Atrial Fibrillation Should Be Considered a First-Line Therapy – Or Not?

Therapy – Or Not?

A. P

, P.D. H

Introduction

In evidence-based medicine, the efficacy and toxicity of therapeutic options for a specific disease are assessed by carrying out comparative therapeutic trials. Only randomised placebo-controlled trials (RCT) can provide valid information on the merits of specific therapeutic manoeuvres in order to rank them as first-line, second-line, or third-line therapies. To the extent that valid RCT comparing ablation for atrial fibrillation (AF) with other AF treat- ments have never been published, the question whether ablation should be a first-line therapy appears premature and cannot be answered on the basis of available scientific information.

Our views on ablation for AF have not changed since our recent editorial on the subject [1]. Here, we will briefly enumerate arguments that cast doubts on recommending ablation for AF as a routine therapeutic procedure and certainly as a first choice or first-line treatment. This should not be mis- interpreted to mean that clinical research in this field is not desirable.

Lack of Considering Extensive Epidemiologic Information

Extensive epidemiologic data indicate that AF in Western societies is a disease of old age [2, 3]. Consecutive enrolments of AF patients are unlikely to yield co- horts with mean ages of 60 years or below. Studies claiming consecutive enrol- ments yet exhibiting young cohorts are puzzling from an epidemiologic viewpoint and raise questions about the nature of the enrolment procedures [1, 4].

Texas Arrhythmia Institute and Baylor College of Medicine, Houston, TX, USA

In studies of AF, cardiovascular risk factors well known to represent AF risk factors, such as hypertension and diabetes [2], should be precisely defined and controlled. The recent demonstration that treatment with ACE inhibitors and/or statins may decrease AF risk appears to support the impor- tance of controlling risk factors [5, 6]. Unfortunately, most AF ablation stud- ies provide little information on risk factors and their control. Because AF relapse may occur as a nocturnal phenomenon [7], it would be important to monitor nocturnal blood pressure to determine whether lack of physiologi- cal nocturnal hypotensive dips in hypertensive patients can be correlated with the risk of AF relapse.

Lack of Considering Previous Trials and Previous Meta-Analyses

Placebo control groups in drug treatment trials of AF have exhibited extremely variable AF recurrence rates [8]. Therefore, studies involving small groups of patients should be interpreted most cautiously. The history of evidence-based medicine has shown that seemingly simple evaluations, such as those comparing two heparin preparations, may yield contradictory results in separate trials involving the randomisation of thousands of patients (for instance, Synergy trial vs previous enoxaparin trials [9]).

Therefore, small studies attempting to evaluate complex highly case-variable procedures such as AF ablation are unlikely to yield conclusive statistical results. Most AF ablation studies fail to define statistical power and are grossly underpowered to assess all-important total death risk. The implica- tion that AF ablation substantially reduces the incidence of sudden cardiac death has no survival–statistical foundation [10].

Lack of Defining Precise Pharmacologic Protocols and Treatment with Antiarrhythmic Drug Therapy

Because so-called antiarrhythmic agents represent drugs with fundamentally

different actions and toxicities, it is highly inappropriate to lump them

together [11]. This is, for instance, true for verapamil, dihydropyridines, and

diltiazem (only verapamil has clinically demonstrated antiarrhythmic

effects). Most important, depending upon the dosages used, so-called anti-

arrhythmic agents may act as pro-arrhythmic agents and thereby increase

mortality [11, 12]. Comparison of ablation with such drugs (particularly

without specifying their dosages) is potentially very misleading. Variable,

not prospectively defined drug administrations after ablation preclude an

assessment of the therapeutic contribution of the invasive intervention to overall outcome [1].

Use of Non-validated Methods of Arrhythmia Detection

Remembered arrhythmia symptoms or symptoms inciting patients to per- form ECG recordings with pocket recorders or to elicit shocks from implant- ed atrial defibrillators have not been shown to represent adequate techniques of AF detection as recorded by implanted devices [13–15]. These methods are deficient particularly because AF episodes are often nocturnal, occurring during sleep [7]. Recent studies with implanted devices confirm that up to 90% of AF episodes are not perceived by patients [13–15]. Further, 24- and 48-h continuous (Holter) recording are highly inadequate sampling tech- niques for the recording of infrequent and highly variable arrhythmia events, such as those encountered in patients suffering from AF.

