Permanent cardiac pacing has been the definitive treatment for symptomatic bradycardia since 1959.^[1] However, as device technology has advanced, notably with the development of dual chamber pacing and, more recently, biventricular pacing, optimal device selection and programming have become more complex. Nowhere is this complexity and controversy more manifest than in those patients with heart failure (HF).

AV Sequential Pacing vs Right Ventricular Apical Pacing

Since Carl Wiggers' seminal observations in 1932, cardiac physiologists have been aware that ectopic ventricular depolarization leads to asynchronous contraction and decreased cardiac output.^[2] Premature ventricular activation leads to atrioventricular (AV), interventricular, and intraventricular dyssynchrony and grossly uncoordinated contraction. In the past decade, several clinical trials have focused on perhaps the most intuitive of these maladaptive changes: AV dyssynchrony. Three large multicenter clinical trials, the Mode Selection Trial (MOST), the Canadian Trial of Physiologic Pacing (CTOPP), and the United Kingdom Pacing and Cardiovascular Events (UKPACE) trial, each randomized over 2000 patients with symptomatic bradycardia and tested the hypothesis that AV sequential pacing (DDD) was superior to right ventricular (RV) apical pacing (VVI).^[3-5] In each of these trials, there was no difference in all-cause mortality, cardiovascular death, or hospitalization for HF between the VVI or DDD pacing groups. Two of these trials did find a decreased risk of atrial fibrillation with DDD pacing, yet the benefit was small (relative risk reduction ~20%). Nonetheless, some investigators have maintained that DDD pacing is preferable to VVI, since DDD pacing is associated with a lower incidence of the pacemaker syndrome and improved quality-of-life scores.^[6,7]

The Dual Chamber And VVI Implantable Defibrillator (DAVID) trial, which compared backup ventricular pacing (VVI-40) with AV sequential pacing (DDDR-70), may explain why prior trials failed to demonstrate a mortality benefit with AV sequential pacing.^[8] DAVID trial investigators hypothesized that in a population of HF patients who had indications for implantable cardioverter defibrillator (ICD) implantation, but no class I indications for pacing, rate-responsive AV sequential pacing with a lower rate limit of 70 beats per minute would allow optimal medical therapy and improve hemodynamics through improved AV synchrony. They further hypothesized that restoration of AV synchrony would lead to improvements in functional class, and decreased mortality. Ultimately, the trial was terminated prematurely because of an increased incidence of death and hospitalization for HF (the primary endpoint) in those randomized to DDDR-70.

Explaining the Results

Why did the patients randomized to DDDR-70 do poorly? The answer lies in the percentage of ventricular pacing in each group: only 1% of the ventricular beats in the VVI-40 arm were paced compared with 60% of all beats in the DDDR-70 arm. Thus, the authors concluded that RV apical pacing may be harmful in patients with HF.

Could it be true? If RV apical pacing is harmful, then why didn't previous pacemaker mode selection trials demonstrate an increased mortality in patients with AV sequential pacing compared with those who were treated with backup VVI? The key difference between these trials lies with the different patient population characteristics. In the DAVID trial, all of the patients had HF and met criteria for ICD implantation. The patients enrolled in DAVID were sicker and had significant left ventricular (LV) dysfunction (LV ejection fraction [LVEF] < 40%), whereas the patients in the mode selection trials, such as MOST, generally had preserved LV function (mean LVEF in MOST was > 55%). This led the DAVID investigators to postulate that RV apical pacing may be harmful because it accelerates the progression of HF in patients with preexisting LV dysfunction. It appears that RV apical pacing, by inducing interventricular and intraventricular dyssynchrony, leads to worsening HF and increased mortality. Of interest, when the events in the MOST trial were analyzed according to the percentage of cumulative ventricular pacing (Figure 1), the investigators found that hospitalization for HF was significantly increased in those patients who experienced greater than 40% cumulative ventricular pacing (hazard ratio [HR] 2.99 [95% CI 1.15 to 7.75]), even in patients with normal LV function (mean LVEF > 55%).^[9]

Figure 1. Rates of heart failure hospitalization in the Mode Selection Trial according to cumulative % of ventricular pacing.^[9]

Treating HF Patients Who Require Antibradycardia Pacing: The Role of Biventricular Pacing

