Recent Developments and Controversies in the Treatment of Resistant Hypertension

Abstract

Resistant hypertension is defined as elevated blood pressure despite the appropriate use of 3 or more antihypertensive drugs, including a diuretic, and constitutes a frequent and important clinical problem with significant disease morbidity and mortality. Several sources of evidence point to the sympathetic nervous system as a major protagonist in this disease entity. The catheter-based, radiofrequency ablation of renal sympathetic nerves (renal denervation) to treat resistant hypertension has sparked great enthusiasm. However, failure of this interventional approach in the randomized, sham-controlled Symplicity HTN-3 trial to reach its efficacy endpoint of attaining a significant blood pressure reduction has called this intervention into substantial question and fueled an ongoing scientific debate. Electrical stimulation of the carotid baroreceptors (baroreflex activation therapy) represents another technique to modulate sympathetic activity currently being studied in several clinical trials. This review summarizes and comments the current literature focusing on the invasive treatment of resistant hypertension.

Key words

resistant hypertension - treatment adherence - renal denervation - baroreceptor stimulation

• References

• 1 Kearney PM, Whelton M, Reynolds K et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365: 217-223 DOI: 10.1016/S0140-6736(05)17741-1.
• 2 Calhoun DA, Jones D, Textor S 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. Circulation 2008; 117: e510-e526 DOI: 10.1161/CIRCULATIONAHA.108.189141.
• 3 Sarafidis PA, Georgianos P, Bakris GL. Resistant hypertension – its identification and epidemiology. Nat Rev Nephrol 2013; 9: 51-58 DOI: 10.1038/nrneph.2012.260.
• 4 Mahfoud F, Luscher TF, Andersson B et al. Expert consensus document from the European Society of Cardiology on catheter-based renal denervation. Eur Heart J 2013; 34: 2149-2157 DOI: 10.1093/eurheartj/eht154.
• 5 Vrijens B, Vincze G, Kristanto P et al. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008; 336: 1114-1117 DOI: 10.1136/bmj.39553.670231.25.
• 6 Jung O, Gechter JL, Wunder C et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens 2013; 31: 766-774 DOI: 10.1097/HJH.0b013e32835e2286.
• 7 Mancia G, Fagard R, Narkiewicz K 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 DOI: 10.1093/eurheartj/eht151.
• 8 Sim JJ, Bhandari SK, Shi J et al. Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension. Kidney Int 2015; 88: 622-632 DOI: 10.1038/ki.2015.142.
• 9 Acelajado MC, Pisoni R, Dudenbostel T et al. Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens (Greenwich) 2012; 14: 7-12 DOI: 10.1111/j.1751-7176.2011.00556.x.
• 10 Cushman WC, Brady WE, Gazdick LP et al. The effect of a losartan-based treatment regimen on isolated systolic hypertension. J Clin Hypertens (Greenwich) 2002; 4: 101-107
• 11 Zhang Y, Zhang X, Liu L et al. Higher cardiovascular risk and impaired benefit of antihypertensive treatment in hypertensive patients requiring additional drugs on top of randomized therapy: is adding drugs always beneficial?. J Hypertens 2012; 30: 2202-2212 DOI: 10.1097/HJH.0b013e3283582eec.
• 12 Weber MA, Julius S, Kjeldsen SE et al. Cardiovascular outcomes in hypertensive patients: comparing single-agent therapy with combination therapy. J Hypertens 2012; 30: 2213-2222 DOI: 10.1097/HJH.0b013e3283582ed6.
• 13 Vaclavik J, Sedlak R, Jarkovsky J et al. Effect of spironolactone in resistant arterial hypertension: a randomized, double-blind, placebo-controlled trial (ASPIRANT-EXT). Medicine (Baltimore) 2014; 93: e162 DOI: 10.1097/MD.0000000000000162.
• 14 Dahal K, Kunwar S, Rijal J et al. The effects of aldosterone antagonists in patients with resistant hypertension: a meta-analysis of randomized and nonrandomized studies. Am J Hypertens 2015; 28: 1376-1385 DOI: 10.1093/ajh/hpv031.
• 15 Williams B, MacDonald TM, Morant S et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; DOI: 10.1016/S0140-6736(15)00257-3.
