You are here

  • Home
  • Archive
  • Volume 99, Issue 21
  • 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

Article Text

Article menu
Hypertension and renovascular disease
Original article
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
  1. James P Howard,
  2. Alexandra N Nowbar,
  3. Darrel P Francis
  1. International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, UK
  1. Correspondence to Dr James P Howard, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59-61 North Wharf Road, London W2 1LA, UK; jphoward{at}doctors.org.uk

Abstract

Objective 30 mm Hg drops in office systolic blood pressure are reported in trials of renal denervation, but ambulatory reductions are much smaller. This disparity is assumed to have a physiological basis and also be present with antihypertensive drugs.

Design We examine this office-ambulatory discrepancy through meta-analysis of drug and denervation trials, categorising by trial design.

Patients (studies) 31 drug trials enrolling 4121 patients and 23 renal denervation trials enrolling 720 patients met the criteria.

Results In drug trials without randomisation or blinding, pressure reductions are 5.6 mm Hg (95% CI 2.98 to 8.22 mm Hg) larger on office measurements than ambulatory blood pressure monitoring (p<0.0001). By contrast, with randomisation and blinding, office reductions are identical to ambulatory reductions (difference −0.88 mm Hg, 95% CI −3.18 to 1.43, p=0.45). For renal denervation, there are no randomised blinded trial results. In unblinded trials, office pressure drops were 27.6 mm Hg versus pretreatment, and 26.6 mm Hg versus unintervened controls. By contrast, ambulatory pressure drops averaged 15.7 mm Hg across all trials. Among those where the baseline ambulatory pressure was not the deciding factor for enrolment (avoiding regression to the mean), ambulatory drops averaged only 11.9 mm Hg.

Conclusions Discrepancies in drug trials between office and ambulatory blood pressure reductions disappear once double-blinded placebo control is implemented. Renal denervation trials may also undergo similar evolution. We predict that as denervation trial designs gradually improve in bias-resistance, office and ambulatory pressure drops will converge. We predict that it is the office drops that will move to match the ambulatory drops, that is, not 30, but nearer 13.

https://doi.org/10.1136/heartjnl-2013-304238

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Renal sympathetic denervation is a recently introduced therapy that has been reported to deliver large reductions in blood pressure in patients with resistant hypertension. This holds promise for reducing morbidity and mortality of cardiovascular disease which globally is now the dominant cause of death.1

    However, the degree of blood pressure reduction has a wide range of reported values. It is conceivable that this is due to differences in the technical method of achieving renal denervation. Alternatively, it could be related to how the study is conducted and how measurements are collected.

    Office blood pressure measurements are widely used in daily clinical practice, but have relatively poor test–retest reproducibility2 as well as challenges, such as digit preference3 and the temptation to remeasure any values that appear clinically inconsistent.4 Ambulatory blood pressure measurement, by capturing and averaging many values over 24 h, offers better test–retest reproducibility.5

    The same denervation studies seem to find ambulatory pressure reductions to be much smaller than the office reductions in the same patients.6–8 It has been claimed that office and ambulatory pressure reductions similarly differ in antihypertensive drug trials.9 ,10 If correct, this would be curious since ambulatory pressures are merely an average of repeated single measurements.

    We formed the Calibration of Office against circadiaN Values: Expectations for Renal denervation-Generated Effect (CONVERGE) working group to explore the disparity between office and ambulatory reductions in order to gauge what blood pressure drop should be genuinely attributed to denervation.

    First, we investigated the hypothesis that ambulatory pressure drops are systematically much smaller than office pressure drops, by meta-analysis of the therapeutic effect of hypertensive drugs on these two markers. Because of potential susceptibility of easily repeated pressure measurements to selection bias,11 we identified studies with two levels of trial design12: (1) uncontrolled, single-armed studies and (2) double-blinded placebo-controlled trials.

    Second, we evaluated the blood pressure drop seen from renal denervation in the context of the type of blood pressure measurement (office or ambulatory), and the choice of comparator for the postdenervation measurements (patients with a procedural failure, predenervation measurements, unblinded controls and blinded controls).

    Methods

    Data sources and search strategy

    Antihypertensive drug trials including baseline and final values for both office and ambulatory pressure were identified through a search of the MEDLINE and EMBASE databases (2000–2012).

    Randomised controlled trials, case series, case-control studies and conference abstracts of renal denervation in resistant hypertension were identified through a search of the MEDLINE and EMBASE databases. In addition, the Hypertension Device Sector of cvPipeline13 was consulted from which first-in-man data from four renal denervation catheters were accessed. Conference presentations of these devices have since been made publicly available.6 ,14–16

    For both searches the strategies are covered in full in online supplementary appendix 1. Search terms were agreed upon by two authors (JPH and ANN) who went on to perform independent review of the articles chosen for further analysis.

    Data processing

    From each study report, the baseline and final values of office and ambulatory systolic blood pressures were extracted. To be categorised as double-blind placebo-controlled randomisation required adequate concealment of future allocation, that is, a randomisation process more bias-resistant than the discredited17 ,18 sealed-envelope method. Papers presenting secondary analyses of patients from previous trials were excluded.

    Statistical analysis was performed using Microsoft Excel 2010 and The Cochrane Collaboration's Review Manager V.5.2.

    Antihypertensive drug trials

    Antihypertensive drug trials were classed as either one-armed trials or double-blinded randomised placebo-controlled trials. Differences in baseline pressures were calculated using an unpaired two-tailed Student t test.

