Complications, and Results?
P.J. SCHWARTZ1, 2, C. SPAZZOLINI1, L. CROTTI1, 2
The number of patients affected by the long QT syndrome (LQTS) who are told by their physicians that they should receive an implantable cardioverter- defibrillator (ICD) is increasing exponentially. Why? In this short essay we will try to provide an answer to this question, and we will also briefly review the data available to assess whether or not adequate information exists on the indications and results of the growing use of the ICD for patients with LQTS. While the data are what they are, the opinions expressed here are our own and reflect to a large extent the clinical experience developed by one of us in managing and treating LQTS patients during the past 35 years [1–4].
The Issue
To simplify matters we will start by stating the obvious: patients who have survived a cardiac arrest should immediately receive an ICD, in addition to traditional therapy. Thus, our entire discussion will concern patients whose only symptom has been one or more syncope episode, before or on therapy.
The possibility of implanting an ICD in an asymptomatic patient is not even discussed, because in a disease whose natural history shows that 50% of patients remain asymptomatic through life without therapy [5], this repre- sents, in our opinion, an aberration. Unfortunately, aberrations do occur.
A second starting point is that the evidence from multiple databases [3]
that cardiac arrest/sudden death (CA/SD) as first episode may occur in up to 12% of patients with LQTS dictates the necessity to treat all LQTS patients
1Department of Cardiology, University of Pavia and IRCCS Policlinico S. Matteo, Pavia;
2Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo, Pavia, Italy
with β-blockers once they have been diagnosed as affected [3]. This rule has few exceptions, largely on the basis of the age of the patient at the time of diagnosis, and in some subgroups (e.g., LQT1) on the basis of gender.
Management and Outcome of Patients with Syncope
Having limited, on the basis of common sense, the discussion to patients with syncope, let us now examine what we know about their prognosis. What happens to a patient treated with β-blockers? Even though the genotype of the patient is usually still unknown when the first decision has to be made, it is no longer acceptable to ignore the practical consequences of genotyping or to look for excuses for being ignorant on this matter. At the present time, 70% of affected patients are positively genoty ped in our laboratory (Molecular Cardiology Laboratory, Policlinico S. Matteo and University of Pavia) within 4–5 months, and the same is true in most laboratories.
Furthermore, for most patients – including those who are genotype-negative – the experienced clinician can predict the genotype fairly accurately [6] on the basis of: (1) the morphology of the T wave [7, 8]; (2) the ‘triggers’ or con- ditions associated with the events [9]; and (3) the different prevalences of the different genotypes [5, 10]. Finally, our evidence that – as predicted in 1980 [11] – low penetrance exists in LQTS, and that therefore within each family several individuals may have a normal QT interval and still be muta- tion carriers [12], makes failure to attempt genotyping in every LQTS patient inexcusable, with significant medico-legal implications.
It is on this rational basis that one should look at the available data. In our study based on the LQTS International Registry [13], Moss et al. [14]
provided data based on 869 patients treated with β-blockers. As always, data from registries and not from randomised trials have to be examined with special care. When the analysis leaves out the survivors of a cardiac arrest (who should receive an ICD in any case), the patients who were off therapy for more than 3 months, and the patients who became symptomatic in the first year of life (because they represent a subgroup at extremely high risk who should be dealt with and considered separately from the rest of the LQTS population), it turns out that mortality on β-blocker therapy was 1.6%!
This is a very important figure to be considered carefully when proposing invasive therapies.
If one looks at genotyped patients, there are important data there as well.
In a three-centre study, all with a high referral rate, in 157 LQT1 patients the combined incidence of CA/SD over a very long average follow-up (12 years) was only 1.2% [15]. In the study from our group based on 187 LQT1 patients
the combined incidence of CA/SD was 1.1% [16]. Thus, these two major stud- ies provide almost identical data which show beyond doubt that 98% of LQT1 patients can do very well on β-blocker therapy. It is very unlikely that a LQT1 patient who has not yet had a cardiac arrest would significantly benefit from an ICD. It is important to remember that LQT1 patients represent at least 50% of all LQTS patients.