• 16 White WB, Turner JR, Sica DA et al. Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum held in Bethesda, MD, U.S.A., October 10^th 2013. J Am Soc Hypertens 2014; 8: 743-757 DOI: 10.1016/j.jash.2014.06.005.
• 17 Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res 2015; 116: 1074-1095 DOI: 10.1161/CIRCRESAHA.116.303603.
• 18 Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension 2009; 54: 690-697 DOI: 10.1161/HYPERTENSIONAHA.108.119883.
• 19 Thorpe JJ, Welch WJ, Poindexter CA. Bilateral thoracolumbar sympathectomy for hypertension; a study of 500 cases. Am J Med 1950; 9: 500-515
• 20 Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc 1953; 152: 1501-1504
• 21 Newcombe CP, Shucksmith HS, Suffern WS. Sympathectomy for hypertension; follow-up of 212 patients. Br Med J 1959; 1: 142-144
• 22 Evelyn KA, Alexander F, Cooper SR. Effect of sympathectomy on blood pressure in hypertension; a review of 13 years’ experience of the Massachusetts General Hospital. J Am Med Assoc 1949; 140: 592-602
• 23 Smithwick RH, Bush RD, Kinsey D et al. Hypertension and associated cardiovascular disease; comparison of male and female mortality rates and their influence on selection of therapy. J Am Med Assoc 1956; 160: 1023-1026
• 24 Grimson KS. Total thoracic and partial to total lumbar sympathectomy and celiac ganglionectomy in the treatment of hypertension. Ann Surg 1941; 114: 753-775
• 25 Smithwick RH. Surgery in hypertension. Lancet 1948; 2: 65
• 26 Grimson KS, Orgain ES, Anderson B et al. Results of treatment of patients with hypertension by total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy. Ann Surg 1949; 129: 850-871
• 27 Krum H, Schlaich M, Whitbourn R et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373: 1275-1281 DOI: 10.1016/S0140-6736(09)60566-3.
• 28 Symplicity HTNI . Esler MD, Krum H et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376: 1903-1909 DOI: 10.1016/S0140-6736(10)62039-9.
• 29 Bhatt DL, Kandzari DE, O'Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014; 370: 1393-1401 DOI: 10.1056/NEJMoa1402670.
• 30 Bisognano JD, Bakris G, Nadim MK et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011; 58: 765-773 DOI: 10.1016/j.jacc.2011.06.008.
• 31 Daemen J. Current technologies: an introduction. EuroIntervention 2013; 9 Suppl R R75-R82 DOI: 10.4244/EIJV9SRA13.
• 32 Parati G, Esler M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur Heart J 2012; 33: 1058-1066 DOI: 10.1093/eurheartj/ehs041.
• 33 Symplicity HTNI . Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57: 911-917 DOI: 10.1161/HYPERTENSIONAHA.110.163014.
• 34 Esler MD, Krum H, Schlaich M et al. 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 DOI: 10.1161/CIRCULATIONAHA.112.130880.
• 35 Esler MD, Bohm M, Sievert H et al. Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial. Eur Heart J 2014; 35: 1752-1759 DOI: 10.1093/eurheartj/ehu209.
• 36 Mahfoud F, Ukena C, Schmieder RE et al. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 2013; 128: 132-140 DOI: 10.1161/CIRCULATIONAHA.112.000949.
• 37 Davis MI, Filion KB, Zhang D et al. Effectiveness of renal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J Am Coll Cardiol 2013; 62: 231-241 DOI: 10.1016/j.jacc.2013.04.010.
• 38 Tsioufis C, Papademetriou V, Tsiachris D et al. Impact of multi-electrode renal sympathetic denervation on short-term blood pressure variability in patients with drug-resistant hypertension. Insights from the EnligHTN I study. Int J Cardiol 2015; 180: 237-242 DOI: 10.1016/j.ijcard.2014.11.121.
• 39 Kiuchi MG, Maia GL, de Queiroz Carreira MA et al. Effects of renal denervation with a standard irrigated cardiac ablation catheter on blood pressure and renal function in patients with chronic kidney disease and resistant hypertension. Eur Heart J 2013; 34: 2114-2121 DOI: 10.1093/eurheartj/eht200.
• 40 Brandt MC, Mahfoud F, Reda S et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012; 59: 901-909 DOI: 10.1016/j.jacc.2011.11.034.
