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Editor's Note
Two landmark studies published in 2002, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)[1] and the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE)[2] trials, found that treating atrial fibrillation (AF) with a rhythm-control strategy involving cardioversion and antiarrhythmic drug (AAD) therapy offers no survival or clinical advantages over simpler rate-control therapy using medications such as calcium channel blockers, beta-blockers, and digoxin. In fact, the potential benefits of a rhythm-control strategy were largely offset by the adverse side effects associated with AAD therapy.
These results led many in the medical community to endorse rate control as the better choice for first-line AF therapy. However, there were important limitations to these studies since they primarily enrolled older patients (over age 65) with persistent AF who were mildly symptomatic. Moreover, in the AFFIRM study, less than two thirds of those in the rhythm control arm were actually able to maintain normal sinus rhythm. Thus, because the scope of these trials was limited, the results cannot be extrapolated to significant subgroups of patients, including: younger patients; those with new, first-onset AF who may benefit from early conversion to sinus rhythm; patients with persistent AF who are highly symptomatic; and patients with poor left ventricular (LV) function or with significant heart failure (HF).
This latter group -- AF patients with LV dysfunction and HF -- are particularly problematic because studies have shown that, over time, AF can accelerate the decline in ventricular function. To gain a perspective on appropriate AF therapy selection in the HF patient population, Medscape recently spoke at length with J. Michael Mangrum, MD, Assistant Professor of Internal Medicine and Director, Atrial Fibrillation Center at the University of Virginia Health System (Charlottesville). According to Dr. Mangrum, safe AAD choices are limited in patients with impaired ventricular function, but there are several established and emerging treatment options, pharmacologic, device-based, and ablation, that can offer these patients significant symptom relief. He believes that ongoing clinical trials will help shed more light on how emerging therapies will ultimately fit into the continuum of care.
AF and HF -- A Vicious Cycle
| Clinical Point Several studies have shown a correlation between the presence of AF and poor outcomes in HF patients. One notable study assessed 1470 participants in the Framingham Heart Study who had new-onset AF or congestive heart failure (CHF) and found that patients who developed both AF and CHF over the course of the study had a poor prognosis.[3] In AF subjects, the subsequent development of CHF was associated with increased mortality (men: HR 2.7; 95% CI, 1.9 to 3.7; women: HR 3.1; 95% CI, 2.2 to 4.2). Similarly, in CHF subjects, later development of AF was associated with increased mortality (men: HR 1.6; 95% CI, 1.2 to 2.1; women: HR 2.7, 95% CI, 2.0 to 3.6). Moreover, preexisting CHF adversely affected survival in individuals with AF, although preexisting AF was not associated with adverse survival in those with CHF. The cumulative incidence curve for the development of CHF after AF is shown in Figure 1. |
Figure 1.Unadjusted cumulative incidence of first AF after HF - Framingham Heart Study.[3] Adapted from Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality -- the Framingham Heart Study. Adapted from Circulation. 2003;107:2920-2925.
Medscape: These data from Framingham demonstrate that AF is associated with a worse prognosis in HF patients. Can you briefly review the link between AF and HF?
Dr. Mangrum: As you see in Figure 1, the longer a patient has HF, the greater the likelihood of developing AF. After about 4 years, 20% of HF patients can be expected to have AF. Additionally, AF is associated with HF of greater severity; the highest AF prevalence is seen in patients with more severe HF (New York Heart Association [NYHA] class III-IV).
This HF/AF relationship is one that evolves into a kind of vicious cycle. For instance, once a patient develops HF, they can demonstrate increased left atrial pressure and elevated systemic levels of the hormones angiotensin II and aldosterone. These changes can cause atrial hypertrophy and, subsequently, atrial fibrosis. This, in combination with stretch in the left atrium, increased sympathetic tone, and greater atrial ectopy, can cause AF. Then, once the patient is in AF, there is a loss of atrial contraction and irregular RR intervals, which worsens the HF and perpetuates this vicious cycle. So in order to treat one or the other of these conditions, you have to address both simultaneously.
Medscape: Does AF have differing effects in HF patients with and without LV dysfunction?