    The disparity between office and ambulatory pressure drops for each class of study were calculated with their 95% CIs using an inverse variance-weighted meta-analysis with a random effects model. For trials which listed only SDs for baseline and final pressures, rather than that of the actual pressure drop, an imputed SD was taken from those that did.

    Renal denervation trials

    Renal denervation trials were classed as either uncontrolled, unblinded controlled, or blinded controlled. For procedural studies, it is also, in principle, possible to compare patients who underwent therapy against those who did not, either because of technical difficulties or because the patient refused.19 Where studies provided this information we calculated the consequent value.

    For each class of study, a weighted mean of systolic blood pressure drop was calculated. Weighting was by sample size.

    Results

    Antihypertensive drug studies reporting both office and ambulatory pressure drops

    Study characteristics

    Seventeen one-armed studies, enrolling a total of 2779 patients met the criteria; 14 double-blinded randomised placebo-controlled trials, enrolling a total of 1342 patients met the criteria. The baseline office and ambulatory blood pressures were similar between one-armed trials (161 and 147 mm Hg, respectively) and double-blinded placebo-controlled trials (159 and 148 mm Hg, respectively) with p=0.49 and 0.76, respectively (table 1). Full baseline blood pressure data and study characteristics are shown in online supplementary appendix 2.

    View this table:
    Table 1

    Antihypertensive drug trials reporting office and ambulatory pressure reductions, categorised as either one-armed or double-blinded randomised placebo controlled trials

    Office and ambulatory pressure drops in one-armed drug trials

    In non-randomised, unblinded drug trials, office pressure drops are 5.60 mm Hg (95% CI 2.98 to 8.22) larger than ambulatory pressure drops (p<0.0001, figure 1A).

    Figure 1
    Figure 1

    (A) Forest plot of office versus ambulatory pressure reductions in open-label drug trials. Office pressure reductions were 5.60 mm Hg higher than ambulatory pressure reductions (p<0.0001). (B) Forest plot of office versus ambulatory pressure reductions in placebo-treated patients in randomised blinded placebo-controlled drug trials. Office pressure reductions were 2.90 mm Hg higher than ambulatory pressure reductions (p=0.002). (C) Forest plot of office versus ambulatory pressure reductions in active drug-treated patients in randomised blinded placebo-controlled drug trials. The incremental effect of the active drugs was identical on office and ambulatory pressure monitoring (office drops numerically 0.88 mm Hg smaller, p=0.45).

    Office and ambulatory pressure drops in randomised placebo-controlled drug trials

    In the placebo arms, the pressure drops documented by staff in the office were 2.90 mm Hg larger than those documented on automatic ambulatory pressure monitoring (95% CI 1.06 to 4.74, p=0.002, figure 1B).

    Beyond this, the incremental effect of the active drugs (ie, the drop genuinely attributable to the drug) was identical between office and ambulatory pressure drops (office drops numerically 0.88 mm Hg smaller; 95% CI −3.18 to 1.43, p=0.45, figure 1C).

    Renal sympathetic denervation trials in drug-resistant hypertension

    Study characteristics

    Twenty-three studies of renal denervation enrolling a total of 720 patients with resistant hypertension were identified reporting drops in either office pressures or ambulatory pressures or both. Two studies were randomised controlled trials, three were case-control studies, and the remainder were one-armed case series. Study characteristics including format, average age and sex of study participants are available in online supplementary appendix 3.

    Ten studies were industry funded and nine did not declare their source of funding. The average age of patients varied across studies between 50 and 69 years. One study used an ultrasound-based renal denervation system.15 The remaining studies used radiofrequency ablation catheters. Eleven measured only office blood pressures. Five measured only ambulatory blood pressures. Seven measured both office and ambulatory blood pressures. While all studies were said to have excluded patients with secondary hypertension, the number that stated how this was done was zero.

    Effect of trial design on relative size of office and ambulatory pressure drops in denervation trials

    The studies and the sizes of the reported drops are shown in table 2. These results were plotted to visualise the impact of the choice of the comparator group, and choice of the variable measured (office or ambulatory pressures) on the size of the pressure drop calculated (figure 2). Where ambulatory drop was reported for only a subset of a main study, we have listed the ambulatory values separately, to recognise that the patients were not exactly the same as the overall cohort.

    View this table:
    Table 2

    The format of renal denervation trials and their outcomes

    Figure 2
    Figure 2

    A plot showing the relationship between trial design and the reductions in office and ambulatory blood pressures. Each data point represents a trial. In unblinded trials, office pressure drops were 27.6 mm Hg versus pretreatment, and 26.6 mm Hg versus unintervened controls. Ambulatory pressure drops averaged 15.7 mm Hg across all trials. Dotted circles representing trials represent those with atypical blood pressure measurement strategies and are discussed in the paper.

    Office pressure drops

    The first category, ‘denervation versus failure’, consisted of one study, Symplicity-HTN 1, which reported office pressure changes separately for patients who successfully underwent the procedure, and those in whom it could not be completed, most often for anatomical reasons. Mean weighted office pressure drop with denervation was 53.0 mm Hg in the ‘denervation versus failure’ category.

    The secondary category, ‘denervation versus preprocedure’ showed a mean weighted office pressure drop of 27.6 mm Hg.

