Discussion

There are two distinct elements to this discussion. First, we must consider the validity, limitations and lessons learnt about the method, which to the best of our knowledge has a degree of innovation. Only then is it useful to consider the reliability and value of what has been learnt in comparing the new technology of aortic root conservation and support with the established aortic root replacement surgery.

Considering its limitations, this novel method of comparison lacks two of the essential elements of an RCT: patients were not allocated by randomisation and the study was not prospective. On the other hand, in RCTs of surgery, blinding is nearly always impossible so bias in the delivery of potentially compensating forms of care, and bias in collection and recording of data, cannot be excluded and so a real difference in outcome may be diminished or not evident. In the present study, the 20 patients who had root replacement were among a very large number of patients having all forms of cardiac surgery. The teams could not know that their routinely collected clinical data would be used for a future comparison with a competing technology. Thus, the use of previously obtained patient data to derive a group for comparison has the incidental advantage that those recording those data had no knowledge of the research question and this may confer a useful advantage.

Our objective in this study was to find a contemporaneous group of patients, operated on by surgeons performing conventional root replacement, uncontaminated by involvement in the development of the new customised external root support. The construction of the comparison group employed the concept of minimisation as a means of ensuring that important variables were as similar as possible in the two groups. Critics of minimisation argue that the opportunity for bias cannot be excluded because the likely allocation of the next patient may be predictable from knowledge of existing mismatches between the groups.24 This problem does not exist, at least not in this precise form, when patients are selected from existing data but the opportunity certainly does for the investigators to select patients in whom the outcome is already known. For that reason, we fastidiously avoided any knowledge of the outcome of these patients being accessible to those involved in the process of deriving the comparison group.

A further limitation in the present study was that the pool of patients for comparison was not large enough to match as completely as we would have liked and failed to achieve balance on sex mix. Also the root replacement group included both those whose root replacement spared or replaced the valve. An ideal study would have representative numbers of these two operations for comparison (composite root replacement with a tissue valve is likely to be infrequent in this age group). We had approached other teams who declined sharing data on this occasion. However, the differences in the outcomes were so large that in this instance we do not believe further matching would have altered the conclusion.

The method includes another useful feature. It shares the principles of an expertise-based study.25 In drug trials, the patient is handed identically labelled packs of pills and no therapeutic expertise is involved but the expertise of the deliverer of care is an important consideration in non-pharmacological interventions.26 This applies in all technical interventions, in physical interventions such as physiotherapy and in psychotherapy; in all these examples, the person providing care is an important element in the potential effectiveness of that care. In the present study, surgeons were not asked to perform operations by random allocation but had already performed their preferred operation in which they were practiced and confident, a feature shared with an expertise-based randomised trial.25

There is a recognised problem in achieving sufficient numbers for conventional study designs in rare diseases.27 It is made more difficult if important outcome measures and adverse events accrue over many years. For example, native valve failure in valve-sparing surgery is important even after 10–15 years of perfect function. A devastating thromboembolic event in the first year after surgery, with residual disability, will dominate the outcome even if there are no subsequent events. Patients will weigh these risks differently as they make choices and they are influenced by both the weight put on them by doctors giving advice and whether they appear imminent or remote.28 Marfan syndrome is uncommon and the number of patients meeting the clinical criteria, such that they are candidates for either operation, is small but, in uncommon diseases, ‘some unbiased evidence is clearly better than none’.27

We believe that this approach to evaluation of a new technology may be generalisable. New interventional procedures are first introduced in one or a few centres while existing practice continues elsewhere. Many of these patients would have been candidates for the new as well the existing procedure, which they have received. By collecting initially only preoperative variables and by placing this process in the hands of the clinical trials unit (Royal Brompton Hospital, CTEU), we ensured that the selection was made only on explicit pre-stated criteria. To generalise the method, the case selection would need to be from as large a pool as possible and carried out by completely uninvolved and impartial investigators, without access to the outcome data at the time that the case selection is being made. If this method is to be replicated, it should be considered mandatory that the process be put in the hands of entirely neutral methodologists, blind to outcomes and with no vested interest in the answer to the research question.

To turn to what we have learnt about the specific subject of our research, we have previously drawn a comparison between the first 20 patients having EARS so the findings presented here are not completely new.21 However, the comparison in the earlier study was with 28 patients having root replacement in the same hospital, not all with Marfans syndrome and who were not candidates for the EARS surgery. The comparison group reported here are non-overlapping, operated on during the same time frame, in other hospitals where external support was not available. All 40 patients were eligible for replacement or aortic root conserving surgery. Although the findings are not surprising, they provide a much better estimate of real differences than we could achieve in our previous study.21

Avoidance of CPB and reduction in transfusion of blood products have been consistent objectives in reducing the detrimental effects of cardiac surgery. In this study, CPB was used as a safety measure in the first patient having aortic root support29 but was not used thereafter. One patient had a single unit blood transfusion. In addition, operative times were shorter even during the learning period for this new operation. There was no interruption to normal physiological myocardial perfusion through the coronary arteries. In contrast, interrupting coronary perfusion, while the myocardium is protected by hypothermic hyperkalaemic cardiac arrest, is mandatory for root replacement and was used from 40 min to up to 4 h, with a median approaching 2 h. These perioperative benefits were anticipated from a theoretical standpoint, being inherent in the non-ablative nature of the surgery, but they cannot be assumed to be consistently achievable. Formal quantification is essential if the data are to be used in decision analysis and health economic evaluation. There are potentially very large differences in the burden of care, costs of care and the potential for harm.