If RV apical pacing is harmful in patients with HF, then what can we offer to our patients who require antibradycardia pacing due to sinus node dysfunction or AV conduction disease? Although no specific trial addresses device and pacing mode selection in HF patients with class I indications for pacemaker implantation, the results of the Left Ventricular Based Cardiac Stimulation Post AV-Nodal Ablation Evaluation (PAVE) study provide important guidance for this relatively new dilemma.^[10]

The PAVE trial enrolled patients with atrial fibrillation and inadequate pharmacologic rate control who required AV nodal ablation and pacemaker implantation. More than 80% of the PAVE patients had class II or III New York Heart Association (NYHA) symptoms, and the mean LVEF was 46%. Following AV nodal ablation, 184 patients were randomized (2:1) to biventricular pacing or rate-responsive RV apical pacing (VVIR). The primary endpoint of the trial was the change in distance during a 6-minute walk after 6 months of therapy. Patients randomized to biventricular pacing had a 31% improvement above baseline compared with 24% in those who received VVIR pacing. Although all-cause mortality was not a prespecified endpoint, there was a trend toward decreased mortality in those who received biventricular pacing compared with VVIR pacing (8 vs 18%, P = .16). Subgroup analysis demonstrated that the benefit in exercise capacity as judged by 6-minute walk was significant in those with NYHA class II/III symptoms or those with LV dysfunction (LVEF < 45%). Finally, the results of PAVE appear to buttress the findings of DAVID. The primary outcome in PAVE was driven not by an improvement in the 6-minute walk test in the biventricular pacemaker patients, but rather by the decline in distance walked in the VVIR patients. Again, it appears that RV apical pacing leads to unfavorable changes and worsening HF.

Biventricular pacing, or cardiac resynchronization therapy (CRT), improves LV function through a variety of mechanisms (Table 1). AV synchrony lengthens diastole, improves atrial contraction and its contribution to diastolic filling, and reduces mitral regurgitation. Additionally, biventricular pacing ameliorates ventricular dyssynchrony, leading to coordinated lateral and septal wall contraction and improved ventricular systolic efficiency.

Table 1. Mechanisms of Cardiac Resynchronization Therapy

AV Synchrony	Ventricular Synchrony
Lengthens diastole Improves atrial contraction and diastolic filling Reduces mitral regurgitation	Coordinates lateral and septal wall contraction Improves mechanical efficiency Decreases wall stress and end systolic volume

Another dilemma in pacing therapy is what to do when patients cannot tolerate beta-blocker therapy following myocardial infarction (MI). Symptomatic bradycardia in the setting of necessary life-saving pharmacotherapy is a class I indication for permanent pacemaker implantation^[11]; nonetheless, many physicians elect to withhold beta-blockade or reduce the dose rather than pursue device therapy. This issue is even more pressing, given the findings of DAVID and the PAVE trial. Many patients following MI have LV dysfunction or will go on to develop LV dysfunction and symptomatic HF. A trial sponsored by the National Institutes of Health is planned to study the role of pacemaker implantation in the setting of post-MI pharmacologic-mediated bradycardia.

How Should the Cardiologist Approach Device Implantation?

Given all of these considerations, how should the cardiologist approach device implantation in those patients who require antibradycardia pacing? First, the clinician should determine whether the patient has a history of HF or LV dysfunction (LVEF < 45%). These are the patients who may go on to develop worsening symptoms, decreased exercise capacity, and perhaps even increased mortality when they are exposed to a high burden of RV apical pacing. If patients do have HF or LV dysfunction, every effort should be made to make sure they are receiving optimal medical therapy including angiotensin-converting enzyme inhibition. Additionally, if the LV dysfunction can be improved through revascularization (percutaneous or surgical) or mechanical therapy (eg, valve repair or replacement), every attempt should be made to improve any reversible LV dysfunction.

If the patient continues to have significant LV dysfunction or HF, consideration should be given to biventricular pacing and CRT. Patients receiving optimal and stable medical therapy who have NYHA class III/IV symptoms, LVEF ≤ 35%, and evidence of electrical dyssynchrony (QRS > 120 ms) meet current criteria for biventricular pacing and should receive CRT.^[12] However, patients who do not meet the full criteria but have LV dysfunction (LVEF < 45%) and class II/III symptoms should also be considered as candidates for biventricular pacing since these patients appear to have worse outcomes with RV apical pacing (Figure 2). Furthermore, up to 50% of patients with a QRS < 120 ms also have evidence of mechanical dyssynchrony.^[13] Novel pacemaker programming, which allows prolonged native AV conduction (AAIR with permissive AV intervals > 300 ms and backup DDDR) can minimize ventricular pacing and may improve outcomes.^[14] Minimal ventricular pacing modes represent an attractive alternative in patients with HF who require antibradycardia pacing.