    The third category, ‘denervation versus open control’ showed a mean weighted office pressure drop of 26.6 mm Hg.

    The fourth category, ‘denervation versus blinded control’ is currently empty, as only now are such trials underway.

    Ambulatory pressure drops

    Mean weighted ambulatory pressure drop was 15.7 mm Hg over all the study categories.

    There were five trials which had two characteristics setting them apart from general clinical practice:

    • office blood pressures were not measured (or at least not reported)

    • enrolment into the trial appeared to have been based solely on the ambulatory pressure that was then also used as the baseline, exposing them to the ‘regression to the mean’ artefact.

    These five trials are marked with dotted circles in figure 2. Their weighted mean ambulatory blood pressure reductions had mean size of 19.3 mm Hg. One of them showed the raw blood pressure values for the patients. All 20 pressure values were multiples of 5 mm Hg.20 The probability of this occurring in values arising from algebraic averaging, or indeed from any form of machine measurement of blood pressure, is (1/5)20, that is, p=0.00000000000001.

    If those five studies are set aside, the remaining seven studies, all of which reported both office and ambulatory pressures, showed a mean ambulatory pressure reduction of 11.9 mm Hg.

    Discussion

    Office pressure drops are larger than ambulatory drops in drug trials, but only when the trial is non-randomised and not blinded. In randomised, blinded drug trials, the incremental office blood pressure drop beyond placebo seems to be no bigger than the corresponding ambulatory pressure drop.

    No randomised blinded denervation study has yet been completed and reported. Our analysis suggests that when this eventually occurs,21 the office and ambulatory blood pressure reductions may converge. It suggests that the incremental office drop beyond placebo (ie, the drop genuinely due to the intervention) under such bias-resistant conditions may decrease to values seen on ambulatory blood pressure monitoring, that is, ∼10–15 mm Hg.

    The office-to-ambulatory ratio of pressure drop in drug trials depends on trial design

    This study finds that the large apparent conflict between office blood pressure drops and ambulatory blood pressure drops with renal denervation is an anomaly not seen in well-designed antihypertensive drug trials.

    Office pressure drops may be artifactually larger than ambulatory drops in renal denervation trials (and patients treated with placebos in drug trials, as shown in our study) because of either overestimation of baseline office pressures, or underestimation of final office pressures.

    Overestimation of baseline blood pressure may occur because of the phenomenon of regression to the mean which applies whenever patients are selected on the basis of exceeding a threshold on any marker that naturally fluctuates with time. In hypertension trials, any patient has a better chance of meeting inclusion criteria on a day when their blood pressure is above their own long-term average. If the patient's blood pressure is then followed up, its average will tend to return to that individual's true mean pressure, even if there was no intervention. This phenomenon is observed frequently in hypertension trials22–24 and is sometimes confused with the placebo effect. The size of the regression to the mean is dependent on the size of the natural variability. Since a 24 h ambulatory average incorporates dozens of raw values, its variation between visits is correspondingly smaller, and regression to the mean is reduced. However, due to day-to-day variations in blood pressure it is not eliminated,2 and could remain a significant source of bias if ambulatory pressures at enrolment are used as the baseline. This could explain why trials only measuring ambulatory blood pressures show a tendency for larger ambulatory blood pressure reductions than trials where ambulatory pressures are measured after enrolment (19.3 mm Hg vs 11.9 mm Hg). This phenomenon can be neutralised in placebo-controlled trials because the office pressure drop in the placebo arm can be subtracted from that in the treatment arm to isolate the true effect.

    Underestimation of final office pressures may be explained by observer bias, a phenomenon noted in other studies.25 This might be an understandable natural extension of the common clinical practice of repeating measurements that seem to be erroneously high. In a patient openly having had treatment, if a final office reading unexpectedly appears to have increased from baseline, the physician may choose to remeasure. For a patient openly in the control arm, however, such a value might not be considered erroneous. Higher than average values will be dismissed for the treatment cohort, but recorded for the control. The rejection of only a few values viewed to be biologically implausible can lead to the emergence of a false trend.4 Blinding of treatment groups would minimise this form of bias, and any residual bias would be evident in the placebo arm.

    There is an additional possibility that undergoing an invasive procedure may affect a patient's compliance with medication. Some patients do not take the medication prescribed. Selecting a cohort of hypertensive patients in whom many drugs are prescribed but the reduction in pressure is small is an excellent way of enriching a population for such non-adherent individuals. Low adherence to medication has been seen in other studies of resistant hypertension.26 ,27 To go on to perform an invasive procedure on patients with such variable medication compliance could be predicted to seriously influence their future medication habits. This may manifest as decreased compliance due to the belief of having received a ‘curative’ procedure, or increased compliance as a catheter ablation may signify the seriousness of their condition. Such phenomena could significantly confound measurements taken to assess a blood pressure reduction from renal denervation. In a double-blinded trial, the bias would be equal in both arms and would therefore be neutralised.

    Curious disappearance of the alerting response in open trials of renal denervation

    If office and ambulatory pressure reductions from renal denervation truly are significantly different, there must be a specific reduction in the size of the ‘white coat effect’.8 Absolute office pressures are typically higher than ambulatory pressures. The term ‘white coat effect’ can be used to refer to this gap. Our analysis shows office pressure drops to be ∼28 mm Hg depending on trial design, while ambulatory pressure drops are significantly smaller. If office pressures fall further than ambulatory pressures, this white coat effect must shrink, as shown in figure 3.

