Navigating the Continuum of Care in Cardiac Arrhythmia

Faculty

Learning Objectives

Expert Case Discussion, Part 1

Ruth is a 66-year-old woman who began experiencing chest palpitations 28 hours ago following a large meal. She presented to the emergency department approximately 5 hours later.

Upon Ruth’s admission, the emergency department physician ordered the standard tests, including lab tests, an ECG and an echo. Lab tests showed no elevation of cardiac troponins, but an LDL cholesterol of 160 mg/dL. The ECG showed atrial fibrillation, with no evidence of myocardial ischemia or previous myocardial infarction.

The on-call cardiologist is now going to assess her condition.

Dr Murphy: Hello Ruth, I’m Dr Murphy – the on-call cardiologist. How are you feeling?

Patient: Not too bad – worried, more than anything.

Dr Murphy: That’s perfectly understandable. Could you please describe for me what happened?

Patient: Well, we had just finished having a fancy lunch for my colleague Elizabeth – she’s retiring. And we were waiting for the taxis to come and pick us up from the restaurant. All of a sudden, I started feeling these… ‘palpitations’, I suppose, in my chest – as if my heart was getting faster or kind of chaotic. Does that make sense?

Dr Murphy: Absolutely. Your heart rate has been fluctuating quite a lot since you arrived – your current readings are around 120 beats/minute, which is reasonable for a rhythm disturbance called “atrial fibrillation” for somebody of your age. Did you experience any chest pain?

Patient: Hmm… I would say it was uncomfortable, rather than painful.

Dr Murphy: That’s good at least. I’ve reviewed your test results, and there’s no evidence that you’ve experienced a heart attack.

Patient: Oh, that’s a relief.

Dr Murphy: Yes, I’m sure it is. Your symptoms occurred because you have atrial fibrillation, or an irregular heartbeat, which I can see on the ECG. It’s quite common. But it does increase your risk of having a stroke, heart failure, or a heart attack at some point in the future. And it can also cause you to continue having unpleasant symptoms that may affect your day-to-day activities.

Patient: I see. Is there anything that can be done about it?

Dr Murphy: There are several other medications that you can take to help you maintain a regular heart rhythm.

Patient: OK.

Dr Murphy: But first of all, we should try to reconvert you back to normal rhythm right away. Because the earlier we do it – the shorter the time that you stay in atrial fibrillation – the better the chances that your heart can reconvert.

Patient: So, how would you do that?

Dr Murphy: There are 2 possibilities. We can either do it with an electrical shock or by giving you an injection. Electrical cardioversion is quite quick and provides an immediate result in most people. But you would need to be either sedated or anesthetized first, as the experience is quite unpleasant. With the medication, it takes longer for your heart to convert.

Patient: I don’t like the idea of having an electrical shock at all!

Dr Murphy: Many people feel that way. I’ll order the medication for you. It’s called ‘flecainide’. We’ll monitor you until your heart rate is stable and you’re ready to go home. Then I’ll prescribe the same medication in a pill form for you in the future. You’ll carry 2 pills with you at all times and, if you feel the palpitations occurring again, you’ll take those 2 pills and lie down or sit down until they have stopped.

Patient: Alright, doctor.

AF and Stroke Risk ^[1-3]

A few more points. This patient has atrial fibrillation with at least 2 risk factors for stroke which are age over 65 and the female gender and in the absence of an obvious reversible cause is likely to need anticoagulation indefinitely. Is the option of enoxaparin up to today's standards? We will discuss this later on. Is the option of bisoprolol 2.5 milligrams sufficient in your experience? This is an interesting question regarding the pharmacotherapy with β-blockers so we may address this later on. Is the option of flecainide sufficiently good in your opinion due to the limited work-up that the patient has received to rule out coronary artery disease? We will also address this.

AF Stroke Prevention Guidelines^[4,5]

Just to give you an update to guide the need for anticoagulant therapy in patients with AF, both European and American guidelines recommend assessment of individual risk for adverse outcomes including stroke. The CHA2DS2-VASc score that was proposed by Professor Lip a few years ago was first incorporated into the ESC guidelines in 2010 and has simplified the initial decision for oral anticoagulant therapy in AF patients mostly allowing to exclude very low-risk patients, the so-called CHA₂DS₂-VASc 0 that do not require anticoagulation at all.