Figure 2. Device selection algorithm.

In patients with preserved LV function, but with NYHA class I HF or risk factors for the development of symptomatic HF (eg, LV hypertrophy), the decision of which device to implant is difficult. Alternative pacing sites, including pacing from the RV outflow tract,^[15,16] may cause less ventricular asynchrony compared with RV apical pacing and are actively being investigated as potential alternatives to apical pacing in patients who are at risk of developing asynchrony but who do not meet full criteria for biventricular pacing. The best available evidence suggests that these patients do not appear to derive a mortality benefit from AV sequential pacing; however, they may have fewer symptoms, a lower risk of pacemaker syndrome, and fewer atrial arrhythmias. On the other hand, every attempt should be made to avoid unnecessary pacing, as adverse outcomes appear to correlate with the cumulative percentage of ventricular pacing. Finally, for those patients who currently have either a dual-chamber or single-chamber pacemaker with evidence of LV dysfunction or worsening HF symptoms, strong consideration should be given to upgrading to biventricular pacing. To date, several trials have shown that patients benefit from the addition of CRT.^[17-19]

Once patients with HF have received a biventricular pacemaker, what mode of pacing should they receive? At the present time, there are no data to guide DDD programming in these patients. Many patients with HF who have a biventricular pacemaker have iatrogenically induced chronotropic incompetence from therapeutic beta-blockade. The possible benefits of atrial support pacing in CRT patients include increased cardiac output, ensuring chronotropic competence, allowance for maximal medical therapy, and a decreased incidence of atrial arrhythmias. Should these patients be programmed to DDD-50 or a higher rate, such as DDD-70? Should they receive rate-responsive pacing (eg, DDDR-60)? Although we don't have answers to these questions at the present time, the Pacing Evaluation-Atrial Support Study in Cardiac Resynchronization Therapy (PEGASUS CRT) trial will provide much needed guidance in these programming decisions. PEGASUS CRT is a multicenter, randomized, controlled trial that will enroll over 1200 CRT patients to 1 of 3 treatment arms: DDD-40, DDD-70, or DDDR-40. Overall mortality, hospitalization for HF, and NYHA class will be compared between treatment groups through a clinical composite score. It is important to recall that the results of the DAVID trial will not apply to these patients, since they will all be receiving biventricular pacing, not solitary RV apical pacing.

Conclusions

Patients with HF who require antibradycardia pacing represent a challenging dilemma. The results of several recent trials have confirmed that RV apical pacing induces ventricular dyssynchrony and is harmful. Although patients on optimal medical therapy who have significant LV dysfunction, a wide QRS, and class III/IV NYHA symptoms should receive biventricular pacing, strong consideration should be given to the implantation of biventricular pacemakers in all patients with symptomatic HF or LV dysfunction who have class I indications for antibradycardia pacing. The data are clear: RV apical pacing is associated with worsening HF and increased mortality. When considering pacemaker implantation in patients with HF, we should remember to do no harm.