Two large series of patients provide data on LQT2 patients. In one [9], based on 91 LQT2 patients all with symptoms, there was a combined 4% inci- dence of CA/SD on therapy. Of note, these were all cases of cardiac arrest and there were no sudden deaths. In the other [16], the combined incidence of CA/SD was 6.6%, but once again these events were all cardiac arrests and there were no deaths. When one looks objectively at these data one has to recognise that 93–96% of LQT2 patients do well on β-blockers even though the protection appears not as complete as for LQT1 patients.
The same two reports, on the other hand, demonstrated a relatively high incidence of CA/SD among LQT3 patients, the most uncommon of the three major genetic subgroups. This incidence of failures in the two studies was, respectively, 17% and 14%. These figures justify serious consideration for therapeutic approaches beyond β-blockers. Such additional approaches include obviously the ICDs, but not only. For LQT3 patients, one can expect a fair amount of benefit by also adding left cardiac sympathetic denervation (LCSD) [17] or the sodium channel blocker mexiletine [4, 18].
Before discussing the actual ICD data it is necessary to recall the alterna- tive options. We presented last year updated information on the long-term results of LCSD. This 35-min operation performed without opening the chest has resulted in a more than 90% reduction in the number of cardiac events [17]. The population under study was one at extremely high risk, as docu- mented by the number of symptomatic patients (99%), the high percentage (75%) of those with cardiac events despite β-blockers, and the extreme aver- age prolongation of the QT interval (QTc = 543 ± 65 ms). Among the patients with syncope, there has been a 5-year mortality rate of 3% and an incidence of resuscitated cardiac arrest of 8%. LCSD also shortened QTc by an average of 40 ms, and we have found that lethal cardiac events after surgery occurred only among those patients who continued to have a QTc greater than 500 ms (Fig. 1). A very important and highly related finding was made in those patients who developed storms or who had multiple shocks following ICD implant; in this unfortunate group LCSD was able to reduce by 95% the number of shocks, thus having a dramatic impact on the quality of life of these patients and of their families (Table 1).
Registries for ICD in LQTS
There are only two relatively large sets of data on LQTS patients who have received an ICD, those from Zareba et al. [19] on 125 patients and those from the European Registry [20], initiated by our group with the support of many European electrophysiologists, which has enrolled so far 112 patients, including most of those recently reported by Mönnig et al. [21]. The number of genotyped patients in the two series is relatively small; nonetheless, it is of Fig. 1.Kaplan–Meier curves of event-free survival and survival according to QTc interval after left cardiac sympathetic denervation in patients with only syncope or aborted car- diac arrest before left cardiac sympathetic denervation (modified with permission from [17])
Table 1.ICD multiple shocks and left cardiac sympathetic denervation (LCSD)
Patients with LCSD post ICD 5
Follow-up ICD LCSD 17±16 months
Follow-up post LCSD 4.1 years
Pre LCSD shocks per patient per year 29.3 Post LCSD shocks per patient per year 3.3
Reduction 95%
ICD implantable cardioverter defibrillator
interest – and probably not by chance – that there is an excess of LQT2 patients.
The available data are rather disquieting. In the two registries, only 43%
and 46% of the implanted patients had had an aborted cardiac arrest, which should be the primary and main reason for implantation. In the series of Zareba et al. 35% received an ICD because of one syncope irrespectively of β-blocker therapy and 13% were mostly asymptomatic individuals who received implants because of a sudden death in the family! The latter deci- sion was taken by physicians apparently unaware of the evidence showing that a sudden death in the family does not increase the risk of lethal events among other family members [22]; if the decision is taken not for true med- ical reasons but because of emotional considerations, then it is a different story. In the European Registry the number of asymptomatic patients who have had an ICD implanted is 5%. In addition, 19% of the patients received an ICD for syncope occurring prior to institution of β-blocker therapy!
These data sadly show that in more than 50% of cases the ICD is implanted in patients who have not had the most appropriate indication, namely a car- diac arrest.
