reported a higher rate of major hemorrhage in the aspirin group compared to placebo, and a 14% increase in the risk of death from any cause over a 5-year period. ‘Nothing could be clearer,’ JMM summed up, ‘don’t use aspirin in the healthy elderly.’

The ongoing use of aspirin in AFib studies is a mystery to me. This Editorial Note at the Journal of the American College of Cardiology summed up years ago that ‘aspirin is ineffective for prevention of thromboembolism (clot) related to nonvalvular atrial fibrillation (AFib).’ Yet researchers are still running trials using aspirin and anticoagulants.

What’s Going On?

A meta-analysis published in 2018 compared DOACs with warfarin, which was the anticoagulant of choice for decades, prescribed to reduce the risk of systemic embolism, stroke associated with AFib, and venous thromboembolism. It has a narrow therapeutic range and causes drug–drug and drug–food interactions. Bleeding is a major issue, and patients need regular monitoring and blood testing.

The finding in this large study was that, ‘Overall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared to warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all-cause mortality compared to warfarin.’

A recent study of almost 600,000 Medicare patients 65 years or older compared the 2 top 2 anticoagulants, and found that rivaroxaban came with ‘a significantly increased risk of major ischemic or hemorrhagic events.’

The study authors said the increased risk was seen ‘in both ischemic stroke and hemorrhagic stroke, as well as nonfatal extracranial bleeding and all-cause mortality.’

‘After adjusting for baseline differences,’ the researchers found that ‘patients on rivaroxaban had a higher risk of the primary outcome (16.1/1000 person-years) than those on apixaban (13.4/1000 person-years).’

Study leader Wayne Ray told Medscape Cardiology: ‘Our results … suggest that apixaban should be the anticoagulant of choice for atrial fibrillation,’

It’s the same story wherever I look.

A study of patients with AFib in Norway found ‘no significant differences in risk of stroke or Systemic Embolism between dabigatran, rivaroxaban, and apixaban. However, dabigatran and apixaban both showed significantly lower risk of major bleeding compared with rivaroxaban.’

ARTESIA is a 2023 trial designed to find out how to treat patients with short duration, sub-clinical AFib (episodes lasting 1.5 – 6 hours). Apixaban, which appears to be the safest of these drugs, produced a 37% reduction in strokes that was offset by a 36% increase in major bleeding. That says it all, doesn’t it?

Dazed and Confused

Where does this leave me?

Wondering why all the doctors I’ve seen in the last couple of years didn’t tell me any of this. They just told me I was at high risk of stroke and I had to take rivaroxiban, the drug with the second-worst safety profile. How did this drug become the market leader among DOACs?

Here’s a clue: marketing. In 2019, J&J ran a bunch of TV ads for Xarelto showing people in strapping good health telling viewers things like: ‘I didn’t have to call 911,’ or ‘I didn’t have to rush someone to the hospital,’ and ‘I didn’t have to inform your family …’  because ‘you didn’t have another heart attack. Not today.’

Here’s an example: Xarelto TV Spot, ‘Not Today: Movie Theater’. Here’s a list of Xarelto TV ads, including one with Arnold Palmer. Some of these are slow to load.

Edoxaban (Savaysa) looks like the biggest loser in this class. The recent NOAH-AFNET 6 trial showed a 19% reduction in strokes, offset by a 31% increase in major bleeding. This is the DOAC promoted by the UK’s NHS because it’s by far the cheapest of these drugs.  JMM’s insights on ARTESIA and NOAH-AFNET 6 here.

Dabigatran (Pradaxa) has the best safety profile among anticoagulants; it inhibits thrombin (coagulation factor II), while the NOACs inhibit clotting factor Xa. 

This discussion between JMM and ARTESIA investigator Jeff Healey is about  how to treat patients with subclinical AFib like me. JMM says ARTESIA doesn’t answer that question. It does explain why aspirin still plays a role, and it shows just how hard it is to unravel this Gordian Knot of AFib.

The Xarelto website also shows these 2 claims, which I find more than puzzling.

Remember, it also states that ‘around 3% of people taking XARELTO in combination with low-dose aspirin experienced a major bleeding event, such as bleeding into the brain, compared to around 2% of people taking low-dose aspirin alone.’

I suspect blind Freddy could work out that giving people 2 blood thinners will increase major bleeding. Yet J&J seems to be saying that the Xarelto/aspirin combo is superior because more people enjoy more bleeding events? What they’re not saying is that the drug combo failed to reduce rates of clotting.