References

1. Elmquist R, Senning A. An implantable pacemaker for the heart. Proceedings of the Second International Conference on Medical Electronics; Paris, France; June 1959.
2. Wiggers CJ. The muscular reactions of the mammalian ventricles to artificial surface stimuli. Am J Physiol. 1925;73:346-378.
3. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med. 2002; 346:1854-1862. Abstract
4. Connolly SJ, Kerr CR, Gent M, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med. 2000;342:1385-1391. Abstract
5. Toff WD, Camm AJ, Skehan JD; United Kingdom Pacing and Cardiovascular Events Trial Investigators. Single-chamber versus dual-chamber pacing for high-grade atrioventricular block. N Engl J Med. 2005;353:145-155. Abstract
6. Sulke N, Chambers J, Dritsas A, et al. A randomized double-blind crossover comparison of four rate-responsive pacing modes. J Am Coll Cardiol. 1991;17:696-706. Abstract
7. Sulke N, Dritsas A, Bostock J, et al. "Subclinical" pacemaker syndrome: a randomised study of symptom free patients with ventricular demand (VVI) pacemakers upgraded to dual chamber devices. Br Heart J. 1992;67:57-64. Abstract
8. Wilkoff BL, Cook JR, Epstein AE , et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288:3115-3123. Abstract
9. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107:2932-2937. Abstract
10. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol. 2005;16:1160-1165. Abstract
11. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation. 2002;106:2145-2161. Abstract
12. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154-e235. Abstract
13. Yu CM, Lin H, Zhang Q, et al. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart. 2003;89:54-60. Abstract
14. Sweeney MO, Shea JB, Fox V, et al. Randomized pilot study of a new atrial-based minimal ventricular pacing mode in dual-chamber implantable cardioverter-defibrillators. Heart Rhythm. 2004;1:160-167. Abstract
15. de Cock CC, Giudini MC, Twisk JW. Comparison of the hemodynamic effects of right ventricular outflow-tract pacing with right ventricular apex pacing. Europace. 2003;5:275-278. Abstract
16. Giudici MC, Barold S, Paul DL, et al. Right ventricular outflow tract placement of defibrillation leads: five year experience. PACE. 2004;27:443-446. Abstract
17. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol. 2002;39:1258-1263. Abstract
18. Baker CM, Christopher TJ, Smith PF, et al. Addition of a left ventricular lead to conventional pacing systems in patients with congestive heart failure: feasibility, safety, and early results in 60 consecutive patients. Pacing Clin Electrophysiol. 2002;25:1166-1171. Abstract
19. Joseph GK, Civello KC, Burkhardt JD, et al. Benefits of cardiac resynchronization therapy extends to patients with mechanical dyssynchrony secondary to right ventricular pacing. Heart Rhythm. 2004;1:S15.

Editor's Note

Microvolt T-wave alternans (MTWA) testing is a noninvasive, electrocardiographic test that can be performed in a physician's office with modifications to currently available exercise testing equipment. The test measures beat-to-beat microvolt variations in the shape, amplitude, or timing of the electrocardiographic T-wave that are linked with the development of clinical ventricular arrhythmias.^[1]

The first large, prospective, multicenter trial to investigate the use of MTWA testing for risk stratification in heart disease patients who are potential candidates for prophylactic implantable cardioverter defibrillator (ICD) implantation was recently published in the Journal of the American College of Cardiology (JACC).^[1] The findings of this study suggest that MTWA testing may be an effective way to identify low-risk patients who are unlikely to benefit from ICD implantation. About one third of the enrolled patients had negative MTWA tests and were classified as low-risk, and in this group, there were significantly fewer deaths and life-threatening arrhythmias over the course of a 2-year follow-up period than in patients with positive or indeterminate tests who were classified as high-risk. Overall survival in the low-risk group was 97.5% at 2 years.

Although the study findings are compelling, they raise several questions about how such a test could be implemented in clinical practice and whether MTWA testing is ready for routine use. Medscape recently sat down with Anne B. Curtis, MD, Director of the Division of Cardiology at the University of South Florida (Tampa, Florida), President of the Heart Rhythm Society, and one of the authors of the aforementioned study, to discuss these and other issues related to MTWA testing. According to Dr. Curtis, MTWA is a very promising test to help rule out ICD therapy in certain patients, but it may not quite be ready for routine clinical use.

Medscape: Can you briefly describe for us how MTWA works and how it reflects arrhythmia risk?

Dr. Curtis: The microvolt T-wave alternans is something that was originally detected on a gross level. There were instances where patients were observed to have alterations in the size of the T-waves grossly on electrocardiogram (ECG), and in some cases these patients actually spontaneously experienced serious arrhythmias as a result. With further study, it was found that this also occurred on a microvolt level -- you couldn't see it with the naked eye, but if you analyzed [the ECG] with the appropriate software, you could detect the differences in the signal. It's not really 100 percent clear how the T-wave alternans actually provokes an arrhythmia, but we've seen a very clear correlation between the two.

Medscape: Is this an easy test for physicians to use and interpret? Can it be utilized widely by non-electrophysiologists, including primary care physicians?

Dr. Curtis: This is a test that can be used widely, but it really isn't easy to interpret. Most of the time, T-wave alternans testing is done on a treadmill to increase the heart rate. You can also use atrial pacing, but of course, unless you've got a pacemaker implanted, that's more invasive.