These differences did not translate into reduced hospital stay in this study. Postoperative stay is likely to be influenced by the chest wall incision, hitherto a signifier of major cardiac surgery. Median sternotomy does not require hospital stay beyond the initial recovery period, say the first night, and much shorter stay is an attainable goal in the future.

None of the existing forms of aortic root surgery, whether they involve mechanical or tissue valve replacement, or valve-sparing surgery, offers a perfect or permanent solution for people with Marfan syndrome.11 30 The first test of effectiveness of this novel technology should be that it is not inferior to the alternatives in terms of the combined lifetime risks of aortic dissection, other Marfan-related cardiovascular events, arterial thromboembolism, anticoagulant-related bleeding, endocarditis and reoperation. Table 4 summarises some of these from a theoretical standpoint and suggests that, for a checklist of preoperative and lifetime hazards, external support has a favourable profile.

The ultimate test of external support is whether it will prevent dissection in the ascending aorta, which is the only achievable objective of surgery. Monitoring of aortic size by echo, and deferring surgery until agreed size criteria are reached, is well-established practice. While the association between dissection and larger aortic size is highly significant, dissection can occur in Marfan syndrome in a relatively small aorta.31 32 While this intimately applied external support might not completely obviate that risk, it seems a reasonable expectation that it will be substantially reduced. It is also probable that if dissection should occur, its consequences will be less severe. There is evidence from an animal study (as yet unpublished) that the mesh of the supporting sleeve becomes incorporated in the aortic adventitia and increases the stress tolerance of the arterial wall. Knowledge of the surgical pathology of aortic dissection encourages us to think that this form of external support will confer these benefits—but nothing other than long-term follow-up will answer those questions.

It should be noted that this computer-designed and customised support, manufactured from a pliant and porous mesh, is very different to wrapping the aorta with the stiff graft material as has previously been proposed.33 34

It has become an entrenched belief that excision of the aorta is an essential component of Marfan root surgery, and reservations about the external support have drawn attention to the fact that the aortic tissue remains and yet the extent of excision in root replacement does not routinely include the entire ascending aorta. For surgeons who perform this surgery without circulatory arrest, the safe placement of an aortic cross-clamp, proximal to the brachiocephalic artery with sufficient clearance for the distal suture line, mandates that at least a couple of centimetres of the ascending aorta remains. Surgeons who routinely perform an ‘open’ distal anastamosis achieve more complete replacement of the aortic root and a more technically satisfactory distal anastamosis, at the price of 10–15 min of total circulatory arrest.35–37 The external mesh supports the aorta to beyond the brachiocephalic artery without the need for any circulatory arrest, obviating this technical debate.

Consideration of these technical details highlights a further consideration in the comparison between valve-sparing root replacement and external support of the existing of aorta and valve. Intraoperative skill and decision making are to a large extent replaced by preoperative measurement and device manufacture, moving the intervention from ‘workmanship of risk’ towards the ‘workmanship of certainty’.38 This concept is well understood in design and production of wooden furniture, which ranges from unique craft made objects to those manufactured to precise and reproducible specifications. While the uniqueness of wooden carving is part of its charm and value, to deliberately retain hazard and uncertainty in a surgical operation, when there is an engineered alternative, would surely be a mistake.

The best evidence for effectiveness and cost-effectiveness would ideally be obtained from direct comparison in a RCT,5 but these first 20 operations were performed by one surgeon in a single institution as part of formal early phase evaluation. Randomisation is not considered possible until the operation is shown to be achieved consistently.1 All 40 patients in this study would have been candidates for either external support or root replacement. Even so, it must be recognised that the cardiologist and/or the patient might have expressed a firm preference for one or the other, thus blocking random allocation. Not all prospective patients who are candidates for root replacement could be randomly allocated to external support or vice versa. The indications for external support and for root replacement overlap but they have important differences. For aortic root replacement, there is no upper size limit and it is not precluded by any severity of aortic regurgitation, whereas at this stage in the evaluation of external support, an already established large aneurysm or aortic regurgitation (more than trivial) would be a contraindication.

An RCT has the potential to provide the definitive answer to one well framed question but there are many other things we need to know in evaluating competing technologies. While considering the data required for health economic evaluation,39 we found that a published decision analysis was severely hampered by lack of data on probability of dissection-free survival of patients with Marfan syndrome.40 Bentall's first patient to have total root replacement as an unplanned procedure had a massive aneurysm, with walls ‘so thin that the blood could be seen eddying within’.41 The most likely natural outcome was death from dissection or rupture of the aortic wall and the ‘number needed to treat’ to save that patient's life was, in all probability, one but the number needed to treat (NNT) to save a single life gets larger as the threshold for any intervention lowers. For example, in carotid endarterectomy, NNT is six for 70%–99% carotid stenosis and rises to 24 for 50%–69% carotid stenosisi based on randomised trials. As surgery has become safer, we have progressively lowered the aortic size at which surgery is performed electively in Marfan syndrome. Some patients, perhaps many, may have lived without progressive dilatation of dissection, and, although how many and who they would have been can never be known, for those patients their operation availed them nothing. Harms become an ever more important part of the equation. Each element of the decision-making process should be updated as practice changes.39 Where contemporary data already exist, without the need for an RCT, it makes sense to use them.