• 41 Dorr O, Liebetrau C, Mollmann H et al. Influence of renal sympathetic denervation on cardiac extracellular matrix turnover and cardiac fibrosis. Am J Hypertens 2015; 28: 1285-1292 DOI: 10.1093/ajh/hpv020.
• 42 Verloop WL, Spiering W, Vink EE et al. Denervation of the renal arteries in metabolic syndrome: the DREAMS-study. Hypertension 2015; 65: 751-757 DOI: 10.1161/HYPERTENSIONAHA.114.04798.
• 43 Bakris GL, Townsend RR, Flack JM et al. 12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial. J Am Coll Cardiol 2015; 65: 1314-1321 DOI: 10.1016/j.jacc.2015.01.037.
• 44 Esler M. Illusions of truths in the Symplicity HTN-3 trial: generic design strengths but neuroscience failings. J Am Soc Hypertens 2014; 8: 593-598 DOI: 10.1016/j.jash.2014.06.001.
• 45 Epstein M, de Marchena E. Is the failure of SYMPLICITY HTN-3 trial to meet its efficacy endpoint the „end of the road“ for renal denervation?. J Am Soc Hypertens 2015; 9: 140-149 DOI: 10.1016/j.jash.2014.12.002.
• 46 Hansson L, Zanchetti A. The Hypertension Optimal Treatment (HOT) Study: 24-month data on blood pressure and tolerability. Blood Press 1997; 6: 313-317
• 47 Flack JM, Bhatt DL, Kandzari DE et al. An analysis of the blood pressure and safety outcomes to renal denervation in African Americans and Non-African Americans in the SYMPLICITY HTN-3 trial. J Am Soc Hypertens 2015; DOI: 10.1016/j.jash.2015.08.001.
• 48 Middlekauff HR. A mechanistic explanation for the minimal impact of renal denervation on 24-h ambulatory blood pressure in SIMPLICITY HTN-3. J Am Coll Cardiol 2015; 65: 959 DOI: 10.1016/j.jacc.2014.10.076.
• 49 Bakris GL, Bhatt DL. Reply: A mechanistic explanation for the minimal impact of renal denervation on 24-h ambulatory blood pressure in SIMPLICITY HTN-3. J Am Coll Cardiol 2015; 65: 959-960 DOI: 10.1016/j.jacc.2014.11.058.
• 50 Kandzari DE, Bhatt DL, Brar S et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J 2015; 36: 219-227 DOI: 10.1093/eurheartj/ehu441.
• 51 Mahfoud F, Luscher TF. Renal denervation: symply trapped by complexity?. Eur Heart J 2015; 36: 199-202 DOI: 10.1093/eurheartj/ehu450.
• 52 Mahfoud F, Bohm M, Azizi M et al. Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. Eur Heart J 2015; 36: 2219-2227 DOI: 10.1093/eurheartj/ehv192.
• 53 Bohm M, Mahfoud F, Ukena C et al. Rationale and design of a large registry on renal denervation: the Global SYMPLICITY registry. EuroIntervention 2013; 9: 484-492 DOI: 10.4244/EIJV9I4A78.
• 54 Bohm M, Mahfoud F, Ukena C et al. First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension 2015; 65: 766-774 DOI: 10.1161/HYPERTENSIONAHA.114.05010.
• 55 Azizi M, Sapoval M, Gosse P et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015; 385: 1957-1965 DOI: 10.1016/S0140-6736(14)61942-5.
• 56 Lobo M, Saxena M, Jain AJ et al. 4a.09: Safety and Performance of the Enlightn Renal Denervation System in Patients with Severe Uncontrolled Hypertension: 12 Month Results from the Enlightn Ii Study. J Hypertens 2015; 33 (Suppl. 01) e51 DOI: 10.1097/01.hjh.0000467483.82320.f7.
• 57 Rosa J, Widimsky P, Tousek P et al. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study. Hypertension 2015; 65: 407-413 DOI: 10.1161/HYPERTENSIONAHA.114.04019.
• 58 Mahfoud F, Ruilope LM, Bohm M et al. Aldosterone antagonists and renal denervation: friends or foes?. Hypertension 2015; 65: 280-282 DOI: 10.1161/HYPERTENSIONAHA.114.04119.
• 59 Desch S, Okon T, Heinemann D et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension 2015; 65: 1202-1208 DOI: 10.1161/HYPERTENSIONAHA.115.05283.