    Figure 3
    Figure 3

    Because of their interlinking (A), the office drop equals the ambulatory drop plus the reduction in white coat effect (B). There was an average 18.75 mm Hg reduction in white coat effect, implying that it either began above 18.75 mm Hg and was reduced by at least this amount, or finished negative (ie, to say blood pressure dropped during clinic measurement), each of would be highly surprising.

    The white coat effect typically averages 10–25 mm Hg.28–31 Results of the three denervation trials reporting ambulatory and office pressure drops indicate that the white coat effect must drop by ∼18 mm Hg from baseline to final (figure 3), implying that the white coat effect almost completely disappears or even reverses. Such a drastic shrinkage or reversal implies that the white coat effect is almost entirely mediated by the renal nerves. This discovery would be profound.

    If renal denervation does eliminate the alerting response, one would expect daytime ambulatory pressures to be reduced far in excess of nocturnal blood pressures. A recent analysis of patients from the Symplicity HTN-1 and Symplicity HTN-2 trials, however, shows this is not the case with daytime and nocturnal ambulatory pressure reductions to be similar at 12.2 and 11.1 mm Hg, respectively.32 It is therefore unlikely that the large disparity between office and ambulatory blood pressure drops is caused by disproportionately higher reductions in daytime, and therefore office, blood pressures.

    Representativeness

    It may at first appear that the major renal denervation trials have focused on patients with unusually severe hypertension who may be very different from patients in drug trials and daily clinical practice. However, the largest ever renal denervation study reporting baseline office and ambulatory blood pressures, EnligHTN-1, showed the baseline ambulatory pressure to be only 150 mm Hg. This is very similar to the 148 mm Hg average ambulatory pressure in the double-blinded randomised drug trials (see online supplementary appendix 2).

    The corresponding baseline ambulatory values for Symplicity-HTN 1 and Symplicity-HTN 2 remain undisclosed, surprisingly.

    Realistic expectation for pressure drop from denervation

    The genuine effect on blood pressure from the act of denervation itself is not directly calculable from routine clinical data. It requires a randomised blinded trial, and ideally one that separates the denervation step from all the accoutrements of the procedure and corresponding bias in the patients’ compliance and observers’ measurements. Patients would need to have a reproducible and bias-resistant baseline assessment of blood pressure, for which ambulatory measurements are well suited.33 They would be randomly allocated to attempted denervation or no attempt at denervation, but would otherwise undergo the same invasive steps, with their status concealed from them by appropriate sedative or amnesic agents. The physicians caring for their blood pressure should likewise be unaware of the allocation arm, and the final measurement should be in a reproducible and bias-resistant modality such as ambulatory pressure. Such trials are now underway.21

    Until these trials report, the most bias-resistant and, therefore, accurate measurements of the true blood pressure reduction from renal denervation are those from trials measuring ambulatory pressure drops.

    Study limitations

    This meta-analysis uses data from multiple hypertension and renal denervation trials. The renal denervation trials appear to be particularly heterogeneous, with a variety of trial designs, inclusion criteria and blood pressure measurement strategies. The methods through which secondary hypertension were excluded were not covered in any of the articles.

    In many of these denervation trials, there were changes in medication during follow-up, so that the net effect on blood pressure cannot be assumed to be caused by denervation alone. However, this should not have caused the divergence between office and ambulatory blood pressure drops that we have observed.

    Only two randomised controlled trials of denervation have so far been reported. The majority of denervation trials included in this analysis were case-control studies or case series (table 2).

    We included all eligible studies, even though there were unclear aspects in some, such as the existence of a five-study subset that described the clinically unusual habit of carrying out only ambulatory pressure measurements with no office pressure measurements at all. The ambulatory pressure drops in them seemed similar to office pressure drops from other denervation studies. Moreover, where raw data were published, the final-digit characteristics suggested (p=0.00000000000001) accidental mislabelling of manually documented office pressures as 24 h ambulatory monitoring. This could easily happen in a fast moving field, such as denervation.

    However, since we cannot tell if all five (or indeed any) had inadvertently mislabelled office measurements as ambulatory, we merely mark them and present separate weighted average responses, with them included and excluded.

    Clinical implications

    If the genuine pressure drop from renal denervation as established from future bias-resistant (blinded, placebo-controlled) trials turns out to be between 10 and 16 mm Hg, this is still a substantial benefit which could be expected to deliver ∼20% reduction in cardiac events and ∼40% reduction in stroke.34 The ability to extrapolate confidently, that is, from a reliable effect size, is important because adequately powered hard endpoint trial results will not arrive soon.

    Conclusion

    The large disparity between office and ambulatory pressure drops reported with renal denervation is unique. If it is to be explained as a recognised feature in drug trials, then it should be noted that it only occurs when the drug trials are open to bias by lack of blinding and lack of controls. With blinding and randomisation implemented, to neutralise bias, the effect disappears, that is, office and ambulatory pressures fall equally. Even with only placebo tablets, staff documenting office blood pressures record significantly larger drops than automatic machines recording ambulatory blood pressures (p=0.002).

    Renal denervation will soon have blinded trial results. If the effect size beyond placebo is not 30 mm Hg, but only a fraction of this, we should not assume that these more rigorously designed trials are the ones in error. Ambulatory pressure drops, from a baseline measured separately from enrolment values, average 11.9 mm Hg. This analysis makes the formal scientific prediction that excess office pressure drop beyond the control arm drop, in bias-resistant trial designs, will converge towards a similar value.

