Author + information
- Evgeny Pokushalov, MD, PhD∗ (, )
- Alexander Romanov, MD,
- Giorgio Corbucci, PhD,
- Sergey Artyomenko, MD,
- Vera Baranova, MD,
- Alex Turov, MD,
- Natalya Shirokova, MD,
- Alexander Karaskov, MD, PhD,
- Suneet Mittal, MD and
- Jonathan S. Steinberg, MD
- ↵∗Arrhythmia Department, State Research Institute of Circulation Pathology, Rechkunovskaya, 15, Novosibirsk, Russia 630055
We appreciate the interest that Dr. Staessen and colleagues have expressed regarding our recently published study (1). We have addressed each of the issues.
1. The original protocol identified office systolic blood pressure (BP) at 2 years, not recurrence of atrial fibrillation (AF) at 1 year, as the primary endpoint that should have informed the sample size calculations. The number of patients actually randomized was 27, 1 more than required according to last version of the protocol at the registry Website, and 82% less than first planned for (N = 150).
The study was initially registered with a larger estimated sample size, formally anticipating correction or revision as the study progressed based on the results of a planned interim analysis and the pilot study. The hypothesis of the study formally stated was renal ablation combined with pulmonary vein isolation (PVI) in patients with resistant hypertension and AF may reduce blood pressure and reduce the burden of AF. The initial sample size took into account anticipated BP control with the planned update to address the AF rates. Because there was absolutely no data to allow a formal sample size based on AF control, it was impossible to do so initially. Data analysis of the initial 27 patients with at least 1 year of follow-up yielded very positive results, and, as a result, the pilot phase of the study was deemed closed.
2. The discrepancy is especially worrisome because the p value for the between-group difference in the incidence of atrial arrhythmia was only 0.033, so that adding a single control patient (14 instead of 13) might have made the statistical significance.
Including an additional patient in the control group does not have any significant effect on the main conclusions. We conducted a sensitivity analysis, and it showed that when we exclude the patient with the recurrence in the control group, the worst case scenario, the p value changed to 0.043 and remained statistically significant.
3. The results of atrial ablation in the control group were dismal.
The results of ablation in the control group who underwent only PVI were suboptimal, but not surprisingly, given that two thirds had persistent AF, a group in whom extra efforts beyond PVI alone are usually required to produce a better AF outcome. In addition, there are no data on the effectiveness of catheter ablation in patients with resistant hypertension; however, hypertension is a well-established predictor of recurrence of AF after PVI. Given the presence of persistent AF and resistant hypertension, the efficacy results obtained in the control group are very much in keeping with published data and clinical experience.
4. Previous use of amiodarone was an exclusion criterion in the published paper, but not in any version of the design in the trial registry.
Amiodarone use was an exclusion criterion, as clearly noted in the Methods section of the paper. Also, this information was available in the full version of the protocol.
5. The original exclusion criterion of secondary atrial hypertension was changed to secondary hypertension without mention of the diagnostic procedures.
All patients underwent a standard full range of diagnostic procedures to evaluate inclusion and exclusion criteria, including the presence of secondary hypertension.
6. At variance with the CONSORT statement, the number of patients screened and invited remains unreported.
The published version of the study had been shortened to comply with an editorial request. We screened 42 patients to generate a 27-patient cohort.
7. The Pokushalov et al. (1) trial was registered as investigator driven without industry sponsor.
There was no financial or other support from industry.
8. Researchers were originally located in Novosibirsk and Athens.
Patient enrollment was originally planned from Russian and Greek sites, but due to unanticipated and unrelated local issues, the Greek institution did not participate.
9. An employee from industry coauthored the published report. The group, who first reported on the blanking period and also received industry support, was also added at the publication stage.
One of the coauthors was employed by industry, but at the time of the study had no involvement in renal artery denervation, nor did his employer. He served as an advisor, and his employer's products were not used in this study. No other member of the authorship team received financial support from industry for this study.
10. Pokushalov et al. (1) excluded the first 3 months after pulmonary vein isolation from the analysis of recurrent AF. This so-called blanking period should not have been longer than 2 to 4 weeks because recurrence of AF significantly decreases after 1 month and thereafter remains stable.
We have scrupulously adhered to the Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA), European Cardiac Arrhythmia Society (ECAS) guidelines for the management of AF, which stipulate a blanking period of 3 months. The paper referenced, of which Dr. Steinberg was a senior author, also concluded that 3 months is a reasonable blanking period.
11. Moreover, all of the patients of Pokushalov et al. (1) were treated with propafenone or flecainide for 6 weeks after the procedure.
The HRS/EHRA/ECAS guidelines for the management of AF indicate the common practice of early post-procedure antiarrhythmic drug therapy, which was discontinued before the completion of the blanking period.
12. The published methods are not detailed enough to allow an independent replication of the study.
We used a technique of renal denervation recently described by Krum et al. (see reference 14 in our paper) for which there is ample description to replicate the results.
