Rationale and design of the Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) trial

Yu Jin, Lotte Jacobs, Marie Baelen, Lutgarde Thijs, Jean Renkin, Frank Hammer, Joelle Kefer, Thibault Petit, Peter Verhamme, Stefan Janssens, Peter Sinnaeve, Jean-Philippe Lengelé, Alexandre Persu, Jan A Staessen, investigator-steered project on intravascular renal denervation for management of drug-resistant hypertension (INSPiRED) investigators, Johan De Sutter, Kristoff Cornelis, Luc Muyldermans, John Thoeng, Michel Henry, Albertino Maimone, Abdelhamid Lalaoui, Philippe Leroy, Gabriela Migali, Jean-François De Wispelaere, Jean-Michel Pochet, Michel Tintillier, Claude Hanet, Antoine Guedes, Vincent Dangoisse, Laurence Gabriel, Alain Brasseur, Philippe Blouard, Patrick Timmermans, Jean-Michel Pochet, Michel Tintillier, Charles Cuvelier, Jean-Philippe Lengelé, Marc Carlier, Amandine Jourdan, Wouter Vinck, Johan Scharpé, Mathias Vrolix, Karl Dujardin, Luc Janssens, Bavo Ector, Jessa Ziekenhuis, Philippe Timmermans, Marc Goethals, Alexandre Persu, Jean-Philippe Lengelé, Jean Renkin, Jean-Benoit le Polain de Waroux, Christophe Scavée, Agnès Pasquet, Frank Hammer, Joëlle Kefer, Francesca Severino, Dominique Huyberechts, Anne Bouvier, Marie Baelen, Erwin Curraj, Jan A Staessen, Peter Sinnaeve, Peter Verhamme, Yu Jin, Lotte Jacobs, Lutgarde Thijs, Thibault Petit, Yu Jin, Lotte Jacobs, Marie Baelen, Lutgarde Thijs, Jean Renkin, Frank Hammer, Joelle Kefer, Thibault Petit, Peter Verhamme, Stefan Janssens, Peter Sinnaeve, Jean-Philippe Lengelé, Alexandre Persu, Jan A Staessen, investigator-steered project on intravascular renal denervation for management of drug-resistant hypertension (INSPiRED) investigators, Johan De Sutter, Kristoff Cornelis, Luc Muyldermans, John Thoeng, Michel Henry, Albertino Maimone, Abdelhamid Lalaoui, Philippe Leroy, Gabriela Migali, Jean-François De Wispelaere, Jean-Michel Pochet, Michel Tintillier, Claude Hanet, Antoine Guedes, Vincent Dangoisse, Laurence Gabriel, Alain Brasseur, Philippe Blouard, Patrick Timmermans, Jean-Michel Pochet, Michel Tintillier, Charles Cuvelier, Jean-Philippe Lengelé, Marc Carlier, Amandine Jourdan, Wouter Vinck, Johan Scharpé, Mathias Vrolix, Karl Dujardin, Luc Janssens, Bavo Ector, Jessa Ziekenhuis, Philippe Timmermans, Marc Goethals, Alexandre Persu, Jean-Philippe Lengelé, Jean Renkin, Jean-Benoit le Polain de Waroux, Christophe Scavée, Agnès Pasquet, Frank Hammer, Joëlle Kefer, Francesca Severino, Dominique Huyberechts, Anne Bouvier, Marie Baelen, Erwin Curraj, Jan A Staessen, Peter Sinnaeve, Peter Verhamme, Yu Jin, Lotte Jacobs, Lutgarde Thijs, Thibault Petit

Abstract

The SYMPLICITY studies showed that renal denervation (RDN) is feasible as novel treatment for resistant hypertension. However, RDN is a costly and invasive procedure, the long-term efficacy and safety of which has not yet been proven. Therefore, we designed the INSPiRED trial to compare the blood pressure lowering efficacy and safety of RDN vs usual medical therapy. INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert hypertension centres in Belgium. Eligible patients, aged 20-69 years old, have a 24-h ambulatory blood pressure of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTN(TM), SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic blood pressure and in glomerular filtration rate as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. Follow-up will continue up to 36 months after randomization. INSPiRED is powered to demonstrate a 10-mmHg difference in systolic blood pressure between randomized groups with a two-sided p-value of 0.01 and 90% power. It will generate long-term efficacy and safety data, identify the subset of treatment-resistant hypertensive patients responsive to RDN, provide information on cost-effectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers.

Trial registration: ClinicalTrials.gov Identifier: NCT 01505010.

Trial registration: ClinicalTrials.gov NCT01505010.

Keywords: Ambulatory blood pressure; randomized controlled trial; renal denervation; resistant hypertension.

Figures

Figure 1.
Figure 1.
Schematic representation of the INSPiRED trial. During the run-in period, antihypertensive drug treatment is optimized and secondary hypertension is excluded. Patients are randomized to renal denervation (RDN) or control. After randomization, optimized drug treatment is continued in both treatment arms, but can be adjusted according to the achieved blood pressure level. After assessment of the endpoints at 6 months, control patients can cross over to renal denervation. Follow-up visits are scheduled at 1, 3 and 6 months after randomization and at 1, 3 and 6 months after renal denervation in control patients crossing over with a visit at 2 months being optional. The long-term follow-up last up to 36 months after randomization.
Figure 2.
Figure 2.
INSPiRED algorithm for adjustment if antihypertensive drug treatment. Recommendation for combining blood-pressure lowering drugs according to the ABCD rule. Modified from: JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association. Heart 2005;91: supplement 5:v1–52. Copyright © 2005 BMJ. Reproduced with permission from BMJ Publishing Group Ltd.