However, technically, it's a little bit more challenging than a routine treadmill test. The key is to get the heart rate elevated, but not too elevated. If you get a very high heart rate, there are people who will have T-wave alternans but it's not very meaningful. What is meaningful, or potentially serious, is if you observe a T-wave alternans at more moderate heart rates, in the range of 105-110 beats per minute.

So the trick is that you've got to get someone walking enough to get the heart rate to that level, but you don't want to push them so hard that they go beyond it. That's why a lot of times a standard [exercise testing] protocol is not appropriate because patients will quickly go beyond the ideal heart-rate range. You need a technician who is knowledgeable enough to take the treadmill test slowly, and when the patient does hit the target heart rate, to maintain that exercise level for a couple of minutes so that the data can be collected.

Interpretation of the results is fairly complicated, and because of this complexity, software has been developed that will basically allow a fairly automatic interpretation of the test. Physicians are supposed to over-read that, but most physicians, even the majority of cardiologists, wouldn't have the expertise to interpret the results of a T-wave alternans test independently without some help from the software. The algorithms are fairly complicated; they're learnable, but they're complicated.

The way the test is interpreted, patients are classified as positive, negative, or indeterminate. Someone can have an indeterminate test because, for example, that person has a lot of PVCs [premature ventricular contractions] and that makes the test hard to read. But the studies seem to indicate that both positive and indeterminate tests carry the same kind of prognostic meaning. As a result, we separate patients into the negatives, or low-risk category, and then lump the positives and indeterminate patients together into the same high-risk category.

Medscape: In presenting the JACC study results, you and the other authors seem to emphasize the utility of MTWA to identify individuals who are not candidates for ICDs, rather than those who are. Is this the most important message we should take from that study -- that MTWA is an effective way to identify low-risk patients who are not likely to benefit from ICD therapy?

Dr. Curtis: Yes, that's the point we were trying to make -- that patients with a negative T-wave alternans test are indeed a low-risk group. Certainly, if a positive test absolutely predicted that somebody was going to have an event, that would be even more powerful, and [a positive T-wave alternans test] does increase the risk of an event quite a bit. You can see that from the hazard ratio in the study [the hazard ratio for the primary endpoint of all-cause mortality, comparing patients with negative vs positive/indeterminate MTWA tests, was 6.5 (95% CI 2.4 to 18.1; P < .001)]. But it's the negative tests that indicate a low risk, so that's the message.

Medscape: Let's talk a bit about patient selection for prophylactic ICD therapy. Why is better risk stratification needed for these patients?

Dr. Curtis: We're putting in a lot of prophylactic defibrillators today. We know that the therapy works and that's why we're doing it, but there are still a lot of patients who get defibrillators and never end up using them. If we could identify a low-risk group in whom it would be safe to avoid ICD implantation then that would be a good thing -- the patient wouldn't have to go through the procedure and it would lower healthcare costs, and have other positive effects as well.

Medscape: What are some of the specific adverse patient effects associated with ICD implantation and therapy that would make patients and physicians want to avoid unnecessary implants?

Dr. Curtis: There are several surgical and mechanical complications associated with the device and the implantation procedure. There are complications related to the implantation procedure itself. The device can get infected and need to be removed. There is also the risk of lead dislodgement, and over the long haul, the leads can break down and need to be replaced.

However, the most important adverse event for the majority of patients is an inappropriate shock. For example, patients will sometimes develop atrial fibrillation, which is a benign arrhythmia, but one that can still make the device discharge. At that point, the ICD becomes a quality-of-life issue for the patient. Obviously an ICD shock is an unpleasant experience for the patient, and both patients and doctors want to avoid unnecessary shocks. So patients end up taking medicines to prevent the arrhythmia and avoid inappropriate shocks.

Medscape: In the JACC study, about one third of the patients enrolled were ruled out for prophylactic ICD therapy because they were deemed low risk as a result of MTWA testing. That's quite a large percentage. Do you think these findings will apply in general practice if the test is used on a wide-scale basis?

Dr. Curtis: I think there's a possibility of that. The results of the study certainly tend to support that idea. There is another study that's in the follow-up phase right now called ABCD [Alternans Before Cardioverter Defibrillator], and it also is looking at the use of T-wave alternans for identifying high- and low-risk groups. If that study confirms these sorts of results, that negative MTWA patients have very low risk, we may well get to the point of being able to eliminate defibrillators in these patients.