Dr. Mangrum: Apparently not in terms of overall survival differences. One study by Parkash and colleagues,[4] which compared outcomes in AF patients with diastolic vs systolic dysfunction, found that the mortality rate was the same regardless of whether the HF patient had LV dysfunction. And that outcome was poor. So, AF appears to be a marker of poor outcome regardless of whether the HF patient has LV dysfunction.
Choosing a Therapy -- Rate vs Rhythm Control
| Clinical Point A recent 245-patient substudy of the AFFIRM trial[5] demonstrated a small but statistically significant difference in functional class among HF patients who were able to maintain sinus rhythm throughout the trial vs those who did not maintain sinus rhythm (Figure 2). Patients in AF had significantly worse NYHA functional class measurements at all follow-up points compared with those who maintained sinus rhythm (P < .0001). In addition, compared with the rate-control group, a significantly greater number of patients in the rhythm-control arm were in sinus rhythm at the conclusion of the trial. Although this does not prove a causative link between sinus rhythm and improved functional class, similar results have been observed in other studies. This substudy also reported a modest improvement in 6-minute walk distance in the rhythm-control arm, with the average walk distance 94 feet greater in the rhythm-control group than in the rate-control group (adjusted P = .049). Moreover, a substudy of the RACE trial[6] reported a survival benefit in HF patients who were able to maintain sinus rhythm. HF patients assigned to the rhythm-control group who maintained sinus rhythm throughout the study demonstrated a cardiovascular mortality rate of 0%, compared with 9.5% in patients who reverted back to AF. Mortality benefits were also observed in the DIAMOND study[7] in CHF patients who maintained sinus rhythm on the AAD dofetilide (see trial glossary below). These and other observations have led some physicians to question whether rhythm control is a better AF treatment strategy in patients with HF, especially if sinus rhythm can be maintained. |
Figure 2.Mean New York Heart Association function class (NYHA-FC) at each visit.[5] Current AF status: current AF vs no current AF present at visit. P value reflects comparison between 2 groups from repeated measures analyses across all visits. Source: Chung MK, Shemanski L, Sherman DG. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol. 2005;46;1891-1899. Permission pending.
Medscape: Do you believe there is now enough evidence to support the routine, widespread use of rhythm control in AF patients with HF?
Dr. Mangrum: Not currently. However, the substudy data on the HF patients from both AFFIRM and RACE (as noted above) are lending evidence that perhaps rhythm control may be preferable in this group. But we must be cautious and bear in mind that these are small substudies, and I don't think there's enough evidence to make a recommendation at this time.
We are awaiting the results of the ongoing AF-CHF trial,[8] a randomized study specifically comparing rate vs rhythm control in the HF population with LV dysfunction. This trial is taking place at 130 centers in Canada, the United States, South America, Europe, and Israel and will enroll a total of 1450 patients with NYHA class II-IV HF and LV ejection fraction (EF) < 35%. The forthcoming results should provide us with very important data to guide therapy.
Medscape: So, one should wait for the results of that trial before making a definitive conclusion about whether rhythm control is the most appropriate therapy in these patients?
Dr. Mangrum: That's correct. There are intriguing data suggesting that rhythm control in HF may be superior, but I think before one makes a firm recommendation, the results of this particular trial should be known.
Symptoms Should Guide Treatment
Medscape: Despite the lack of data from large trials in the HF population, there is some evidence to suggest that maintaining sinus rhythm may be a key factor in improved survival and other functional and quality-of-life indicators in HF patients with AF. Although rhythm control with AADs may not be ready for routine use, at what point does establishing and maintaining sinus rhythm become an important goal in the treatment of HF patients, and when should physicians consider a rhythm-control strategy to achieve this goal?
Dr. Mangrum: There are 2 issues involved in choosing a treatment for AF in HF patients. First, we must ask: Is there improved survival of one strategy over the other? Currently there are no hard data to say that one strategy [rate or rhythm control] is better than another in terms of survival benefits. The second issue is morbidity. I think that attempting a rhythm-control strategy would be the next thing to do in the group of AF patients who have significant symptoms despite being on a good HF medical regimen (including angiotensin converting enzyme [ACE] inhibitors and beta-blockers) and despite having adequate ventricular rate control.