Now there is strong evidence to support the use of an oral anticoagulant in patients with at least 2 stroke risk factors regardless of whether the AF pattern is paroxysmal, persistent, or permanent. We have a strange, let us say, CHADS₂ score in this patient because one of the components is the female gender, so this will merit some discussion and we will address this later on.

Oral Anticoagulants and Their Pharmacologic Properties^[6]

The patient was put on a NOAC. We have several options. As a matter of fact, this patient was put on apixaban 5 milligrams b.i.d. which is certainly a reasonable choice. I remind you that the guidelines say that when a CHA₂DS₂-VASc score in men, you should really mandate anticoagulation for women when it is more than 2. Patients without clinical stroke risk factor do not generally require antithrombotic therapy. However, even in the absence of any stroke risk factor, anticoagulation is a reasonable precaution for some patients and I remind you that around cardioversion, this is mandated.

I remind you the points of the CHA₂DS₂-VASc score: the presence of heart failure, 1 point; hypertension defined as over 140/90 milliliters of mercury, 1 point; age over 75 scores 2, while age 65 to 74 score 1 point; the presence of diabetes, 1 point; previous stroke scores 2 points. We have vascular disease 1 point and the sex category, the female gender, 1 point.

Briefly, I will take you through a summary of what we know about the anticoagulant therapy that is mandated in most cases of atrial fibrillation. Vitamin K antagonist, for example warfarin, most largely used anticoagulant in Europe reduces the stroke risk by two-thirds and mortality by one-fourth compared with aspirin or no therapy.

NOACs Compared With Warfarin for Bleeding Endpoints^[7]

The use, however, of warfarin and of other vitamin K antagonists is limited by the narrow therapeutic level necessitating frequent monitoring and dose adjustments. This has prompted the use and the widespread acceptance of the known vitamin K antagonist oral coagulants, what we call NOACs. They have been proven to be suitable alternative to vitamin K antagonists with increased penetration on the market. They have a very predictable effect. The onset is quick. The offset is also quick without the need of regular anticoagulation monitoring. We have 4 of them approved at the moment.

In Europe, one is dabigatran. Dabigatran in the setting of the RE-LY study compared with warfarin. At the higher dose tested, 150 milligrams b.i.d. reduced stroke and systemic embolism significantly by 35% compared with warfarin without a significant difference in overall major bleeding. At the lower dose, 110 milligrams b.i.d., dabigatran proved to be non-inferior for the prevention of stroke and systemic embolism but was associated with a benefit of 20% fewer major bleeding events. There was a significant increase in GI bleeding reported with the 150 b.i.d. dose.

We have the category of factor Xa inhibitors. Apixaban in the setting of the ARISTOTLE trial compared with warfarin, reduced stroke and systemic embolism by 21%, major bleeding by 31%, and also all-cause mortality by 11%. Apixaban is also in another trial, which was a head-to-head comparison with aspirin in patients that were considered unsuitable for oral anticoagulation with warfarin. In this case, apixaban reduced stroke and systemic embolism compared with aspirin by 55% with no difference or only a small difference in the rates of major bleeding and no differences at all in intracranial hemorrhage.

Edoxaban has been approved for stroke prevention at the dose of 60 milligrams reduced to 30 in particular conditions. It is a once daily drug. Compared with warfarin, edoxaban 60 milligrams once daily reduced stroke and systemic embolism by 21% and also reduced major bleeding events by 20%. Certain patients require a dose reduction to 30 mg once daily.

Rivaroxaban tested in the ROCKET AF against warfarin in patients of particularly high risk of stroke. This dosage was adjusted to 15 milligrams in a minority of patients with an estimated creatinine clearance less than 50 but equal or more than 30, was non-inferior to warfarin for the prevention of stroke, systemic embolism, and increased likely the rate of gastrointestinal bleeding events.

Now you have this patient that has been discharged from the hospital. Let us see what happens approximately 7 months after the hospital discharge.

Dr Shah: Hello Ruth.

Patient: Hello doctor.

Dr Shah: So, I last saw you around 6 months ago – a couple of weeks after you had been discharged from the hospital. We did an echocardiogram, and everything looked good on that. How have you been since then?