U.S. Pharmacist summed up the results of the related clinical trial this way, ‘… patients on combination therapy had significantly higher rates of bleeding and hospitalizations for bleeding without observed difference in thrombosis rates.’

The claim on the left talks about reducing the risk of ‘cardiovascular death’, a sure sign that there was no reduction in deaths from any cause. We’re wrestling with Orwellian Double-Speak here.

The claim on the right is more of the same: it states that 1 in 25 subjects in the trial had a heart attack, stroke or died from a cardiovascular event. How is this good news?

A new treatment option has emerged recently: Left Atrial Appendage Closure  (LAAC), which JMM has serious reservations about. ‘The positive results will probably lead to many more of these unproven devices being implanted,’ he says. ‘As I wrote earlier this week, the OPTION trial was designed to deliver positive results. And so it did.’ 

What Patients Say

Here are some user reviews of Xarelto at Drugs.com. It’s a small sample of 54 reviews; 28% are positive, and 57% negative. I’ve shortened most of the reviews posted to save space.

‘Felt horrible for every day on this drug. Pain, dizzy, felt like I was being poisoned. If I didn’t get off this poison, I would have lost my job, as I could not function!’

‘I ended up with the most painful legs, felt as if they were on fire. Now the same pain has started in my arms. I also find great difficulty controlling my bladder.’ 

‘Please do not take this drug, my husband died on this. He had been on Warfarin for 7 years with no problems. Cardiologist swapped him to Xarelto, within 5 months he was coughing up blood, having dizzy spells, aneurysms, lung problems … ‘

‘On Xarelto I didn’t have a stroke, but hair fell out a ton. Also, short of breath, and ears started ringing (tinnitus) and are driving me nuts.’ 

‘I had extreme fatigue and my feet and ankles swelled up. My knees became very painful and my stomach was upset. My vision was blurred. My blood pressure rose significantly. For me, this drug is a killer. Stay away from it.’

‘My mom has AF and the doctor prescribed Xarelto. 25 days later, she got brain bleeding and needed surgery. 2 weeks later, she had the second brain bleeding, and a few weeks later, she passed away. What should I say?’

‘I have blood in my stool, shortness of breath, rash, stomach pain, blood pressure spikes. But hey, no stroke, just no life. I’ve tried a few and they are all poison to me.’

‘I was never told it would cause blood in your urine. I had trouble peeing and pain in my lower back. I stopped taking this drug, and everything cleared up in a week.’

‘Xarelto caused A-fib, which was the worst thing. It caused my heart to race and actually hurt my heart. It took six months for me to return to anything normal in my life. This drug is dangerous. Stay away from it.’

‘On Eliquis, my blood pressure went sky-high and I started to develop diarrhea. As it got worse, they agreed to switch me to Xarelto. After about a week, my diarrhea was out of control and there was blood in the stool. BAD DRUG!!!’

‘ … almost uncontrollable nose bleeds, a small cut on my lower leg that would not heal. Fought with the doctor … It took about two weeks for the bleeding to subside. I refuse to take this or any similar medication again.’

‘I believe Xarelto caused four episodes of near-fatal GI bleeding over a seven-month time frame. I am a 62-year-old male.’

The Washup

After two years, the flurry of heart disease consultations, tests and procedures, and now the deep dive into AFib, I’m feeling more relaxed than before it all started.

Now I’m going to catch up on that sleep I lost worrying, before I discovered this latest research.

I’m nudging eighty years of age and:

• I avoided Xarelto, bleeding and Andexxa.
• I avoided ablation which almost certainly wouldn’t have worked in my case.
• I’m taking natural blood thinners to minimise my risk of a clot causing a stroke.
• My AFib risk score is 3 (over 4 is of concern).
• I have a very healthy diet.
• I exercise seven days a week.
• My weight has been optimum for nearly three decades.

I hope it puts your mind and heart to rest, too.

***

I’ve just finished my long-ago-started eBook on heart disease; talk about a long and winding road! It turned out to be more tortuous that even I imagined. That’s why it’s longer than my other eBooks.

You can read the full story on heart disease – the explosion in incidence since the 1920s, the treatments that do more harm than good and the many ways you can avoid them AND the disease – in my new eBook: Heart Disease: Take Back Control.

If you click below, you can see what’s inside.