    In our search for device-based therapies for hypertension, we have a responsibility to derive the most reliable information from patients volunteering to undergo permanent physiological modification to advance science. Now that our analysis is published, we recommend future investigators, seeking to quantify the true effect of renal denervation on blood pressure, should avoid further unblinded studies using office measurements. These two ingredients have been a recipe for gross exaggeration.

    References

    1. ↵
      1. Finegold JA,
      2. Asaria P,
      3. Francis DP
      . Mortality from ischaemic heart disease by country, region, and age: Statistics from World Health Organisation and United Nations. Int J Cardiol 2012. Published Online First: Epub Date. doi:10.1016/j.ijcard.2012.10.046
    2. ↵
      1. Warren RE,
      2. Marshall T,
      3. Padfield PL,
      4. et al
      . Variability of office, 24-hour ambulatory, and self-monitored blood pressure measurements. Br J Gen Pract 2010;60:675–80.
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Nietert PJ,
      2. Wessell AM,
      3. Feifer C,
      4. et al
      . Effect of terminal digit preference on blood pressure measurement and treatment in primary care. Am J Hypertens 2006;19:147–52.
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Shun-Shin M,
      2. Francis DP
      . Why even more clinical research studies may be false: effect of asymmetrical handling of clinically unexpected values. Plos ONE 2013 Jun 25;8(6):e65323. doi: 10.1371/journal.pone.0065323
    5. ↵
      1. O'Brien E,
      2. Coats A,
      3. Owens P,
      4. et al
      . Use and interpretation of ambulatory blood pressure monitoring: recommendations of the British Hypertension Society. BMJ 2000;320:1128.
      OpenUrlFREE Full Text
    6. ↵
      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.
    7. ↵
      1. Symplicity HTNI,
      2. Esler MD,
      3. Krum H,
      4. et al
      . Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903–9.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Doumas M,
      2. Anyfanti P,
      3. Bakris G
      . Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension: a perspective. J Hypertens 2012;30:874–6.
      OpenUrlCrossRefPubMed
    9. ↵
      1. Mahfoud F,
      2. Cremers B,
      3. Janker J,
      4. et al
      . Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension 2012;60:419–24.
      OpenUrlCrossRef
    10. ↵
      1. Mancia G,
      2. Parati G
      . Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: a meta-analysis. J Hypertens 2004;22:435–45.
      OpenUrlCrossRefPubMed
    11. ↵
      1. Shun-Shin M,
      2. Francis DP
      . Why are some studies of cardiovascular markers unreliable? The role of measurement variability and what an aspiring clinician scientist can do before it is too late. Prog Cardiovasc Dis 2012;55:14–24.
      OpenUrlCrossRefPubMed
    12. ↵
      1. Nijjer SS,
      2. Pabari PA,
      3. Stegemann B,
      4. et al
      . The limit of plausibility for predictors of response: application to biventricular pacing. JACC Cardiovasc Imaging 2012;5:1046–65.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      MarketMonitors Inc. cvPipeline. Secondary cvPipeline. http://www.cvpipeline.com/
    14. ↵
      1. Ormiston J,
      2. Watson T,
      3. van Pelt N,
      4. et al
      . TCT-212 first report of the 6-month first in human results of the OneShot™ Renal Denervation System: the RHAS study. J Am Coll Cardiol 2012;60(17_S). Published Online First: Epub Date. doi:10.1016/j.jacc.2012.08.234
    15. ↵
      Results from the REDUCE trial of the Paradise Renal Denervation Catheter. Transcatheter Cardiovascular Therapeutics; 2012; Miama, Florida.
    16. ↵
      Session IV. Emerging Technologies for Renal Denervation, V2 (Vessix Vascular). Transcatheter Cardiovascular Therapeutics; 2012; Miami, Florida.
    17. ↵
      1. Peto R
      . Failure of randomisation by “sealed” envelope. Lancet 1999;354:73.
      OpenUrlPubMed
    18. ↵
      1. Torgerson DJ,
      2. Roberts C
      . Randomisation methods: concealment. BMJ 1999;319:375–6.
      OpenUrlFREE Full Text
    19. ↵
      1. Cole G,
      2. Francis DP
      . Comparable or STAR-heartlingly different left ventricular ejection fraction at baseline? Eur J Heart Fail 2011;13:234–4.
      OpenUrlCrossRefPubMed
    20. ↵
      1. Simonetti G,
      2. Spinelli A,
      3. Gandini R,
      4. et al
      . Endovascular radiofrequency renal denervation in treating refractory arterial hypertension: a preliminary experience. Radiol Med 2012;117:426–44.
      OpenUrlCrossRefPubMed
    21. ↵
      1. Kandzari DE,
      2. Bhatt DL,
      3. Sobotka PA,
      4. et al
      . Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 trial. Clin Cardiol 2012;35:528–35.
      OpenUrlCrossRefPubMed
    22. ↵
      1. Hossmann V,
      2. FitzGerald GA,
      3. Dollery CT
      . Influence of hospitalization and placebo therapy on blood pressure and sympathetic function in essential hypertension. Hypertension 1981;3:113–18.