The biggest issue and what's so tough for physicians is deciding what our tolerance is for any event beyond zero in these low-risk patients. I am confident that a negative result on T-wave alternans testing makes the likelihood of an event much lower. But if you take the likelihood of an event and you drop it down to a 99% assurance that nothing's going to happen, is that good enough? That still means there's a 1% chance that something is going to go wrong. The problem is that if you're in that 1%, you want to have a defibrillator, but then the other 99% are treated unnecessarily. So we may need to reach some consensus as to what level of risk we're willing to accept. Maybe an event risk of 1% to 2% over time fits into the acceptable range because that's about the risk of a complication with the ICD implantation procedure, but we haven't reached that consensus yet.

Medscape: Despite these issues, in your opinion, are there now enough data to suggest that MTWA should be used routinely to screen potential patients for prophylactic ICD therapy?

Dr. Curtis: I think the test is useful for ruling out ICD therapy in selected patients, particularly ones who are reluctant to have a defibrillator implanted. I've occasionally used tests like this in patients who are older or who are reluctant to get an ICD, and if the test is negative, I feel more comfortable about the decision not to implant. I'm personally not using it as a routine screening tool right now to eliminate defibrillators in patients. I'm waiting for the results of the ABCD study to see how that pans out before I make a final decision.

Medscape: What about study duration and additional testing? The JACC study followed patients for 2 years and measured MTWA only once. Is there a need for longer-term follow-up and perhaps repeat measurements in patients who are initially ruled out for an ICD before we can say that this test should be used routinely?

Dr. Curtis: I don't know how much longer-term follow-up is necessary, but I think one thing that would be interesting is to repeat the MTWA testing periodically and see if the patient changes. That hasn't been studied specifically in trials performed to date. I think it would be interesting to see over time whether the MTWA findings change in many of the patients so that some of those who were in the low-risk group at the beginning of the study change to the high-risk group later on.

Medscape: Are there other risk predictors that could be combined with MTWA to further improve risk stratification? Some studies suggest that BNP (B-type natriuretic protein) levels may also predict risk in potential ICD patients.

Dr. Curtis: I think BNP is unlikely to be very helpful for us in stratifying these patients because BNP levels rise for so many reasons. And when BNP goes up for reasons related to sudden death, it's usually because of poor heart function.

The biggest problem we have in all of this risk stratification business is that the most important risk stratifier is low EF [ejection fraction]. We know that, but we also know that not everyone with a low EF has a cardiac arrest. So if a very potent risk stratifier like EF doesn't tell me who's at highest risk for an event, what else can I use?

There have been other tests used in the past. We used to look at PVCs and hope that by quantifying them, we could tell who was at risk. Well, that didn't work out very well. Signal-averaged ECG was touted for a while, but it was determined to have a very low positive predictive value. All of these tests tend to be better at ruling out people than ruling in who's going to need a device. So no matter what risk stratifier we use, we're always going to be faced with the situation that we can rule out only a minority of patients. One third of patients isn't bad, but unless we significantly improve our understanding of the pathophysiology of heart disease in individual patients, I can't see us ever getting to a point where we'd be able to identify a certain 5% of the population that is at highest risk and classify everyone else at much lower risk.

Medscape: What about liability issues for physicians if they're going to try to rule out patients? Do you think physicians are going to accept risk stratifiers like MTWA as a means for limiting ICD therapy, or are the Centers for Medicare and Medicaid Services going to have to come in and mandate the test as a benchmark? What do you think it will take for physicians to accept this?

Dr.Curtis: Probably clinical practice guidelines. If guidelines are revised to recommend this test, then that indicates there's enough data out there to feel comfortable about this. Guidelines do drive practice because major organizations have come together and made these determinations. I think that does make people feel very comfortable.

Short of that, as I said before, we'll need to reach some type of consensus about how much risk we're willing to accept. Today, when we have a heart failure patient with a low EF, we need to implant because SCD-HeFT [Sudden Cardiac Death in Heart Failure Trial]^[2] really did not eliminate people for any reason, as long as they had heart failure and a low EF. But if we use risk stratifiers like MTWA, other questions arise. When does low risk become low enough that physicians don't have to worry that if someone has an event, they're going to be questioned about why they didn't implant in that patient?

Medscape: Thank you for taking the time to speak with us today.

