Friday, May 25, 2007
cardioversion 3de blz van het artikel state of the art
Maintenance of Sinus Rhythm Following Cardioversion
Even if the patient is cardioverted successfully, AF can recur. In the long-term, this will relate to the underlying pathology, that is, the combination of substrate and triggers which initiated the process in the first place. As discussed above, AF itself induces further electrophysiological and structural changes perpetuating the arrhythmia. A proportion of these are reversible in the face of the continued maintenance of sinus rhythm. These changes contribute additionally to the risks of immediate and early post-cardioversion failure. In the absence of anti-arrhythmic medication, the risk of recurrent AF following cardioversion in unselected patients is approximately 65%.[86] This can be reduced to approximately 50% using conventional drugs, such as quinidine, sotalol, flecainide, propafenone, and to approximately 35% with amiodarone.[87-90] The wisdom of considering cardioversion without concomitant anti-arrhythmic medication must be questionable other than in specific cases where the risk of recurrence is deemed to be low; for instance where AF occurs in the context of a transient medical condition, such as intoxication, thoracic surgery, or pneumonia.
Numerous studies over the last four decades investigating the effectiveness of anti-arrhythmic medication in this respect have been comprehensively reviewed in the ACC/AHA/ESC guidance on AF management[1] and by McNamara et al.[2] Drugs may themselves occasionally induce cardioversion in AF of short duration, that is, less than 7 days. Pharmacological attempts at cardioversion can be tried, particularly if electrical cardioversion is acutely contraindicated for anesthetic reasons. Furthermore, in selected patients it may be safe for these medications to be initiated on an outpatient basis in order to prevent hospital admission. This is the so-called "pill-in-the-pocket" approach and can be both clinically effective and cost-effective.[90]
The choice of anti-arrhythmic medication depends largely on patient factors. Class Ic drugs tend to be well-tolerated in young patients and are generally safe in patients with structurally normal hearts. Sotalol may be less well-tolerated by the young but may be preferable in those with coronary disease; its potential for proarrhythmia is shared by class Ia agents. Medication that has some intrinsic rate-slowing action (e.g., sotalol, propafenone) is often better tolerated should AF recur. Amiodarone is clearly the most effective agent with the lowest risk of proarrhythmia but its long-term extracardiac side effects are a significant limitation.
Recent advances in our understanding of the pathophysiology of AF have suggested two new strategies to improve long-term outcomes following cardioversion. Firstly, it is possible that drugs not conventionally thought to affect atrial electrophysiology may be of benefit, partly by reversing the effects of AF-induced remodeling. Secondly, early cardioversion may attenuate adverse atrial remodeling which may in turn promote the long-term maintenance of sinus rhythm.
Calcium Channel Blockade
Intracellular calcium overload appears to be an important step in the induction of AF-induced electrical remodeling. It has therefore been postulated that the use of calcium channel blockers may prevent or help to reverse this change. This hypothesis has led a number of groups to investigate the use of this medication in the prevention of AF recurrence. These studies are summarized in Table 4 . A proportion had positive outcomes, perhaps suggesting some role in the first week post-cardioversion. Not all of the studies were positive, however, and the use of this medication routinely for anything other than rate control remains controversial and is not formally recommended in current guidance.
Renin-Angiotensin System
As discussed earlier, the renin-angiotensin system appears important in atrial remodeling and may therefore contribute to the perpetuation of AF. Several studies, which have been published examining the effects of inhibitors of this system, are summarized in Table 4 . Although there are limited data, these medications may well affect recurrence, at least in the medium term. This impression is also suggested by the results of two recent meta-analyses[102,103] which examined the effects of these classes of drugs on AF in major, multi-center trials of hypertension, heart failure, and post-myocardial infarction patients. More studies are needed to prove this conclusively and whether this will lead to long-term improvements in sinus rhythm maintenance is uncertain.
HMG CoA Reductase Inhibitors
There is some evidence of the importance of oxidative stress and inflammation in the atria of AF patients. It has been the hypothesis in a couple of studies that treatment with the HMG CoA reductase inhibitors, the statins, may affect AF. A retrospective study of 62 patients strongly suggested a benefit from statin use[104] but this was not confirmed in the prospective randomized study of Tveit et al. in 114 patients.[105] Statin use cannot therefore be recommended at this stage for the prevention of recurrent AF following cardioversion.
Early Cardioversion as a Strategy to Prevent Remodeling
As remodeling is clearly important in the perpetuation of AF, at least a proportion of which is reversible, the concept of early and repeated cardioversion developed; the theory being that as the remodeling reversed, the time between AF recurrences would gradually lengthen, eventually producing long-term sinus rhythm maintenance. This has been examined in small studies[106]; although atrial electrophysiology appeared to improve, the effect on clinical outcome was disappointing. In order to simplify the process, an implantable atrial defibrillator was developed[107]; however, again the results were unsatisfactory in the long-term in a significant proportion of patients.[108] Clearly AF triggers and at least a part of the AF substrate remained; in a proportion the repeated shocks, even at low energy, were a significant disadvantage. The standalone atrial defibrillator never found widespread use although the capability to cardiovert AF, automatically or on command, remains a feature of certain ICDs.
Cardioversion of sustained AF traditionally requires a period of prior anti-coagulation (a month, following current guidelines) to minimize the thromboembolic risk. In theory this delay should increase atrial remodeling and thus the risk of AF recurrence after cardioversion. The ACUTE study[109,110] compared the strategy of early cardioversion guided by trans-esophageal echocardiography (TEE; to exclude pre-existing left atrial thrombus) to the conventional approach. One thousand two hundred and twenty-two patients with AF of more than 48 hours duration were randomized to either a conventional approach or a TEE-guided approach. Those in the TEE group were cardioverted sooner (TEE: 3.0 ± 5.6 days vs conventional: 30.6 ± 10.6 days; P < 0.001) and suffered fewer major and minor hemorrhagic events (TEE: 2.9% vs conventional: 5.5%; P = 0.03). Embolic events were equally infrequent, however (TEE: 0.8% vs conventional: 0.5%; P = 0.5). Acute cardioversion success was not different (TEE: 80.3% vs conventional: 79.9%; P = 0.9) as was maintenance of sinus rhythm at 8 weeks (TEE: 52.7% vs conventional: 50.4%; P = 0.43). Although this important study confirmed the safety of the echo-guided approach, it was disappointing in that the accelerated cardioversion strategy failed to have any impact on AF recurrence.
In conclusion, while this approach is safe, the shortening of the period before cardioversion may be insufficient to have a significant impact on atrial remodeling, and thus to improve the maintenance of sinus rhythm.
Future Developments/Research
While the overall technique of cardioversion has changed little over the past 40 years, there have been a number of technical developments which have improved acute success rates. These include the rigorous attention to technical detail, biphasic cardioversion, and the use of adjuvant drugs for almost all from the start, including anti-arrhythmics and others. For those who remain resistant to this approach, internal cardioversion remains a potential option. The major challenge however is the prevention of recurrence; this can certainly be improved with conventional adjuvant anti-arrhythmics, probably with angiotensin converting enzyme (ACE) inhibition, and possibly with calcium antagonists in addition. A large trial examining the combination of all of these would be of great interest. It should of course be emphasized that a single recurrence on one anti-arrhythmic does not necessarily mean that the option has failed; for some patients infrequent periodic cardioversion, perhaps once a year, may be a very satisfactory result. In spite of the negative findings from ACUTE, it seems reasonable to cardiovert as early as practicable. In the future, the continued development of AF ablation will change the role of cardioversion; the return of sinus rhythm is only the start of the process. It is likely that the technique will further develop with new shock waveforms,[111] new anti-coagulants,[112] and novel atrial-selective anti-arrhythmics.[113] Cardioversion should therefore not be considered a strategy in itself, more part of a number of anti-arrhythmic strategies which can be selected for patients on an individual basis involving medication, ablation, and device therapies.
