Physicians' Academy for Cardiovascular Education

Post hoc analyses of SYMPLICITY HTN-3 shed light on potential source of unexpected trial outcome

Kandzari DE et al., Eur Heart J. 2014

Predictors of blood pressure response in the SYMPLICITY HTN-3 trial

Kandzari DE, Bhatt DL, Brar S, et al.
Eur Heart J. 2014 Nov 16. pii: ehu441


Several strategies have been explored to interrupt the sympathetic contribution to hypertension, especially in patients with resistant hypertension. Surgical sympathectomy yielded reduction of blood pressure for some patients, but also had serious side effects [1,2].
A catheter-based approach to renal denervation (RDN) has shown sensory and sympathetic efferent denervation with decreased renal norepinephrine spill over, halving of renin activity and increased renal plasma flow [3]. Clinically significant, sustained reductions in office systolic blood pressure (SBP) have also been observed after RDN, in unblinded studies [4,5]. In a less-selected real-world patient population BP reductions were seen across a broader range of baseline BPs and the safety of radiofrequency RDN was confirmed [6].
The SYMPLICITY HTN-3 trial also confirmed safety of RDN, but did not show a significant difference in BP decline at 6 months, between the real and a sham procedure, in 535 patients with treatment resistant hypertension [7].
This study explored key factors that may have contributed to the puzzling results in SYMPLICITY HTN-3, namely the less than expected RDN treatment effect and a more pronounced response to a sham procedure. Information on changes in antihypertensive medications, outcomes in selected subgroups and detailed assessment of procedural data were studied, in order to identify potential confounding factors that may have impacted the delivery of effective RDN.

Main results

  • In the overall group, multivariable analysis identified baseline office SBP>180 mmHg and prescription of an aldosterone antagonist at baseline as positive predictions for increasing 6-months change from baseline in office SBP.
    Prescription of a vasodilator at baseline was a negative predictor of office BP reduction.
  • After randomisation, 39% of patients had a change in dose or drug class between baseline and 6-months.
  • Vasodilators were the only baseline medications that were differentially prescribed between treatment groups. Among African-Americans, more sham patients (56%) than RDN patients (46.7%) received them, and among non-African-Americans 40.5% (sham) vs. 33.7% (RDN) respectively received vasodilators.
    African-Americans undergoing a sham procedure and receiving a vasodilator showed a particularly large decline in SBP (-21.9+29.1 mmHg), which was not seen in the other subgroups. In non-African-Americans, patients not prescribed a vasodilator showed a greater change in office SBP (-17.6 mmHg in RDN and -10.4 mmHg in sham group, difference: -7.1, 95%CI: -13.7 to -0.6, P=0.03).
  • When control and RDN patients were propensity matched according to baseline characteristics, statistically significant increasing trends were seen for the difference in office SBP, and heart rate, with increasing numbers of ablations delivered to the RDN group.
    No increase in safety events occurred with increasing number of renal artery ablations.


These post hoc analyses of the SYMPLICITY HTN-3 trial critically examined the results in the context of existing RDN data and clinical trial design. The unexpectedly large SBP decline in African-American control patients may indicate a change in medical adherence or type of therapy in this group. African-Americans indeed received vasodilators more often. While the exact reasons for the observed difference remain unclear, it underscores the importance of standardised and consistent BP care in future trials. A better understanding of how RDN translates to sympathetic activity is needed, and may require revisiting the basic science of RDN.

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1. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc 1953;152:1501–1504.
2. Longland CJ, Gibb WE. Sympathectomy in the treatment of benign and malignant hypertension; a review of 76 patients. Br J Surg 1954;41:382–392.
3. DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010;298:R245–R253.
4. Esler MD, Krum H, Schlaich M, Schmieder RE, Bohm M, Sobotka PA; for the Symplicity HTN-2 Investigators. Renal sympathetic denervation for treatment
of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 2012;126:2976–2982.
5. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383: 622–629.
6. Mahfoud F, Mancia G, Schlaich MP, et al. Reduction in office blood pressure after renal denervation in a large real world patient population with uncontrolled hypertension: interim 12-month results from the Global SYMPLICITY registry. Presented at the European Society of Cardiology, Barcelona 2014; p62.
7. Bhatt DL, Kandzari DE, O’NeillWW, et al. SYMPLICITY HTN-3 Investigators.A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–1401.