Patient: Well, I’ve been fine, I suppose. But I’ve had to use the 2 pills to stop the palpitations several times.

Dr Shah: How often have you had to do that during the last 6 months?

Patient: I kept notes – 4 times. They’re not as bad as they were when I had to go to the emergency department – my heart doesn’t feel quite so chaotic. So, as soon as it started I just took the pills and rested for a couple of hours.

Dr Shah: Hmm, I see. And they helped?

Patient: Yes, the palpitations usually went away within an hour.

Dr Shah: Did you experience any different symptoms that hadn’t occurred during previous episodes, such as shortness of breath, wheezing, dizziness, or fainting – either before or after you took the pills?

Patient: No, nothing like that.

Dr Shah: Good… Your heart rate is much lower now – down to 60 beats/minute. and your latest ECG does still shows sinus rhythm, which is the normal heart rhythm.

Patient: I had a feeling that was the case. Does it mean the medications aren’t working?

Dr Shah: Not necessarily. Some people with atrial fibrillation are able to keep their heart rhythm controlled most of the time, and only occasionally need to take the flecainide pills. Others, however, do better when they take the pills every day.

Patient: OK, so do you think I should take them every day?

Dr Shah: Yes – instead of taking the pills whenever you experience palpitations, I would recommend that you take one 50 mg tablet every morning when you get up, and another 50 mg tablet 12 hours later, and then in 4 weeks we’ll increase the dose to a 100 mg tablet twice a day.

Patient: So, I’ll take 2 tablets every day?

Dr Shah: That’s right. And then if you still find that’s not helping, we can talk about some other options.

Patient: OK.

AF is associated with an increased risk of all-cause deaths, which is twofold in women, 1.5 fold in men. The increased mortality in atrial fibrillation is primarily associated with cardiovascular causes; sudden death, heart failure and stroke. Remember that 20 to 30% of all strokes are estimated to be due to atrial fibrillation. I also remind you that paroxysmal AF is often diagnosed after a stroke or other cardiovascular events.

Increased Risk of Morbidity and Mortality in Patients With AF^[8-12]

Even on optimal therapy, major cardiovascular complications are common in patients with AF. Ten to forty percent of people are hospitalized each year, often for AF management, heart failure, myocardial infarction, complications associated with AF treatment. Left ventricular dysfunction is found in 20 to 30% of AF patients and can be caused or exacerbated by atrial fibrillation. Certainly AF has a major effect on the quality of life. There is evidence that AF is associated also with an increased risk of cognitive decline.

We have done considerable progress in the management of atrial fibrillation with the use of drugs or with the use of procedures, but this important burden of the disease still remains nowadays. We will discuss later on how much new treatment may impact these adverse outcomes.

As discussed in the first part, the risk of stroke and stroke-related death can be significantly reduced by effective anticoagulant therapy, but this is not all the problem of atrial fibrillation because we have to deal with the problem of rhythm control vs rate control that are both integral components of the AF management.

AFFIRM Trial: Cumulative Mortality From Any Cause, Rate vs Rhythm Control^[13]

The improved AF-related symptoms may preserve cardiac function, but so far, it has not been clearly shown to impact mortality. Remember that comprehensive analysis of data from over 160 studies involving more than 28,000 patients found that anti-arrhythmic drugs and rate control medications have comparable efficacy across outcomes in primarily older patients with mild AF symptoms. Neither anti-arrhythmic drugs nor rate control medications have been demonstrated to reduce long-term morbidity and mortality.

Now let us see what happens again to our patient, Ruth. This will lead to the discussion mostly focusing on these on the third part on the next part of this symposium. Ruth, indeed, after her adjustment of her regimen returned to the emergency department.

Patient: But if I have the procedure, the problem is fixed once and for all?

Dr Murphy: Sometimes, yes. But in some patients it has to be repeated, and in some patients it doesn’t work at all. And in any case you should be kept on bisoprolol, the anticoagulant and – at least for some time – also on flecainide.

Patient: So there are no guarantees, either way.

Dr Murphy: That’s true – atrial fibrillation can be rather unpredictable. Also, you are getting older – and atrial fibrillation tends to relapse more frequently in elderly people.

Dr Murphy: Eventually you might have to live with atrial fibrillation, despite medication or several attempts at ablation. But we would hope to be able to provide you with some years without having to cope with the symptoms.

Patient: What would be your recommendation, doctor?

Dr Murphy: Well Ruth, at the end of the day, it is your decision. And perhaps something you should speak to your husband about. But here is my suggestion: increase the dose of bisoprolol to make AF better tolerated when it occurs. Do not undergo ablation at the age of 66. But other doctors may think differently.

You see that we have assembled a so-called atrial fibrillation team here. Indeed, we have 2 brilliant electrophysiologists and 3 brilliant non-electrophysiologists, that is Dr Lip, Dr Murphy, and me. This will be the challenge for you in the next part because, I think, this is a recurrent problem in atrial fibrillation to have a joint decision between different cardiologists.

What is your opinion about this? The efficacy of anti-arrhythmic drugs in individual patients is inconsistent and interesting, ablation as an alternative to drugs has increased substantially over the years.

Indications for Catheter Ablation in AF^[4,14]

Multi-centered prospective studies, including those listed here, have suggested that ablation is more efficacious than anti-arrhythmic drug therapy. However, these studies were relatively small and did not provide the comprehensive representation of the broad AF population and typically provided the relatively short period of follow-up. This paved the way for a larger, longer comparison of anti-arrhythmic drugs and catheter ablation, the CABANA study that we will discuss later on.

I remind you, however, that current ESC guidelines advise as follows: AF ablation when performed in experienced centers by adequately trained teams is more effective than anti-arrhythmic drug therapy in maintaining sinus rhythm and the complication rate, though not negligible, is similar to the complication rate of anti-arrhythmic drugs. In patients who experience symptomatic recurrences of AF despite anti-arrhythmic drug therapy, catheter ablation has been shown to produce better maintenance of sinus rhythm compared with anti-arrhythmic drugs.

Thank you for your attention. The panel and I will now get together and we will discuss moving beyond pharmacological therapy in cardiac arrhythmia management. Thank you for the moment.

Moving Beyond Pharmacologic Therapy in Cardiac Arrhythmia Management

NOACs vs Warfarin: Significant Reductions in Stroke and Intracranial Hemorrhage^[15]

• Absent a serious risk of bleeding, anticoagulation is indicated in patients with AF in order to reduce the risk of stroke 
• For many years, the standard of care had been warfarin; however, warfarin comes with a substantial bleeding risk and its narrow therapeutic index requires continual monitoring
• Newer NOACs offer better stroke risk reduction with less risk of bleeding compared with warfarin

Atrial Fibrillation Better Care (ABC) Pathway^[16]

• The ABC pathway tries to make certain that everyone treating the patient with AF is on the same page
• Basically, the principle was to devise an easily understood continuum of care extending from the specialist to primary care and even to patient self-care

Women, and Particularly Older Women, With AF Are at Greater Risk of Stroke Compared to Men With AF^[17]

• Female gender is a risk factor for stroke, as is older age, in patients with AF
• Among women with AF over the age of 65 years, female gender becomes more of a risk modifier than a risk factor

ORs (95% CI) for AF by Presence of Individual Comorbidities^[18]

• Both incidence of AF and worsening of AF are associated with a number of modifiable risk factors, including overweight/obesity and cigarette smoking
• The burden of AF may be reduced by addressing these risk factors

AF Taxonomy: Paroxysmal, Persistent, Permanent^[19]

• It is now known that stroke risk may be increased dependent upon the type of AF, and the persistence and progression of AF
• When evaluating patients for stroke risk, it is critical to understand that risk is not a static phenomenon, and that as a patient ages, and perhaps acquires other comorbidities, stroke risk will likely increase

CHA₂DS₂-VASc Score Changes and Stroke Risk in Patients With AF^[20]

• In AF patients, stroke risk is dynamic and changes over time
• In this study by Yoon and colleagues, stroke rates increased as patients developed more risk factors and migrated into higher CHA₂DS₂-VASc score categories
• Stroke risk reassessment needs to be an ongoing feature of patient care

AF Pathophysiology and Potential Biomarkers^[21]

• Left atrial diameter, or left atrial size, may also be an AF biomarker, as it has been shown to correlate with underlying hypertension and heart failure, and increased risk of stroke^[22]
• Left atrial size has also been associated with AF recurrence post-catheter ablation^[22]

Pharmacotherapy for AF: Rhythm-Control Plus Rate-Control Agents?