Even if the patient is cardioverted successfully, AF can recur. In the long-term, this will relate to the underlying pathology, that is, the combination of substrate and triggers which initiated the process in the first place. As discussed above, AF itself induces further electrophysiological and structural changes perpetuating the arrhythmia. A proportion of these are reversible in the face of the continued maintenance of sinus rhythm. These changes contribute additionally to the risks of immediate and early post-cardioversion failure. In the absence of anti-arrhythmic medication, the risk of recurrent AF following cardioversion in unselected patients is approximately 65%.[86] This can be reduced to approximately 50% using conventional drugs, such as quinidine, sotalol, flecainide, propafenone, and to approximately 35% with amiodarone.[87-90] The wisdom of considering cardioversion without concomitant anti-arrhythmic medication must be questionable other than in specific cases where the risk of recurrence is deemed to be low; for instance where AF occurs in the context of a transient medical condition, such as intoxication, thoracic surgery, or pneumonia.
Numerous studies over the last four decades investigating the effectiveness of anti-arrhythmic medication in this respect have been comprehensively reviewed in the ACC/AHA/ESC guidance on AF management[1] and by McNamara et al.[2] Drugs may themselves occasionally induce cardioversion in AF of short duration, that is, less than 7 days. Pharmacological attempts at cardioversion can be tried, particularly if electrical cardioversion is acutely contraindicated for anesthetic reasons. Furthermore, in selected patients it may be safe for these medications to be initiated on an outpatient basis in order to prevent hospital admission. This is the so-called "pill-in-the-pocket" approach and can be both clinically effective and cost-effective.[90]
The choice of anti-arrhythmic medication depends largely on patient factors. Class Ic drugs tend to be well-tolerated in young patients and are generally safe in patients with structurally normal hearts. Sotalol may be less well-tolerated by the young but may be preferable in those with coronary disease; its potential for proarrhythmia is shared by class Ia agents. Medication that has some intrinsic rate-slowing action (e.g., sotalol, propafenone) is often better tolerated should AF recur. Amiodarone is clearly the most effective agent with the lowest risk of proarrhythmia but its long-term extracardiac side effects are a significant limitation.
Recent advances in our understanding of the pathophysiology of AF have suggested two new strategies to improve long-term outcomes following cardioversion. Firstly, it is possible that drugs not conventionally thought to affect atrial electrophysiology may be of benefit, partly by reversing the effects of AF-induced remodeling. Secondly, early cardioversion may attenuate adverse atrial remodeling which may in turn promote the long-term maintenance of sinus rhythm.
Calcium Channel Blockade
Intracellular calcium overload appears to be an important step in the induction of AF-induced electrical remodeling. It has therefore been postulated that the use of calcium channel blockers may prevent or help to reverse this change. This hypothesis has led a number of groups to investigate the use of this medication in the prevention of AF recurrence. These studies are summarized in Table 4 . A proportion had positive outcomes, perhaps suggesting some role in the first week post-cardioversion. Not all of the studies were positive, however, and the use of this medication routinely for anything other than rate control remains controversial and is not formally recommended in current guidance.
Renin-Angiotensin System
As discussed earlier, the renin-angiotensin system appears important in atrial remodeling and may therefore contribute to the perpetuation of AF. Several studies, which have been published examining the effects of inhibitors of this system, are summarized in Table 4 . Although there are limited data, these medications may well affect recurrence, at least in the medium term. This impression is also suggested by the results of two recent meta-analyses[102,103] which examined the effects of these classes of drugs on AF in major, multi-center trials of hypertension, heart failure, and post-myocardial infarction patients. More studies are needed to prove this conclusively and whether this will lead to long-term improvements in sinus rhythm maintenance is uncertain.