      OpenUrlCrossRef
    23. ↵
      1. Pitts SR,
      2. Adams RP
      . Emergency department hypertension and regression to the mean. Ann Emerg Med 1998;31:214–18.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. McDonald CJ,
      2. Mazzuca SA,
      3. McCabe GP Jr.
      . How much of the placebo ‘effect’ is really statistical regression? Stat Med 1983;2:417–27.
      OpenUrlCrossRefPubMed
    25. ↵
      1. Bruce NG,
      2. Shaper AG,
      3. Walker M,
      4. et al
      . Observer bias in blood pressure studies. J Hypertens 1988;6:375–80.
      OpenUrlPubMedWeb of Science
    26. ↵
      1. Jung O,
      2. Gechter JL,
      3. Wunder C,
      4. et al
      . Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens 2013;31:766–74.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      1. Bunker J,
      2. Callister W,
      3. Chang C,
      4. et al
      . How common is true resistant hypertension? J Hum Hypertens 2010;25:137–40.
      OpenUrlPubMed
    28. ↵
      1. Mancia G,
      2. Sega R,
      3. Bravi C,
      4. et al
      . Ambulatory blood pressure normality: results from the PAMELA study. J Hypertens 1995;13(12 Pt 1):1377.
      OpenUrlPubMedWeb of Science
    29. ↵
      1. Sega R,
      2. Cesana G,
      3. Milesi C,
      4. et al
      . Ambulatory and home blood pressure normality in the elderly: data from the PAMELA population. Hypertension 1997;30:1–6.
      OpenUrlCrossRef
    30. ↵
      1. Mancia G,
      2. Parati G,
      3. Pomidossi G,
      4. et al
      . Alerting reaction and rise in blood pressure during measurement by physician and nurse. Hypertension 1987;9:209–15.
      OpenUrlCrossRef
    31. ↵
      1. Parati G,
      2. Omboni S,
      3. Staessen J,
      4. et al
      . Limitations of the difference between clinic and daytime blood pressure as a surrogate measure of the'white-coat'effect. J Hypertens 1998;16:23–9.
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Mahfoud F,
      2. Ukena C,
      3. Schmieder RE,
      4. et al
      . Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 2013.
    33. ↵
      1. O'Brien E
      . Twenty-four-hour ambulatory blood pressure measurement in clinical practice and research: a critical review of a technique in need of implementation. J Intern Med 2011;269:478–95.
      OpenUrlCrossRefPubMed
    34. ↵
      1. Law M,
      2. Morris J,
      3. Wald N
      . Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:1245–53.
      OpenUrl
    35. ↵
      1. Davies JE,
      2. Manisty CH,
      3. Petraco R,
      4. et al
      . First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol 2013;162:189–92.
      OpenUrlCrossRefPubMed
    36. ↵
      ClinicalTrials.gov. Renal Artery Denervation in Chronic Heart Failure Study (REACH). Secondary Renal Artery Denervation in Chronic Heart Failure Study (REACH). http://clinicaltrials.gov/show/NCT01639378
      1. Parra Carrillo J,
      2. Fernández M,
      3. Barrera M,
      4. et al
      . Effect of telmisartan 80 mg once daily on 24-h blood pressure profile in patients with mild-to-moderate hypertension failing to respond to prior antihypertensive therapy. Int J Clin Pract 2004;58(s145):9–15.
      OpenUrl
      1. Middlemost SJ,
      2. Sack M,
      3. Davis J,
      4. et al
      . Effects of long-acting nifedipine on casual office blood pressure measurements, 24-hour ambulatory blood pressure profiles, exercise parameters and left ventricular mass and function in black patients with mild to moderate systemic hypertension. Am J Cardiol 1992;70:474–8.
      OpenUrlCrossRefPubMed
      1. Scholze J,
      2. Bramlage P,
      3. Trenkwalder P,
      4. et al
      . Efficacy and safety of a fixed-dose combination of lercanidipine and enalapril in daily practice. A comparison of office, self-measured and ambulatory blood pressure. Expert Opin Pharmacother 2011;12:2771–9.
      OpenUrlCrossRefPubMedWeb of Science
      1. Coca A,
      2. Calvo C,
      3. Sobrino J,
      4. et al
      . Once-daily fixed-combination irbesartan 300 mg/hydrochlorothiazide 25 mg and circadian blood pressure profile in patients with essential hypertension. Clin Ther 2003;25:2849–64.
      OpenUrlCrossRefPubMed
      1. Mancia G,
      2. Zanchetti A,
      3. Agebiti-Rosei E,
      4. et al
      . Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation 1997;95:1464–70.
      OpenUrlAbstract/FREE Full Text
      1. Coca A,
      2. Sobrino J,
      3. Soler J,
      4. et al
      . Trough-to-peak ratio and circadian blood pressure profile after treatment with once-daily extended-release diltiazem, 240 mg, in patients with mild-to-moderate essential hypertension. J Cardiovasc Pharmacol 1997;29:316–22.
      OpenUrlCrossRefPubMed
      1. Omboni S,
      2. Fogari R,
      3. Mancia G
      . A smooth blood pressure control is obtained over 24 h by delapril in mild to moderate essential hypertensives. Blood Press 2001;10:170–5.
      OpenUrlCrossRefPubMed
      1. Ouzan J,
      2. Perault C,
      3. Lincoff AM,
      4. et al
      . The role of spironolactone in the treatment of patients with refractory hypertension. Am J Hypertens 2002;15(4 Pt 1):333–9.
