Office blood pressure reduction in non-blinded trials often overestimated
Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4121 patients with focus on trial design: the CONVERGE report
Howard JP, Nowbar AN, Francis DP
BackgroundRenal denervation has recently gained much attention since it can yield large reductions in blood pressure (BP) in patients with resistant hypertension. However, a wide range of BP reductions have been reported. This could either be due to technical differences in the method of renal denervation, or in differences in study and BP measurement method.
Ambulatory BP reductions appear much smaller than office BP reductions [1-3]. In antihypertensive drug trials, it has been claimed that office and ambulatory pressure reductions differ to a similar extent [4,5]. However, ambulatory pressures are merely an average of repeated single measurements.
The Calibration of Office against circadian Values: Expectations for Renal denervation-Generated Effect (CONVERGE) working group set out to explore the disparity between office and ambulatory reductions in order to assess what BP drop should be genuinely attributed to denervation.
A meta-analysis of the therapeutic effect of hypertensive drugs on ambulatory and office BP drops was performed. In order to account for the potential susceptibility of easily repeated pressure measurement to selection bias, studies with two levels of trial design were included, to wit uncontrolled, single-armed studies (n=17, 2779 patients) and double-blinded placebo controlled trials (n=14, 1342 patients). Furthermore, BP drop seen after renal denervation was evaluated with regard to the type of BP measurement.
- Baseline office and ambulatory BP were similar between one-armed trials and double-blinded placebo-controlled trials (159 vs. 148 mmHg respectively). In non-randomised , unblinded drug trials office pressure drops were 5.6 mmHg (95%CI: 2.98-8.22, P<0.0001) larger than ambulatory pressure drops. In randomized controlled drug trials, the BP decrease was 2.90 mmHg (95%CI: 1.06-4.74, P=0.002) larger in the placebo arm, documented by staff in the office, than those documented with automatic ambulatory pressure monitoring.
- The calculated pressure drop was highest in the only trial with a ‘denervation vs. failure’-design, the Symplicity-HTN 1 trial, which reported office BP changes separately for patients who successfully underwent the procedure and those in which it could not be completed. Mean weighted office BP with denervation was 53.0 mmHg in this group.
A mean weighted office BP of 27.6 mmHg was seen in trials with a ‘denervation vs. preprocedure’ design, and 26.6 mmHg in trials with a ‘denervation vs. open control’.
- Mean weighted ambulatory pressure drop was 15.7 mmHg over all study categories.
5 trials were analysed separately because office BP was not reported, or because enrolment was based on ambulatory pressure and this was used as baseline, exposing them to the regression to the mean-artefact. Those studies showed a mean ambulatory BP reductions of 19.3 mmHg. The remaining studies showed a mean ambulatory pressure reduction of 11.9 mmHg.
ConclusionNon-randomised, non-blinded drug trials show larger drops in office BP than ambulatory drops. In randomized, blinded trials the incremental office BP drop beyond placebo seems to be no bigger than the corresponding ambulatory pressure drop. These results suggest that in bias-resistant conditions, the genuine BP drop as a result of an intervention may decrease to values seen on ambulatory BP monitoring, thus 10-15 mmHg. It is expected that this would also be the case in a randomized, blinded denervation study.
The previously described disparity between office and ambulatory BP drops with renal denervation appears an anomaly that is not seen in well-designed anti-hypertensive drug trials. It is predicted that excess office pressure drop beyond the control arm drop, in bias-resistant trial designs, will converge towards a value similar to ambulatory pressure drops.
It is recommended that future investigators who will investigate the true effect of renal denervation on BP, avoid unblinded studies using office measurements, as these aspects have been a source of exaggeration of the effect.
1. AHA Scientific Sessions. EnligHTN I—A Novel Multi-Electrode Renal Denervation Catheter in Patients With Drug-Resistant Hypertension. Secondary EnligHTN I—A Novel Multi-Electrode Renal Denervation Ctheter in Patients With Drug-Resistant Hypertension 2012. http://www.cardiosource.org/Science-And-Quality/Clinical-Trials/ E/EnligHTN-1.aspx
2. Symplicity HTNI, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 2010;376:1903–9.
3. Doumas M, Anyfanti P, Bakris G. Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension: a perspective. J Hypertens 2012;30:874–6.
4. Mahfoud F, Cremers B, Janker J, et al. Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension 2012;60:419–24.
5. Mancia G, Parati G. Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: a meta-analysis. J Hypertens 2004;22:435–45.