HMG CoA Reductase Inhibitors
There is some evidence of the importance of oxidative stress and inflammation in the atria of AF patients. It has been the hypothesis in a couple of studies that treatment with the HMG CoA reductase inhibitors, the statins, may affect AF. A retrospective study of 62 patients strongly suggested a benefit from statin use[104] but this was not confirmed in the prospective randomized study of Tveit et al. in 114 patients.[105] Statin use cannot therefore be recommended at this stage for the prevention of recurrent AF following cardioversion.
Early Cardioversion as a Strategy to Prevent Remodeling
As remodeling is clearly important in the perpetuation of AF, at least a proportion of which is reversible, the concept of early and repeated cardioversion developed; the theory being that as the remodeling reversed, the time between AF recurrences would gradually lengthen, eventually producing long-term sinus rhythm maintenance. This has been examined in small studies[106]; although atrial electrophysiology appeared to improve, the effect on clinical outcome was disappointing. In order to simplify the process, an implantable atrial defibrillator was developed[107]; however, again the results were unsatisfactory in the long-term in a significant proportion of patients.[108] Clearly AF triggers and at least a part of the AF substrate remained; in a proportion the repeated shocks, even at low energy, were a significant disadvantage. The standalone atrial defibrillator never found widespread use although the capability to cardiovert AF, automatically or on command, remains a feature of certain ICDs.
Cardioversion of sustained AF traditionally requires a period of prior anti-coagulation (a month, following current guidelines) to minimize the thromboembolic risk. In theory this delay should increase atrial remodeling and thus the risk of AF recurrence after cardioversion. The ACUTE study[109,110] compared the strategy of early cardioversion guided by trans-esophageal echocardiography (TEE; to exclude pre-existing left atrial thrombus) to the conventional approach. One thousand two hundred and twenty-two patients with AF of more than 48 hours duration were randomized to either a conventional approach or a TEE-guided approach. Those in the TEE group were cardioverted sooner (TEE: 3.0 ± 5.6 days vs conventional: 30.6 ± 10.6 days; P < 0.001) and suffered fewer major and minor hemorrhagic events (TEE: 2.9% vs conventional: 5.5%; P = 0.03). Embolic events were equally infrequent, however (TEE: 0.8% vs conventional: 0.5%; P = 0.5). Acute cardioversion success was not different (TEE: 80.3% vs conventional: 79.9%; P = 0.9) as was maintenance of sinus rhythm at 8 weeks (TEE: 52.7% vs conventional: 50.4%; P = 0.43). Although this important study confirmed the safety of the echo-guided approach, it was disappointing in that the accelerated cardioversion strategy failed to have any impact on AF recurrence.
In conclusion, while this approach is safe, the shortening of the period before cardioversion may be insufficient to have a significant impact on atrial remodeling, and thus to improve the maintenance of sinus rhythm.
Future Developments/Research
While the overall technique of cardioversion has changed little over the past 40 years, there have been a number of technical developments which have improved acute success rates. These include the rigorous attention to technical detail, biphasic cardioversion, and the use of adjuvant drugs for almost all from the start, including anti-arrhythmics and others. For those who remain resistant to this approach, internal cardioversion remains a potential option. The major challenge however is the prevention of recurrence; this can certainly be improved with conventional adjuvant anti-arrhythmics, probably with angiotensin converting enzyme (ACE) inhibition, and possibly with calcium antagonists in addition. A large trial examining the combination of all of these would be of great interest. It should of course be emphasized that a single recurrence on one anti-arrhythmic does not necessarily mean that the option has failed; for some patients infrequent periodic cardioversion, perhaps once a year, may be a very satisfactory result. In spite of the negative findings from ACUTE, it seems reasonable to cardiovert as early as practicable. In the future, the continued development of AF ablation will change the role of cardioversion; the return of sinus rhythm is only the start of the process. It is likely that the technique will further develop with new shock waveforms,[111] new anti-coagulants,[112] and novel atrial-selective anti-arrhythmics.[113] Cardioversion should therefore not be considered a strategy in itself, more part of a number of anti-arrhythmic strategies which can be selected for patients on an individual basis involving medication, ablation, and device therapies.
# posted by roodbont @ 12:39 PM 