13. The catheter used to stimulate the renal nerves is not mentioned.
High-frequency stimulation was performed via the ablation catheter, as is clearly noted in the Methods section.
14. An exhaustive Internet search for the Stimulator B-53 led us to http://www.biotok.ru. This company is currently located in Tomsk, not in St. Petersburg.
The stimulator was manufactured by a Russian concern and has been used in many of our previously published studies of ablation of ganglionated plexi. It is correct that this company is located in Tomsk. The editorial staff inadvertently inserted the city St. Petersburg, which should have been corrected on the proofs.
15. We could not access their Website because of an HTTP 500 Internal Server Error.
If the authors had difficulty accessing their Website, we suggest that they try again or consider calling them by phone (the director of company is Aleksandr Oferkin, telephone number +79059918134).
16. Furthermore, the Pokushalov et al. (1) paper does not provide any information on the technique or reproducibility of the echocardiographic measurements.
Echocardiographic measurements were a secondary endpoint; only standard measurement techniques were used, and results were reported and presented in a conventional manner.
17. There are possible differences between described and applied statistical methods. The authors stated that continuous variables were presented as mean ± SD and analyzed by a Student t test. Systolic/diastolic blood pressure averaged 178 ± 8 mm Hg/96 ± 4 mm Hg in 14 control patients and 181 ± 7 mm Hg/97 ± 6 mm Hg in 13 patients of the intervention group. For the blood pressure level, SDs around 8 mm Hg systolic and 5 mm Hg diastolic seem unrealistic unless patients were selected within narrow BP limits.
The patients indeed had narrow BP limits, and the statistical analysis is straightforward (Fig. 1A).
18. Reportedly, in the intervention group, the decrease in blood pressure at 12 months averaged −25 ± 5 mm Hg systolic and −10 ± 2 mm Hg diastolic, whereas the change read from Figure 5 was −25 ± 3 mm Hg systolic.
In this figure, 95% confidence intervals were used (Fig. 1B).
19. Recalculation of the p values, using an unpaired Student t test and the BP changes digitized from Figure 5, showed that the measure of spread for both BP and BP decrease was probably not SD, but more likely SE.
The statistical analysis and data as published are correct (Fig. 1B).
20. Pokushalov et al. (1) did not report key test statistics and rounded measures of central tendency and spread to a single meaningful digit. In a parallel-group trial, p values for the within-group changes in an outcome variable provide some information, but the main test statistics should rest on baseline-adjusted between-group differences in the endpoint. Pokushalov et al. (1) did not show these key statistical parameters.
This paper uses the traditional form of statistical analysis. The limited sample size did not allow a stratified log-rank test or another multivariate survival analysis to be conducted, nor did we plan to do so. By design, the analyses were exploratory in nature, and the study was considered a pilot investigation.
21. Furthermore, the echocardiographic results were not consistently reported throughout paper. Table 1 shows baseline values only for left atrial diameter and left ventricular ejection fraction. Next, Table 2 gives changes from baseline in thickness of the interventricular septum, posterior wall, left ventricular internal diameter, and left ventricular mass index, for which baseline values were not given.
Echocardiographic measurements were a secondary endpoint; therefore, they were not presented in the paper's Table 1.
22. Moreover, echocardiographic measurements were expressed in unusual units: centimeters instead of millimeters for the interventricular septum, the posterior wall, and the left ventricular internal diameter, and g/m, not g/m2, for left ventricular mass index. This issue is not trivial, as the changes in left ventricular walls and internal diameter were small with average within-group changes ranging from 0.1 mm to 1 mm. Rounding measures of central tendency and spread to a single meaningful decimal and reporting left ventricular echocardiographic measurements in centimeters rather than millimeters makes it difficult to reproduce p values from the published data.
Echocardiographic measurements were a secondary endpoint, and the presentation and analyses are similar to those of many published studies.
23. One other potential inaccuracy pertains to the number of drugs taken. According to Table 1 (1), the number of antiarrhythmic drugs averaged 3.6 (range 2 to 5) in control patients and 3.8 (range 2 to 5) in the intervention group. The number of antihypertensive drugs was the same, albeit with different ranges as reported in the Results: 3.6 (range 3 to 5) and 3.8 (range 3 to 5), respectively. The use of 5 antiarrhythmic drugs in a single patient is incompatible with current guidelines.
The number of antiarrhythmic drugs represents the number of previous failed treatments, not active treatment, as has been incorrectly assumed. This count was accurate as was the count for the number of antihypertensive drugs, coincidentally similar to the antiarrhythmic drug count.
Please note: Dr. Corbucci was an employee of Medtronic. Dr. Steinberg has served as a consultant for St. Jude Medical, Medtronic, sanofi-aventis, Janssen, and Biosense-Webster and has received research grants from Medtronic and Biosense-Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation