Evaluation of Risk in Research must be Judged on Evidence, not Personal Opinion

We were previously aware of Eston’s opinion on the current study [3], as in 2014 he wrote a similar letter directly to the Head of NHS National Research Ethics. Based solely on a reference to this study in a discussion article [6], Eston stated that the protocol posed an unacceptable risk to patients. However, it was the view of the five senior clinicians who judged the grant application which funded this study, a Chief Medical Officer of a UK NHS Trust and Oxford Professor, and two separate NHS Research Ethics Committees, that Eston’s concerns were not justified. Therefore, three years later it is surprising to receive a further letter on this matter.

Selig’s letter claims that the self-paced exercise protocol used in our study carries an undue risk, yet no hard evidence of actual harm to patients is presented. Participant safety is at the heart of ethics in research, and in this study patient safety and well-being was our primary concern. The NHS ethical approval process is thorough and robust, and we would not have gained approval if the protocol presented undue risk to patient health. In clinical populations, the risk of any exercise is higher when there are co-morbidities present, and the degree of risk broadly proportional to the co-morbidities. In pre-operative exercise testing (and also to an extent in cardiac exercise testing) there is an inevitable circular argument: the impact of co-morbidities is often unknown without exercise testing, which actually itself quantifies the impact (but also is itself a risk). Indeed, exercise testing is well established as a means of detecting ischaemic heart disease in untreated patients, and determining need for surgery and its type. In this regard, maximal exercise testing is deemed safe with cardiac patients [1], within 7 days of PCI [4], and even on the day of, or after stenting [7]. There is also evidence demonstrating maximal self-paced testing to be safe in clinical patients [2].

We would argue that a self-paced method has an inherent safety valve due to its patient centred approach, unlike standard CPETs which are protocol driven. Nevertheless, any maximal exercise testing can pose a heightened risk to patients, but when properly controlled and supervised this rarely materializes. Indeed, in a cohort of 2037 heart failure patients who completed 4411 CPETs, there were no deaths, and the rate of nonfatal major cardiovascular events was <0.5 per 1000 tests [5]. Strikingly, as reported in our study, no adverse events occurred during either of the maximal exercise test protocols. As such, the available evidence suggests that the SPV poses no additional risk to patients than standard CPET protocols.

During our work in these studies, the known risks of exercising with clinical patients were mitigated in the following ways:

1. The exercise protocol is self-paced;

2. Patients were treated (i. e. post PCI);

3. Patients were deemed fit to exercise on clinical grounds;

4. The protocol occurred within hospital and was supervised by suitably qualified senior clinicians;

5. The protocol formed part of a trial wherein adverse events were reported to guide any early cessation of the trial if necessary;

6. The protocol was fully reviewed by several layers of regulations, from grant review, R&D and ethics.

On the basis of the information presented, it is unfounded to suggest that the SPV presents the level of risk suggested by Selig and colleagues.

An issue with standard maximal CPET’s in clinical testing is that the patient can give up long before true exhaustion, so that their ‘maximal’ O₂ uptake readings are not achieved. To mitigate risk associated with maximal testing, some have proposed submaximal tests to estimate of V̇O_2max, but these present a greater degree of error associated with the prediction. Both of these scenarios can mislead interpretation of data which is routinely used in guiding clinical decision making. In other words, failure to complete an exercise test protocol, or error within a predictive value, carries longer term risk (e. g., the patient does not get the surgery or gets a different, less optimal type of surgery based on the misleading outcome).

We acknowledge that there are many methods which can be used to work towards the same outcome. We are not suggesting that the SPV is a silver bullet for exercising testing, merely that it provides another tool in the exercise physiologists and clinicians tool box. Whilst we encourage open debate and academic questioning we would respectfully request that this is based upon scientific evidence rather than personal opinion which attempts to undermine the research area.

• References

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• 2 Foster C, Coye RB, Crowe A, Dumit M, Lettau S, Young H, Volkert P. Comparison of free range and graded exercise testing. Med Sci Sports Exerc 1997; 29: 1521-1526
• 3 Jenkins LA, Mauger A, Fisher J, Hopker J. Reliability and Validity of a Self-paced Cardiopulmonary Exercise Test in Post-MI Patients. Int J Sports Med 2017; 38: 300-306
• 4 Kanthan A, Tan TC, Zecchin RP, Denniss AR. Early exercise stress testing is safe after primary percutaneous coronary intervention. Eur Heart J Acute Cardiovasc Care 2012; 1: 153-157
• 5 Keteyian SJ, Isaac D, Thadani U, Roy BA, Bensimhon DR, McKelvie R, Russell SD, Hellkamp AS, Kraus WE. HF-ACTION Investigators. Safety of symptom-limited cardiopulmonary exercise testing in patients with chronic heart failure due to severe left ventricular systolic dysfunction. Am Heart J 2009; 158: S72-S77
• 6 Mauger AR, Metcalfe AJ, Taylor L, Castle PC. Reply to “Discussion: Efficacy of the self-paced VO_2max test to measure maximal oxygen uptake in treadmill running”. Appl Physiol Nutr Metab 2013; 39: 594-595
• 7 Roffi M, Wenaweser P, Windecker S, Mehta H, Eberli FR, Seiler C, Fleisch M, Garachemani A, Pedrazzini GB, Hess OM, Meier B. Early exercise after coronary stenting is safe. J Am Coll Cardiol. 2003; 42: 1569-1573