References

1. Bloomfield DM, Bigger, JT, Steinman RC, et al. Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006;47:456-463. Abstract
2. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-237. Abstract

As noted in the recently released Heart Failure Society of America 2006 Comprehensive Heart Failure Practice Guideline,^[1] the routine use of dual chamber pacemaker therapy is not recommended for patients with heart failure (HF) in the absence of symptomatic bradycardia or high-grade atrioventricular block. This is based on the results of the Dual-Chamber and VVI Implantable Defibrillator (DAVID)^[2] trial, which found that in patients with an indication for implantable cardioverter defibrillator (ICD) therapy, no indication for cardiac pacing, and left ventricular (LV) dysfunction (left ventricular ejection fraction [EF] ≤ 40%), chronic right ventricular pacing (RVP) offers "no clinical advantage over ventricular backup pacing and may be detrimental by increasing the combined endpoint of death or hospitalization for HF."

The detrimental effects of RVP are more pronounced in patients with higher percentages of ventricular paced beats.^[3] For example, in the DAVID trial, pacing accounted for only 1% of all beats in the ventricular-only backup pacing (VVI) group vs 60% in the dual-chamber rate-responsive pacing (DDDR) group,^[4] which was associated with the unfavorable finding in the latter treatment group. In a subsequent DAVID substudy, investigators reported that frequent RVP, not device, was an independent predictor of adverse events and that patients treated with a DDDR device with less than 40% of ventricular beats paced had similar or better outcomes than patients in the VVI back-up pacing group.^[5] Similarly, in a substudy from the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II trial,^[6] investigators found that patients who were "predominantly paced" had a higher rate of new or worsened HF compared with patients who were only infrequently paced (cumulative pacing > 50% vs ≤ 50%).

Simply summarized, the deleterious effects of chronic RVP are attributable to deterioration of LV function brought on by RVP-induced left-bundle branch block (LBBB) that results in uncoordinated ventricular activation, known as ventricular dyssynchrony.^[1,7] This pacing-induced state increases end-systolic volume and wall stress and reduces systolic function and cardiac output,^[4] which are clinically manifested by shortness of breath, fluid retention, fatigue, and other symptoms.

Cardiac resynchronization therapy (CRT), also known as biventricular pacing (BVP), specifically targets the adverse effects of ventricular dyssynchrony, secondary to LBBB.^[7] Using 2 ventricular leads, BVP is designed to simultaneously stimulate the left and right ventricles,^[4] which leads to coordinated lateral and septal wall contraction and improved ventricular systolic efficiency.^[8]

An accompanying editorial published with the DAVID report in JAMA^[4] questions whether the study's findings imply that any patient with underlying, but minimal, HF symptoms should always receive a CRT device or "whether leaving well enough alone is preferred, by reducing the backup rate to pace the heart only if really needed." The editorialist suggests that, "In an era of rapidly advancing and costly technology, the simpler solution is attractive." But, he argues, a clear consensus cannot be drawn "from currently available data and will require more studies."^[4]

Although the above comments refer to the role of backup ICD pacing in a patient with impaired LV function but no pacing indication, the same question applies regarding the role of CRT in HF patients with an indication for antibradycardia pacing. The role of CRT in this setting continues to be a focus among researchers, albeit in relatively small studies. The following provides a brief summation of recent studies suggesting that CRT may be more favorable than RVP when managing patients with HF and an indication for pacing.

BVP Reduces Progression of HF. The adverse effects associated with ventricular dyssynchrony and LV deterioration secondary to RVP are made worse by existing underlying LV dysfunction. The results of a retrospective study conducted by Ritter and colleagues^[9] suggest that the exacerbation of HF in patients with LV dysfunction at baseline is evident within as early as 6 months of initiating pacing therapy. The progression of HF, measured by echocardiographic parameters, New York Heart Association (NYHA) functional class, and incidence of HF hospitalization, was compared between patients treated with RVP (n = 59) and those treated with BVP (n = 48). Of note, patients in the BVP group had more advanced HF than patients in the RVP group at baseline (EF 23% vs 43%). Despite this statistic, investigators found that following 6 months of assigned therapy, EF significantly decreased and LV end-diastolic diameter (LVEDD) significantly increased in the RVP group compared with baseline measures. By contrast, in the BVP group, EF significantly increased and LVEDD significantly decreased from baseline to follow-up. In addition, patients in the RVP group had a higher rate of hospitalizations for HF than in the BVP group (P < .05 for all comparisons). On the basis of their findings, the authors concluded that "patients with an indication for pacemaker therapy because of bradycardia and coexisting mild-to-moderate heart failure might benefit from early implantation of a CRT system." (Int J Cardiol. 2005 Nov 15; [Epub ahead of print]; Abstract.)