Clark and colleagues[9] published data showing the detrimental hemodynamic effects of AF (Figure 3). In this small, 16-patient study, the patients' hemodynamics were assessed invasively prior to atrioventricular (AV) nodal ablation and pacemaker insertion. The hemodynamic parameters were evaluated in normal rhythm, in AF, and just after initiating ventricular pacing at various rates. They demonstrated a hemodynamic superiority of sinus rhythm. So, in a patient with HF who has compromised LV function, rhythm control might provide significant hemodynamic improvement (improved cardiac output, lowering LV filling pressures, etc).
Figure 3.Acute hemodynamic effects of atrial fibrillation -- effects of AF on (A) cardiac output and (B) pulmonary capillary wedge pressure (PCWP).[9] Adapted from Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. Adapted from J Am Coll Cardiol. 1997;30:1039-1045.
Medscape: When you say you would consider rhythm control in patients with significant symptoms, are you referring to symptoms related to HF or to AF?
Dr. Mangrum: In many ways, they are one and the same. HF symptoms, such as shortness of breath or worsening paroxysmal nocturnal dyspnea, may be a direct result of the AF. Many times when we think of the symptoms of AF, we think of things such as a rapid heartbeat. But shortness of breath [in HF patients] may also be a result of the AF. So I look at them as one and the same.
Medscape: So would you consider rhythm control in HF patients who are in AF and who continue to have significant HF symptoms and detrimental hemodynamic changes despite treatment with HF drugs?
Dr. Mangrum: Yes, if the ventricular rate is controlled and they're on a good medical regimen for their HF and are still having HF symptoms, then I think trying a rhythm-control strategy for their AF is very reasonable.
Medscape: What rhythm-control strategy would you use first?
Dr. Mangrum: First-line therapy would be an AAD with cardioversion. It may be that they will convert to a normal rhythm with an AAD alone. But after an appropriate loading dose of AAD, if they are still in AF, then I would use cardioversion.
Medscape: Does AAD therapy pose a greater risk in HF patients? How can physicians minimize this risk?
Dr. Mangrum: The choice of antiarrhythmic drug is based on a number of factors, primarily safety. For patients who have significant LV dysfunction and HF, there are certainly a limited number of drugs to safely choose from, usually amiodarone or dofetilide. Amiodarone has been investigated in the HF population in a number of studies, including GESICA,[10] EMIAT,[11] and CAMIAT,[12] and has been shown to be safe in this particular patient population. That is, the drug is not associated with increased mortality; however, with amiodarone one always has to be cognizant of other side effects, such as thyroid toxicity and, less frequently, pulmonary or liver toxicities. For dofetilide, the primary concern is torsade de pointes, and the incidence is roughly 3% in patients who have significant LV dysfunction. So, patients must be monitored carefully during the initial drug loading, which involves a 72-hour hospital admission.
Medscape: Do the confounding side effects associated with AADs make it difficult to assess comparative study results in these patients, assuming the benefits of maintaining sinus rhythm are at least partially masked by the detrimental side effects of the drugs?
Dr. Mangrum: I think that's a very valid point, and it is indeed hard to make an analysis as there can be quite a high incidence of side effects with AADs. Ideally, we could have more studies in which patients are randomized to different AADs with extensive cardiac monitoring to assure sinus rhythm.
Role of AF Ablation
| Clinical Point The APAF trial,[13] presented at this year's American College of Cardiology meeting, as well as a smaller study published this March in The New England Journal of Medicine,[14] showed that catheter-based AF ablation performed via circumferential pulmonary vein ablation is more effective than AADs for the treatment of paroxysmal and chronic AF, respectively. In the NEJM study, a significantly higher number of patients in the ablation arm were able to maintain sinus rhythm over a 12-month period than in the AAD arm (Figure 4). Similarly, in the APAF trial, 87% of the ablation group was free from AF recurrence at 9 months, compared with 29% of the drug-treatment group (P < .001). Moreover, none of the patients in the APAF ablation group who achieved persistent sinus rhythm required AADs, and all but 1 were able to discontinue their anticoagulant medication. The APAF study also demonstrated positive left atrial remodeling in patients receiving ablation therapy. |
Figure 4.Percentages of patients without AF and atrial flutter in the absence of AAD therapy.[14] Patients in the control group who had recurrent AF and subsequently underwent circumferential pulmonary-vein ablation or resumed amiodarone therapy for recurrent AF were considered to have remained in AF for the remainder of the study. Therefore, the total number of patients randomly assigned to each study group was used as the denominator in calculating the proportions for the respective study groups. Source: Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med. 2006;354:934-941. Permission pending.