Failure To Perform Trials with Appropriate Placebo Controls and To Give Possible Placebo Effects Serious Consideration

The inclusion of groups randomised to placebo or sham interventions is cru- cial in trials. For instance, comparison of two potentially toxic medications, such as chemotherapeutic or antiarrhythmic agents, without placebo com- parison does not answer the important question whether these agents pro- long or shorten survival. Furthermore, the lack of controls involving placebo or sham interventions precludes appraisal of placebo effects [16, 17]. Recent cardiological studies [18, 19] have re-emphasised the importance of placebo effects, extensively discussed in the surgical literature [16].

Failure To Develop Standard Techniques Necessary To Conduct Credible Multi-Centre Trials

One hallmark of the AF ablation literature is the continual proposal of new

ablation procedures involving new instruments and techniques. The authors

jump to new procedures before characterising long-term effects of their previ-

ous apparently abandoned procedures. For instance, long-term effects of right

atrial ablation, advocated in early trials [20], remain largely uncharacterised. A

similar difficulty was observed with the Maze operations for AF. Although each

Maze procedure was claimed to be definitive, new improved procedures were

described subsequently. Lack of developing standardised procedures largely prevents the implementation of credible multicentre studies.

Conduction of Studies Under the Exclusive Supervision of Clinicians Identifiable as Proponents of Ablation for Atrial Fibrillation

In modern trials, it is customary to assemble several neutral committees for the monitoring of patient selection, randomisation, data collection, adverse events, and outcomes. In AF ablation trials, objective monitoring by indepen- dent observers has almost always been omitted.

Variable or Absent Definition of the Term Cure of Atrial Fibrillation

In many AF ablation studies, claim of cure is made. Unfortunately, the term cure is rarely clearly defined. The outcomes of ablation procedures com- pared to those obtained with selected antiarrhythmic agents, such as amio- darone, sotalol, and propafenone, have yielded 1-year relapse-free survivals of the same order of magnitude (about 60% of the patients) [8]. Such appar- ently event-free survivals are probably only slightly better that those obtained without specific therapies. Cure after only 12 months cannot be claimed because the long-term course of AF is highly variable and may evolve over a lifetime [1]. It is disconcerting that investigators can claim cure based on subjective information, apparently not considering that the detec- tion of AF relapses requires special diagnostic strategies [13–15].

Absent or Invalid Data on the Most Important Complications of Atrial Fibrillation, Including Stroke, Heart Failure, All-Cause Death,

and Cardiovascular Death

Because AF is relatively well-tolerated, the rates of interventional complica- tions, such as stroke, pulmonary vein stenosis, haemopericadium, and phrenic nerve paralysis, must be evaluated most carefully [21, 22]. In many AF ablation studies, no estimates of cumulative radiation dosage (fluo- roscopy) are provided. It has been demonstrated that AF may be complicated by microembolic brain disease and cognitive deficits without signs of stroke [23, 24]. Therefore, absence of obvious stroke events by no means demon- st rates the safet y of AF ablat ion in ter ms of emb olic brain injur y.

Unfortunately, no AF ablation study has included serial brain imaging stud-

ies and none has focused on intervention-related cognitive deficits.

Conclusions

The literature on ablation for AF has many of the features of clinical research in the era preceding evidence-based medicine and randomised trials. Many studies emanate from single centres, involve low patient numbers, and fail to provide adequate statistical analysis, including intention to treat analysis and evaluation of statistical power. As was the case with Maze operations, new procedures are continually proposed without completing satisfactory evalua- tions of previously proposed procedures. Very worrisome is that most stud- ies have not involved neutral committees for the recording and supervision of severe complications.

The belief that AF ablation now represents a standard or, indeed, first-line treatment is excessively optimistic and may reflect occupational and eco- nomic factors encouraging mechanistic invasive procedures.