      OpenUrlAbstract/FREE Full Text
      1. de Souza F,
      2. Muxfeldt E,
      3. Fiszman R,
      4. et al
      . Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension 2010;55:147–52.
      OpenUrlCrossRef
      1. Antonicelli R,
      2. Omboni S,
      3. Giovanni DC,
      4. et al
      . Smooth blood pressure control obtained with extended-release felodipine in elderly patients with hypertension: evaluation by 24-hour ambulatory blood pressure monitoring. Drugs Aging 2002;19:541–51.
      OpenUrlCrossRefPubMed
      1. Calhoun DA,
      2. White WB
      . Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. J Am Soc Hypertens 2008;2:462–8.
      OpenUrlCrossRefPubMed
      1. White WB,
      2. Giles T,
      3. Bakris GL,
      4. et al
      . Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in the primary care setting. Am Heart J 2006;151:176–84.
      OpenUrlCrossRefPubMedWeb of Science
      1. Oren S,
      2. Viskoper JR,
      3. Zilles P
      . Antihypertensive efficacy of a once a day verapamil SR/trandolapril combination. Int J Cardiol 1996;55:97–102.
      OpenUrlCrossRefPubMed
      1. Finkielman JD,
      2. Schwartz GL,
      3. Chapman AB,
      4. et al
      . Lack of agreement between office and ambulatory blood pressure responses to hydrochlorothiazide. Am J Hypertens 2005;18:398–402.
      OpenUrlAbstract/FREE Full Text
      1. Mion D Jr.,
      2. Ortega KC,
      3. Gomes MA,
      4. et al
      . Amlodipine 2.5 mg once daily in older hypertensives: a Brazilian multi-centre study. Blood Press Monit 2004;9:83–9.
      OpenUrlCrossRefPubMedWeb of Science
      1. Spratt JC,
      2. Webb DJ,
      3. Shiels A,
      4. et al
      . Effects of candesartan on cardiac and arterial structure and function in hypertensive subjects. J Renin Angiotensin Aldosterone Syst 2001;2:227–32.
      OpenUrlAbstract/FREE Full Text
      1. Martina B,
      2. Weinbacher M,
      3. Gasser P,
      4. et al
      . Efficacy and tolerability of 5 mg of cilazapril plus 12.5 mg of hydrochlorothiazide in mild-to-moderate hypertension: results of 24-hour ambulatory blood pressure monitoring. J Cardiovasc Pharmacol 1994;24(Suppl 3):S89–92.
      OpenUrlPubMed
      1. Omboni S,
      2. Zanchetti A
      . Antihypertensive efficacy of lercanidipine at 2.5, 5 and 10 mg in mild to moderate essential hypertensives assessed by clinic and ambulatory blood pressure measurements. J Hypertens 1998;16:1831–8.
      OpenUrlCrossRefPubMedWeb of Science
      1. Fogari R,
      2. Ambrosoli S,
      3. Corradi L,
      4. et al
      . 24-Hour blood pressure control by once-daily administration of irbesartan assessed by ambulatory blood pressure monitoring. J Hypertens 1997;15:1511–18.
      OpenUrlCrossRefPubMedWeb of Science
      1. Mancia G,
      2. Omboni S,
      3. Grassi G
      . Combination treatment in hypertension the VeraTran Study. Am J Hypertens 1997;10:153S–58S.
      OpenUrlCrossRefPubMed
      1. Guthrie R,
      2. Reggi DR,
      3. Plesher MM,
      4. et al
      . Efficacy and safety of fosinopril/hydrochlorothiazide combinations on ambulatory blood pressure profiles in hypertension. Am J Hypertens 1996;9:306–11.
      OpenUrlCrossRefPubMed
      1. Neutel JM,
      2. Buckalew V,
      3. Chrysant SG,
      4. et al
      . Efficacy and tolerability of tasosartan, a novel angiotensin II receptor blocker: Results from a 10-week, double-blind, placebo-controlled, dose-titration study. Am Heart J 1999;137:118–25.
      OpenUrlCrossRefPubMedWeb of Science
      1. Myers MG,
      2. Asmar R,
      3. Leenen FH,
      4. et al
      . Fixed low-dose combination therapy in hypertension-a dose response study of perindopril and indapamide. J Hypertens 2000;18:317–25.
      OpenUrlCrossRefPubMedWeb of Science
      1. van den Meiracker AH,
      2. Admiraal PJ,
      3. Janssen JA,
      4. et al
      . Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. Hypertension 1995;25:22–9.
      OpenUrlCrossRef
      1. Lacourcière Y,
      2. Pool JL,
      3. Svetkey L,
      4. et al
      . A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Am J Hypertens 1998;11:454–61.
      OpenUrlAbstract/FREE Full Text
      1. Vaclavik J,
      2. Sedlak R,
      3. Plachy M,
      4. et al
      . Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011;57:1069–75.
      OpenUrlCrossRef
      1. Svensson P,
      2. de Faire U,
      3. Sleight P,
      4. et al
      . Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE Substudy. Hypertension 2001;38:E28–32.
      OpenUrlCrossRef
      1. Lacourciere Y,
      2. Poirier L,
      3. Levesque C,
      4. et al
      . Ambulatory blood pressure monitoring for the assessment of nicardipine as a third drug in severe essential hypertension. Eur J Clin Pharmacol 1992;42:131–6.
      OpenUrlCrossRefPubMed
      1. Starmans-Kool MJ,
      2. Kleinjans HA,
      3. Lustermans FA,
      4. et al
      . Treatment of elderly patients with isolated systolic hypertension with isosorbide dinitrate in an asymmetric dosing schedule. J Hum Hypertens 1998;12:557–61.
