Author + information
- Costas Tsioufis, MD⁎ (, )
- Dimitris Tsiachris, MD,
- Vasilios Papademetriou, MD and
- Christodoulos Stefanadis, MD
- ↵⁎First Cardiology Clinic, University of Athens, 3 Kolokotroni Street, P. Penteli, 15236 Athens, Greece
We read with interest the elegantly written paper by Bisognano et al. (1) relating to the double-blind, randomized, placebo-controlled Rheos Pivotal Trial, which demonstrated that over the long-term, baroreflex activation therapy (BAT) can safely reduce systolic blood pressure (SBP) in patients with resistant hypertension.
We congratulate the authors for this hard-to-perform trial and the promising results in the field of resistant hypertension. However, we have some major concerns regarding the failure of the study to meet 1 of the 2 pre-specified primary endpoints of efficacy. In particular:
1. The definition of resistant hypertension was based on 1 outpatient, in-office SBP reading ≥160 mm Hg after 1 month of maximally tolerated therapy. A minimum duration of such therapy for at least 3 months and an in-office SBP reading >160 mm Hg on at least 2 consecutive visits would better identify patients with true resistant hypertension.
2. Although ambulatory SBP ≥135 mmHg constituted an inclusion criterion, reduction of ambulatory SBP was not considered an endpoint, thus preventing us from analyzing specific uninterpretable findings, such as the larger-than-anticipated reduction in SBP in patients not receiving BAT and the increased SD of blood pressure (BP) differences during follow-up. As the authors noted, the significant reduction of clinical SBP in the control group during the initial 6 months could not be satisfactorily justified by possible changes of antihypertensive treatment, Hawthorne effect, or placebo effect. This phenomenon probably implies either an inappropriate study design (e.g., inadequate number of BP measurements) or unsuitable patient selection. Conversely, such an unusually large and puzzling “placebo” effect was also present in the referred Darusentan-Resistant Hypertension Trial (2) and in the African American Study of Kidney Disease and Hypertension (3). Based on the above study results, along with the pitfall of arbitrarily selecting a specific endpoint in time for BP outcome, Bakris et al. (2) highlighted the importance of ambulatory BP endpoints in the design of hypertension studies. Similarly, the increased SD of BP differences during follow-up illustrates the great variability of BAT on BP reduction and the occurrence of diverse levels of response to this therapy. Data derived from ambulatory BP monitoring that demonstrate a sympathetic overactivity, such as early morning surge, could be identified as predictors of response to BAT and used in the selection of patients with resistant hypertension (4).
An additional point closely associated with questioning the efficacy of BAT is related to the possible changes in antihypertensive treatment during the course of the trial. Did the BAT responders in these 12 months receive a higher dosage or additional drug classes, such as aldosterone antagonists (which were used only by 18% of study participants at baseline)?
Moreover, data on parallel decreases in heart rate (and even at what level) and on the presence of comorbidities frequently associated with resistant hypertension (e.g., sleep apnea syndrome, chronic kidney disease) (5) have not been provided.
Furthermore, the relatively high incidence (25.5%) of procedure-related adverse events may suggest that a greater number (>2, as required in the present study) of open label implantations is needed for optimal learning curve, especially in the era of percutaneous renal sympathetic denervation (6). In addition, based on experience with other device implantations (i.e., pacemakers), studies of quality of life are needed in the setting of resistant-to-treatment but still asymptomatic hypertensive patients.
- American College of Cardiology Foundation
- Bisognano J.D.,
- Bakris G.,
- Nadim M.K.,
- et al.
- Kario K.