Medscape: How does AF ablation therapy currently fit into the treatment continuum for AF patients with HF? Have any studies been performed in this patient population? (Studies mentioned above did not include patients with LV dysfunction.)
Dr. Mangrum: In December 2004, Hsu and colleagues[15] published a study that evaluated the effects of catheter ablation for AF on HF patients with LV dysfunction. After 1 year, maintenance of sinus rhythm without the need for AAD therapy was seen in 69% of patients. Furthermore, maintenance of sinus rhythm was associated with improved clinical function (exercise capacity, quality of life, symptoms) and improved hemodynamics (Figure 5).
Figure 5.Improvement in LV function and dimensions after ablation in patients with CHF. Plotted values are means ± SD. P values, which are for comparison with baseline data, were determined with the use of Fisher's least significant-difference test. The numbers of patients included at each time point were as follows: 0 months, 58; 1 month, 55; 3 months, 48; 6 months, 40; and 12 months, 34. Source: Hsu L, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351:2373-2383. Permission pending.
Medscape: Should AF ablation be considered a first-line therapy in AF patients with low EF?
Dr. Mangrum: In terms of considering it as a first-line therapy, there's not enough data. But in terms of a second-line therapy, if someone with HF and AF is failing AADs, then I think it's certainly appropriate to refer that patient for a catheter-based ablation. In the study mentioned above, these were patients who had already failed at least 2 AADs.
Medscape: Are there subgroups of HF patients who should not receive an AF ablation procedure?
Dr. Mangrum: I think currently it's difficult in the minimally symptomatic AF/HF patient to recommend an ablation procedure. AF ablation, or even a rhythm-control drug strategy, needs to be directed at improving a patient's hemodynamic status or symptoms. There is no evidence yet to suggest that there is a survival benefit associated with one strategy vs another, so at this point, I direct care based on the patient's symptoms.
AV Node Ablation and Pacing -- Should BVP Be Pacing Method of Choice?
| Clinical Point Another treatment option for refractory AF is ablation of the AV node and placement of a permanent pacemaker. Although historically this has been accomplished using a pacemaker that paces only the right side of the heart, the PAVE study[16] was a prospective, randomized, multicenter trial that looked at the use of biventricular pacing (BVP; also known as cardiac resynchronization therapy) in AV node ablation patients, comparing BVP with right ventricular pacing (RVP). After 6 months, better results were demonstrated in both the 6-minute hall walk test and ejection fraction in patients in the BVP arm who had symptomatic HF (NYHA class II/III) and reduced ventricular function (EF ≤ 45%). Those who received BVP had a 31% improvement in hall walk distance, compared with a 24% improvement in the RVP group (P = .04), and EF remained fairly stable in the BVP group, whereas it deteriorated nearly 4% in the RVP group (Figure 6). Patients with a more normal EF and mild HF symptoms demonstrated the same outcomes with both types of pacing devices, so the benefits of BVP appear to be limited to those with more severe HF. The study authors concluded that a BVP device should be considered in AF patients who require AV node ablation and have NYHA class II/III HF symptoms or reduced ventricular function in order to avoid the adverse effects of chronic RVP. |
Figure 6.PAVE results: left ventricular ejection fraction; 6-minute walk test; and Kaplan-Meier survival curves - right ventricular (RV) pacing vs biventricular (BV) pacing. Source: St. Jude Medical, 2006. Available at: http://www.sjm.com/resources/pave.aspx?section=Results.
Medscape: Can you briefly discuss the role of AV node ablation in HF patients with AF? Do you think BVP should be the pacing method of choice in these patients?
Dr. Mangrum: Wood and colleagues[17] provided a nice meta-analysis of AV node ablation in AF patients with poor rate control (Figure 7). Their results showed overall improvement in hemodynamics and functional status in these patients following AV node ablation and pacemaker placement. However, the DAVID trial,[18] which compared dual- vs single-chamber pacing in patients with implantable cardioverter defibrillators, found that those who received dual-chamber devices, and thus had more RVP, developed more HF. I think we've come to realize that we can create ventricular dyssynchrony when we pace the right ventricle over an extended period of time, and that can actually worsen HF in patients with LV dysfunction.
Figure 7.Graphic representations of effect sizes (F) and 95% CIs (error bars) following AV junctional ablation and pacing for measures of: (A) exercise duration, heart rate, and percentage of patients who improved; (B) left ventricular function, healthcare use, and New York Heart Association (NYHA) functional classification; and (C) quality of life and symptoms.[17] Adapted from Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation. 2000;101:1138-1144.
The PAVE trial was designed to compare BVP with RVP to determine whether synchronizing the ventricles with BVP would result in better outcomes following ablation for AF. In fact, the study found that compared with patients who received RVP, those treated with BVP had greater stability in EF and had greater functional improvement. So, I think there are data to suggest that patients who have failed a pharmacologic rate-control strategy and require an AV node ablation should receive BVP. Otherwise, their cardiac output may worsen and they may not gain the improvement in functional class that they could have achieved with BVP.
Medscape: Should BVP be used in patients with any degree of LV dysfunction, or only in a more select group?
Dr. Mangrum: I would follow the criteria used in PAVE, which enrolled patients who were NYHA class II/III with an EF < 45%.
Medscape: Would you try a rhythm-control strategy before you resorted to AV junction ablation and pacing?
Dr. Mangrum: Generally I would; there are some data to support that view. The PABA-CHF study,[19] which was reported at the 2005 meeting of the American Heart Association, compared AF ablation vs AV node ablation with BVP. Although it was a small study, it showed a nice comparison of these 2 treatment modalities. In this unpublished trial, 25 patients were randomized to catheter-based pulmonary vein AF ablation and 26 to AV node ablation plus pacing. At 6-month follow-up, there was a significant improvement in EF in the ablation patients. Also, 6-minute walk scores and quality-of-life scores were higher in the AF ablation group.
So I believe that the message from this study is that if physicians are considering an invasive strategy and the choices are either AV node ablation with BVP or AF ablation, there are some data to suggest that AF ablation should be the first step.
Medscape: The data on catheter-based ablation are increasingly positive. Does that make this a more attractive option for a greater number of HF/AF patients in this "invasive strategy" category?
Dr. Mangrum: Yes, I think that's right.
Medscape: What other clinical studies would you like to see performed to help identify the best treatment strategy for the HF/AF patient population?
Dr. Mangrum: Aside from the AF-CHF study, I'd like to see a larger, multicenter trial comparing AF ablation vs AADs in this particular patient population.
Summary: Current Treatment Recommendations
Medscape: Until further evidence comes to light, what would you recommend to physicians right now as the best way to handle patients with AF and ventricular dysfunction?
Dr. Mangrum: I believe the first step is to make sure the patient is on a good medical regimen for HF and LV dysfunction. This would include at least an ACE inhibitor and beta-blocker. Next, I would assure adequate ventricular rate control with medications --usually a beta-blocker and digoxin, since calcium-channel blockers may further suppress LV function. A target resting heart rate would be approximately 80 bpm and and an exertional heart rate < 110-120 bpm. If this is not achievable or if the patient remains in HF despite good rate control, then I would change to a rhythm-control strategy with cardioversion and an AAD. If there is symptom improvement with rhythm-control drugs, but the medication eventually fails or the patient can no longer tolerate it, then I would refer that patient for an AF ablation. Finally, AV node ablation should be considered if the AF ablation doesn't work and the patient continues to have significant symptoms. Also, whichever treatment strategy is chosen (rate or rhythm control), anticoagulation with warfarin to achieve an INR of 2.0-3.0 should be initiated and maintained.
Trial Glossary
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References
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