References

    1. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57:1076–1080.
    1. de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Oliveras A, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:889–890.
    1. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:75–197.
    1. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–1281.
    1. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet. 2010;376:1903–1909.
    1. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation – Ultima ratio or standard in treatment- resistant hypertension. Hypertension. 2012;60:596–606.
    1. Jin Y, Persu A, Staessen JA. Renal denervation in the management of resistant hypertension: Current evidence and perspectives. Curr Opin Nephrol Hypertens. 2013;22:511–518.
    1. Howard JP, Nowbar AN, Francis DP. 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. Heart. 2013;99:1579–1587.
    1. Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, 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;60:1163–1170.
    1. Staessen JA, Jin Y, Alexandre P, Azizi M, Kjeldsen S. First-in-man randomized clinical trial of renal denervation for atrial arrhythmia raises concern. J Am Coll Cardiol. 2013;62:e445–e446.
    1. Hopewell S, Clarke M, Moher D, Wager E, Middleton P, Altman DG, et al. CONSORT for reporting randomised trials in journal and conference abstracts. Lancet. 2008;371:281–283.
    1. Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med. 1999;130:461–470.
    1. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: Diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research . Hypertension. 2008;51:1403–1419.
    1. Kuznetsova T, Herbots L, López B, Jin Y, Richart T, Thijs L, et al. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail. 2009;2:102–112.
    1. Kloch-Badelek M, Kuznetsova T, Sakiewicz W, Tikhonoff V, Ryabikov A, Gonzalez A, et al. Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds. Cardiovasc Ultrasound. 2012;10:10.
    1. Liu YP, Richart T, Jin Y, Struijker Boudier HA, Staessen JA. Retinal arterial and venular phenotypes in a Flemish population: Reproducibility and correlates. Artery Res. 2011;5:72–79.
    1. British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association. JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular diseases in clinical practice. Heart. 2005;91:1–52.
    1. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Eur Heart J. 2013;34:2159–2219.
    1. Hernández-Hernández R, Armas de Hernández MJ, Armas-Padilla MC, Carvajal AR, Guerrero-Pajuelo J. The effect of missing dose of enalapril versus amlodipine on ambulatory blood pressure. Blood Press Monit. 1996;1:121–126.
    1. Chobanian AV, Bakris GL, Black BK, Cushman WC, Green LA, Izzo JL, Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252.
    1. Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell’Italia LJ, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: Results from a randomized trial. Hypertension. 2008;54:475–481.
    1. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31:1731–1768.
    1. O’Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, et al. Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement. J Hypertens. 2005;23:697–701.
    1. Pickering TG, Houston Miller N, Ogedegbe G, Krakoff LR, Artinian NT, Goff D. Call to action on use and reimbursement for home blood pressure monitoring. A joint scientific statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association . Hypertension. 2008;52:10–29.
    1. Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens. 2008;10:348–354.
    1. Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis . J Hypertens. 2013;31:766–774.
    1. Liu PS, Platt JF. CT angiography of the renal circulation. Radiol Clin North Am. 2010;48:347–365.
    1. Turba UC, Uflacker R, Bozlar U, Hagspiel KD. Normal renal arterial anatomy assessed by multidetector CT angiography: Are there differences between men and women ? Clin Anat. 2009;22:236–242.
    1. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use . Circulation. 1996;93:1043–1065.
    1. Malliani A, Montano N. Emerging excitatory role of cardiovascular sympathetic afferents in pathophysiological conditions. Hypertension. 2002;39:63–68.
    1. Stolarz K, Staessen JA, Kawecka-Jaszcz K, Brand E, Bianchi G, Kuznetsova T, et al. Genetic variation in CYP11B2 and AT1R influences heart rate variability conditional on sodium excretion. Hypertension. 2004;44:156–162.
    1. Stolarz K, Staessen JA, Kuznetsova T, Tikhonoff V, State D, Babeanu S, et al. Host and environmental determinants of heart rate and heart rate variability in four European populations. J Hypertens. 2003;21:525–535.
    1. Aubert AE, Seps B, Beckers F. Heart rate variability in athletes. Sports Med. 2003;33:889–919.
    1. Chinushi M, Izumi D, Iijima K, Suzuki K, Furushima H, Saitoh O, et al. Blood pressure and autonomic responses to electrical stimulation of the renal arterial nerves before and after ablation of the renal artery. Hypertension. 2013;61:450–456.
    1. Zürbig P, Jerums G, Hovind P, Macisaac RJ, Mischak H, Nielsen SE, et al. Urinary proteomics for early diagnosis in diabetic nephropathy. Diabetes. 2012;61:3304–3313.
    1. Albalat A, Husi H, Stalmach A, Schanstra JP, Mischak H. Classical MALDI-MS versus CE-based ESI-MS proteomic profiling in urine for clinical applications. Bioanalysis. 2014;6:247–266.
    1. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–1898.
    1. Haller H, Ito S, Izzo JL, Jr, Januszewics A, Katayama S, Menne J, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364:907–917.
    1. Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med. 1999;18:1341–1354.
    1. Krum H, Schlaich MP, Böhm M, Mahfoud F, Rocha-Singh K, Katholi R, 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.

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