References

1. Pacifico A, Henry PD (2004) Ablation for atrial fibrillation: are cures really achie- ved? J Am Coll Cardiol 43:1940–1942

2. Kannel WB, Wolf PA, Benjamin EJ et al (1998) Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 82(suppl 8A):2N–9N

3. Wattigney WA, Mensah GA, Croft JB (2003) Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999. Implication for primary prevention. Circulation 108:711–716

4. Pappone C, Oreto G, Rosanio S et al (2001) Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation – Efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 104:2539–2544

5. Maggioni AP, Latini R, Carson PE et al (2005) Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the valsartan heart fai- lure trial (Val-Heft). Am Heart J 149:548–557

6. Young-Xu Y, Jabbour S, Goldberg R et al (2003) Usefulness of statin drugs in pro- tecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 92:1379–1383

7. Ciaroni S, Cuenoud L, Bloch A (2000) Clinical study to investigate the predictive parameters for the onset of atrial fibrillation in patients with essential hyperten- sion. Am Heart J 139:814–819

8. Nichol G, McAllister F, Laupacis A et al (2002) Meta-analysis of randomised con- trolled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. Heart 87:535–543

9. Ferguson JJ, Califf RM, Antman EM et al (2004) Enoxaparin vs unfractioned hepa-

rin in high-risk patients with non-ST-segment elevation acute coronary syndromes

managed with an intended early invasive strategy: primary results of the

SYNERGY randomized trial. JAMA 292:45–54

10. Pappone C, Rosanio S, Augello G et al (2003) Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation – Outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 42:185–197 11. Pacifico A, Henry PD (1996) Class I or Class III agents for atrial fibrillation: are we

asking the right question? Pacing Clin Electrophysiol 26:1613–1619

12. Waldo AL, Camm AJ, deRuyter H et al for the SWORD Investigators (2003). Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 348:6–11

13. Savelieva I, Camm AJ (2000) Clinical relevance of silent atrial fibrillation: prevalen- ce, prognosis, quality of life, and management. J Interv Card Electrophysiol 4:369–382

14. Israel CW, Grönefeld G, Ehrlich JR et al (2004) Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device. J Am Coll Cardiol 43:47–52

15. Strickberger SA, Ip J, Saksena S et al (2005) Relationship between atrial tachyarrhythmias and symptoms. Heart Rhythm 2:125–131

16. Cook RC, Alscher KT, Hsiang YN (2003) A debate on the value and necessity of cli- nical trials in surgery. Am J Surg 185:305–310

17. Wingerchuk DM, Noseworthy JH (2002) Randomised controlled trials to assess therapies of multiple sclerosis. Neurology 58:S40–S48

18. Saririan M, Eisenberg M J (2003) Myocardial laser revascularization for the treat- ment of end-stage coronary artery disease. J Am Coll Cardiol 41:173–183

19. Grines C, Rubanyi GM, Kleiman NS et al (2003) Angiogenic therapy with adenovi- rus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease. Am J Cardiol 92:21N–31N

20. Gaita F, Riccardi R, Calò L et al (1998) Atrial mapping and radiofrequency catheter ablation in patients with idiopathic atrial fibrillation - Electrophysiological fin- dings and ablation results. Circulation 97:2136–2145

21. Bertaglia E, Stabile G (2005) Catheter Ablation for the Cure of Atrial Fibrillation (CACAF). Late-Braking Clinical Trials II, March 8, 2005. 54th Annual Scientific Session of the American College of Cardiology, Orlando, Florida

22. Saad EB, Rossillo A, Saad CP et al (2003) Pulmonary vein stenosis after radiofre- quency ablation of atrial fibrillation – Functional characterization, evolution, and influence of the ablation strategy. Circulation 108:3102–3107

23. Ezekowitz MD, James KE, Nazarian SM et al (1995) Silent cerebral infarction in patients with nonrheumatic atrial fibrillation. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillatiion Investigators. Circulation 92:2178–2182

24. Sabatini T, Frisoni GB, Barbisoni P et al (2000) Atrial fibrillation and cognitive

disorders in older people. J Am Geriatr Soc 48:387–390