BVP Following Long-term RVP. The results of a small, randomized, double-blind crossover study^[10] suggest that pacemaker patients with severe HF benefit from an upgrade to BVP. The study included 10 patients with a dominant paced rhythm and no LBBB in the pre-pacing electrocardiogram who developed severe HF (NYHA class III-IV) after receiving a conventional RV pacemaker for bradyarrhythmia. Patients were randomized to a 2-month period of either RVP or BVP, after which they were crossed over to the other pacing mode. Investigators reported that distance walked, BNP levels, and symptom scores all significantly improved during the BVP period compared with both baseline and RVP. By contrast, during the RVP period, these parameters showed a slight trend toward deterioration from baseline, but the differences were not significant. Despite the obvious limitation posed by the small number of patients, the authors believe that their study is "the first study of patients with long-term RVP (median 5.7 years)" and "represent[s] the everyday spectrum of pacemaker patients." (Europace. 2006;8:51-55.)

BVP Lessens the Pathogenesis of HF. The authors of this study^[11] sought to determine whether the benefits of upgrading to BVP from RVP correlated with changes in indices of peripheral immune activation (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and indices of oxidative stress (nitric oxide metabolites [NO(x)] and malondialdehyde [MDA]) -- all measurable factors in HF. The study included 28 patients with existing BVP system that were "switched" back to RVP for 1 week and then returned to the BVP mode. Echocardiographic and serum assessments were measured immediately prior to, and 48 hours after, returning to BVP. Investigators found that after 48 hours of returning to BVP, LV systolic function significantly improved (P < .001) and mitral regurgitation (MR) significantly decreased (P = .003). These changes were also accompanied by a decrease in TNF-alpha (P = .02), IL-6 (P < .001), and MDA (P < .001) and an increase in NO(x) (P = .04). The decreases in TNF-alpha, IL-6, and MDA noted during BVP occurred in both responders and nonresponders and were accompanied by a reduction in MR, investigators reported. These findings, they conclude, suggest that, "The beneficial effect of BVP compared to RVP extends beyond improving cardiac haemodynamics and comprises a decrease in immune activation accompanied by an increase in serum NO(x) and decrease in serum MDA." (Eur J Heart Failure. 2006 Feb 4; [Epub ahead of print]; Abstract.)

References

1. Adams KF, Lindenfeld J, Arnold JMO, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Cardiac Failure. 2006;12:e1-e122.
2. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288:3115-3123. Abstract
3. Auricchio A. Cardiac resynchronization therapy: does varying the pacing site or combination of sites improve cardiac function? Nat Clin Pract Cardiovasc Med. 2005;2:288-289. Abstract
4. Kass DA. Pathophysiology of physiologic cardiac pacing: advantages of leaving well enough alone. JAMA. 2002;288:3159-3161. Abstract
5. Sharma AD, Rizo-Patron C, Hallstrom AP, et al; DAVID Investigators. Percent right ventricular pacing predicts outcomes in the DAVID trial. Heart Rhythm. 2005;2:830-834. Abstract
6. Steinberg JS, Fischer A, Wang P, et al; MADIT II Investigators. The clinical implications of cumulative right ventricular pacing in the multicenter automatic defibrillator trial II. J Cardiovasc Electrophysiol. 2005;16:359-365. Abstract
7. Sweeney MO. Minimizing right ventricular pacing: a new paradigm in cardiac pacing. Medscape Cardiology 2004. Available at: http://www.medscape.com/viewarticle/481135.
8. Hranitzky P. Pacing in heart failure: First, do no harm. Medscape Cardiology 2006.
9. Ritter O, Koller ML, Fey B, et al. Progression of heart failure in right univentricular pacing compared to biventricular pacing. Int J Cardiol. 2005 Nov 15; [Epub ahead of print].
10. Höijer CJ, Meurling C, Brandt J. Upgrade to biventricular pacing in patients with conventional pacemakers and heart failure: a double-blind, randomized crossover study. Europace. 2006;8:51-55.
11. Rubaj A, Rucinski P, Rejdak K, et al. Biventricular versus right ventricular pacing decreases immune activation and augments nitric oxide production in patients with chronic heart failure. Eur J Heart Fail. 2006 Feb 4; [Epub ahead of print].

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