• Is the first-line combination of a rhythm-control agent (eg, flecainide) plus a rate control agent (eg, a beta-blocker, bisoprolol) necessary to address AF symptoms?

Metoprolol: Patient Subgroups Experiencing an AF Relapse^[22]

• It might be that other beta-blockers might have advantages over bisoprolol
• In the trial by Kulhkamp and colleagues comparing metoprolol vs placebo in patients with persistent AF after cardioversion, the beta-blocker was associated with fewer AF relapses across a number of subgroups
• Metoprolol also has the advantage of a fast onset of action

Successful Conversions to Sinus Rhythm: Vernakalant vs Placebo^[23]

• Vernakalant is a relatively atrial-selective AAD that may be used instead of flecainide as pharmacologic therapy for patients with AF
• In this study by Beatch and colleagues, vernakalant compared to placebo was assessed in 217 patients with recent-onset symptomatic AF
• Rapid cardioversion of recent-onset AF occurred in 45.7% of the patients who received vernakalant compared with 1.5% of patients who received placebo

Indications for Catheter Ablation in AF^[14]

• The burden of AF may be reduced by addressing these risk factors
• Failure of pharmacologic therapy, particularly 2 failed attempts at controlling AF symptoms with AADs, would be an indication for catheter ablation

Electrical Cardioversion Has a High Rate of Success^[24]

• Electrical cardioversion should be strongly advocated for in most patients with newly diagnosed AF; it is highly effective and safe, and reconversion to sinus rhythm is rapidly achieved
• In this study of registry data by Kiliszek and colleagues, nearly all the patients opting for electrical cardioversion achieved a return to sinus rhythm
• The complication rate was low (2.8%) for the combined electrical and pharmacologic cardioversion; the most serious adverse events were 1 transient ischemic attack and 1 pulmonary embolism

Recurrence of AF Requiring Multiple Catheter Ablations^[25-27]

• It is important that the patient with AF be made to understand that the condition can recur -- even subsequent to successful cardioversion or catheter ablation
• The patient needs to be reassured that recurrence of AF symptoms is not life-threatening and that they can be treated

Utility of an MRI in Older Patients With AF

RAAFT-2: Primary and Secondary Endpoint Results^[28]

• Relapse, or recurrence of arrhythmias, may be less frequent with catheter ablation vs pharmacotherapy
• The RAAFT-2 study randomly assigned 127 treatment-naive patients with paroxysmal AF to either catheter ablation (radiofrequency) or AADs
• At 2 years, fewer patients who received ablation vs AADs experienced recurrence of atrial tachyarrhythmias

Evolution of Catheter Ablation in AF^[14,29]

• Electrophysiologic procedures aimed at ablating AF triggers have been continuously improving
• With more precise technologies and interventions, pulmonary vein (PV) isolation -- – if that is, indeed, the trigger for AF in a specific case -- has become really durable. At least in centers of excellence it is quite rare to observe PV reconnection. So, if the arrhythmia is PV mediated, it can be cured

Quality-of-Life Issues and Impact of Symptoms in AF^[30]

• While it is questionable whether any specific treatment for AF will prevent recurrence and reduce the risk of mortality, all treatments should be concerned about improving the quality of life of the patient with AF

AF: Epidemiology and Clinical Course^[4,31-33]

• It is difficult to predict, in any particular patient with AF, whether or not a given therapy will eliminate symptoms without recurrence, whether or not the AF will progress, and what the impact of AF will be on that individual's overall clinical condition

POWDER-AF Study Results^[34]

• POWDER-AF was a multicenter, randomized controlled trial evaluating patients who received AAD therapy and were now undergoing catheter ablation
• If, after the procedure, patients were AF free, they were randomly assigned to continue or discontinue AAD therapy
• Risk of AF recurrence was significantly reduced (P < .001) in the cohort that continued with AAD therapy

CABANA: Purpose and Endpoints^[35]

CABANA: Primary Endpoint Results^[35]

CABANA: Selected Adverse Events in the Ablation Cohort^[35]

CABANA: Results From the On-Treatment Analysis (Per Protocol Patients^[35]

Summary and Conclusions

Thank You

This content has been condensed for improved clarity.