      OpenUrlCrossRefPubMed
      1. Staessen JA,
      2. Thijs L,
      3. Mancia G,
      4. et al
      . Clinical trials with ambulatory blood pressure monitoring: fewer patients needed? Syst-Eur Investigators. Lancet 1994;344:1552–6.
      OpenUrlCrossRefPubMedWeb of Science
      1. Blanchett DG,
      2. Corder CN,
      3. Kezdi P,
      4. et al
      . Antihypertensive effect of tiapamil from ambulatory and clinic methods. Int J Clin Pharmacol Ther Toxicol 1991;29:59–63.
      OpenUrlPubMed
      1. Krum H,
      2. Schlaich M,
      3. Whitbourn R,
      4. et al
      . Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81.
      OpenUrlCrossRefPubMedWeb of Science
      1. Ahmed H,
      2. Neuzil P,
      3. Skoda J,
      4. et al
      . Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of drug-resistant hypertension. JACC Cardiovasc Interv 2012;5:758–65.
      OpenUrlCrossRefPubMedWeb of Science
      1. Dörr O,
      2. Liebetrau C,
      3. Möllmann H,
      4. et al
      . Renal sympathetic denervation does not aggravate functional or structural renal damage. J Am Coll Cardiol 2013;61:479–80.
      OpenUrlCrossRefPubMedWeb of Science
      1. Zuern CS,
      2. Rizas KD,
      3. Eick C,
      4. et al
      . Effects of renal sympathetic denervation on 24-hour blood pressure variability. Front Physiol 2012;3.
      1. Hering D,
      2. Mahfoud F,
      3. Walton AS,
      4. et al
      . Renal denervation in moderate to severe CKD. J Am Soc Nephrol 2012;23:1250.
      OpenUrlAbstract/FREE Full Text
      1. Himmel F,
      2. Weil J,
      3. Reppel M,
      4. et al
      . Improved heart rate dynamics in patients undergoing percutaneous renal denervation. J Clin Hypertens 2012;14:654–5.
      OpenUrlCrossRef
      1. Mylotte D,
      2. Benamer H,
      3. Unterseeh T,
      4. et al
      . Percutaneous renal denervation for resistant hypertension: real world outcomes. J Am Coll Cardiol 2012;59(13s1):E1708.
      OpenUrlCrossRef
      1. Prochnau D,
      2. Figulla HR,
      3. Surber R
      . Efficacy of renal denervation with a standard EP catheter in the 24-h ambulatory blood pressure monitoring—long-term follow-up. Int J Cardiol 2012;157:447–8.
      OpenUrlCrossRefPubMed
      1. Vase H,
      2. Mathiassen ON,
      3. Kaltoft A,
      4. et al
      . Catheter-based renal denervation for treatment of resistant hypertension. Dan Med J 2012;59:A4439.
      OpenUrlPubMed
      1. Verloop W,
      2. Spiering W,
      3. Agostoni P,
      4. et al
      . 6-months follow up in a real life situation after renal denervation. J Am Coll Cardiol 2012;59(13s1):E1706.
      OpenUrlCrossRef
      1. Voskuil M,
      2. Verloop W,
      3. Blankestijn P,
      4. et al
      . Percutaneous renal denervation for the treatment of resistant essential hypertension; the first Dutch experience. Neth Heart J 2011;19:319–23.
      OpenUrlCrossRefPubMedWeb of Science
      1. Witkowski A,
      2. Prejbisz A,
      3. Florczak E,
      4. et al
      . Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559–65.
      OpenUrlCrossRef
      1. Pokushalov E,
      2. Romanov A,
      3. Corbucci G,
      4. et al
      . A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60:1163–70.
      OpenUrlCrossRefPubMedWeb of Science
      1. Mahfoud F,
      2. Schlaich M,
      3. Kindermann I,
      4. et al
      . Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertensionClinical perspective: a Pilot study. Circulation 2011;123:1940–6.
      OpenUrlAbstract/FREE Full Text
      1. Brandt MC,
      2. Mahfoud F,
      3. Reda S,
      4. et al
      . Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012;59:901–9.
      OpenUrlCrossRefPubMedWeb of Science

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Files in this Data Supplement:

    Footnotes

    • Contributors JPH: designed the study; retrieved and processed the data; designed the images; drafted and revised the manuscript; ANN: codesigned the study; retrieved and processed the data; designed the images; drafted and revised the manuscript; DPF: initiated the study; codesigned the study; designed the images; drafted and revised the manuscript. Guarantor: DPF.

    • Funding DPF is funded by a British Heart Foundation Senior Research Fellowship FS/10/038.

    • Competing interests DPF is a consultant to Medtronic Inc, which manufactures devices for renal denervation. This analysis is a permissible independent academic activity not instigated, supported, censored or condoned by industry. Data used are in the public domain. We have no knowledge of the data of the Symplicity-HTN-3 trial and no involvement in its design. We have reported an unblinded, uncontrolled pilot study of renal denervation in heart failure,35 and are now conducting a blinded randomised controlled trial.36

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All data analysed within this study are available from the corresponding papers. All data used is visible within this paper and the online supplementary appendices 1–3.