The number of appropriate shocks during follow-up in patients not implanted for cardiac arrest is a very important one. Unfortunately, we have not been able to find this number in the article by Zareba et al. In our data set this figure is 12% within an average follow-up of 3 years.
Zareba et al. [19] tried to demonstrate the beneficial effect of the ICD by comparing mortality in this group to a group of LQTS patients considered to be similar to those who received the ICD and who continued to be treated conventionally. They concluded by stating that LQTS-related deaths occurred in 1.3% vs 16% (P = 0.07), thus showing the superiority of the ICD vs the non-ICD therapy. As commented by others [23], these data generate numer- ous questions. This was a retrospective comparison in which the control (non-ICD) group was chosen by the authors among the patients in the LQTS registry. Two aspects cause concern. One is that 16% mortality in properly treated LQTS is, to say the least, an exceptionally high figure. The second is that more than half of these deaths occurred within 3 months from the moment selected retrospectively by the authors to be regarded as time zero for this statistical analysis. It seems to us that comparisons on the life expectancy of LQTS patients treated or not treated with an ICD should require a more rigorous analysis and that, once again, it should be limited to the patients without cardiac arrest about whom there seems to be an ongo- ing debate.
One has also to look also at the down side. In the report by Zareba et al.
there were two deaths, giving an incidence of 1.6% which – interestingly, and worth remembering – is the same as that among patients without cardiac
arrest in the large report by Moss et al. [14] discussed above. One patient, a child, died because of recurrent torsades-de-pointes; the other, a 21-year-old girl, committed suicide. The possibility that the suicide was related to the ICD (as previously reported for other cases) was not considered, and the sta- tistical analysis has included only 1 LQTS-related death. In the European Registry inappropriate shocks occurred in 10% of patients and 8% had mul- tiple repetitive discharges. Importantly, given the relatively short follow-up of 3 years, 27% of the patients underwent invasive/surgical interventions on either the generator or the leads of the ICD for a variety of reasons ranging from end-of-life of battery to lead fracture or lead dysfunction, or others.
The bottom line here is that the implantation of an ICD is not the end of the problems for many LQTS patients. This is one important reason, not to mention the significant and often devastating psychological impact, espe- cially in young patients, for doing everything possible to limit the ICD implants to those patients who really are appropriate candidates.
Having looked at the available data, one inescapable conclusion is that too many patients receive an ICD for questionable or incorrect indications.
Of the several reasons which may underlie this reality one merits attention, and this is the physician’s fear of medico-legal consequences for not having implanted an ICD in a patient who subsequently develops a cardiac arrest or dies suddenly. Clearly, to recommend an ICD implies no fears about survival, it is simple and fast, and if complications do occur that is just too bad. To explain to patients or parents that non-ICD therapies, despite their high degree of efficacy, do not offer a 100% protection and a tragic event cannot be ruled out; that the potential complications of an ICD during a lifetime should be carefully weighed against the almost 100% survival; that quality of life would be impacted differently by the various options: all these consider- ations take a lot of time and emotional involvement by the physician, who often chooses the simplest solution. While we understand these practical reasons, our concern is that too often the final decision is made more for the physician’s than for the patient’s protection.
Conclusions
There is a high and in many cases inappropriate use of ICDs in patients with long QT syndrome with syncope. The pros and cons of the ICD and of the other available therapies should be clearly explained to all patients before recommending one or another.
It should be remembered that LQTS is profoundly different from most of the more prevalent conditions for which an ICD is usually recommended, and that among the special features of LQTS the tight relationship between
release of catecholamines and life-threatening arrhythmias is an important one capable of initiating storms of shocks.
The wise use of the ICD in LQTS can save many lives. The unwise use of the ICD in LQTS can ruin many lives. A competent and caring physician should not be unmindful of his/her complex responsibilities toward the – usually young – LQTS patients.
Acknowledgements
The authors are grateful to Medtronic-Bakken Research Center B.V., The Netherlands, and to Guidant Italia Srl for their support of the European ICD Registry for the Long QT Syndrome. They also thanks Pinuccia De Tomasi for expert editorial support.
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