• 60 Whitbourn R, Harding SA, Walton A. Symplicity multi-electrode radiofrequency renal denervation system feasibility study. EuroIntervention 2015; 11: 104-109 DOI: 10.4244/EIJV11I1A18.
• 61 Rong S, Zhu H, Liu D et al. Noninvasive renal denervation for resistant hypertension using high-intensity focused ultrasound. Hypertension 2015; 66: e22-e25 DOI: 10.1161/HYPERTENSIONAHA.115.05754.
• 62 Pancholy SB, Shantha GP, Patel TM et al. Meta-analysis of the effect of renal denervation on blood pressure and pulse pressure in patients with resistant systemic hypertension. Am J Cardiol 2014; 114: 856-861 DOI: 10.1016/j.amjcard.2014.06.018.
• 63 Mancia G, Ludbrook J, Ferrari A et al. Baroreceptor reflexes in human hypertension. Circ Res 1978; 43: 170-177
• 64 Agishi T, Temples J, Peirce 2nd EC. Electrical stimulation of the carotid sinus nerve as an experimental treatment of hypertension. J Surg Res 1969; 9: 305-309
• 65 Bilgutay AM, Lillehei CW. Treatment of hypertension with an implantable electronic device. JAMA 1965; 191: 649-653
• 66 Bilgutay AM, Lillehei CW. Surgical treatment of hypertension with reference to baropacing. Am J Cardiol 1966; 17: 663-667
• 67 Brest AN, Wiener L, Bachrach B. Bilateral carotid sinus nerve stimulation in the treatment of hypertension. Am J Cardiol 1972; 29: 821-825
• 68 Carlsten A, Folkow B, Grimby G et al. Cardiovascular effects of direct stimulation of the carotid sinus nerve in man. Acta Physiol Scand 1958; 44: 138-145 DOI: 10.1111/j.1748-1716.1958.tb01615.x.
• 69 Warner HR. The frequency-dependent nature of blood pressure regulation by the carotid sinus studied with an electric analog. Circ Res 1958; 6: 35-40
• 70 Illig KA, Levy M, Sanchez L et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg 2006; 44: 1213-1218 DOI: 10.1016/j.jvs.2006.08.024.
• 71 Hoppe UC, Brandt MC, Wachter R et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens 2012; 6: 270-276 DOI: 10.1016/j.jash.2012.04.004.
• 72 Bakris GL, Nadim MK, Haller H et al. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens 2012; 6: 152-158 DOI: 10.1016/j.jash.2012.01.003.
• 73 Alnima T, Goedhart EJ, Seelen R et al. Baroreflex activation therapy lowers arterial pressure without apparent stimulation of the carotid bodies. Hypertension 2015; 65: 1217-1222 DOI: 10.1161/HYPERTENSIONAHA.114.04354.
• 74 Scheffers IJ, Kroon AA, Schmidli J et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010; 56: 1254-1258 DOI: 10.1016/j.jacc.2010.03.089.
• 75 Alnima T, Scheffers I, De Leeuw PW et al. Sustained acute voltage-dependent blood pressure decrease with prolonged carotid baroreflex activation in therapy-resistant hypertension. J Hypertens 2012; 30: 1665-1670 DOI: 10.1097/HJH.0b013e3283551f10.
• 76 Wustmann K, Kucera JP, Scheffers I et al. Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension. Hypertension 2009; 54: 530-536 DOI: 10.1161/HYPERTENSIONAHA.109.134023.
• 77 de Leeuw PW, Alnima T, Lovett E et al. Bilateral or unilateral stimulation for baroreflex activation therapy. Hypertension 2015; 65: 187-192 DOI: 10.1161/HYPERTENSIONAHA.114.04492.
• 78 Halbach M, Hickethier T, Madershahian N et al. Acute on/off effects and chronic blood pressure reduction after long-term baroreflex activation therapy in resistant hypertension. J Hypertens 2015; 33: 1697-1703 DOI: 10.1097/HJH.0000000000000586.
• 79 Zile MR, Abraham WT, Weaver FA et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail 2015; 17: 1066-1074 DOI: 10.1002/ejhf.299.
• 80 Abraham WT, Zile MR, Weaver FA et al. Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction. JACC Heart Fail 2015; 3: 487-496 DOI: 10.1016/j.jchf.2015.02.006.
• 81 Brandt MC, Madershahian N, Velden R et al. Baroreflex activation as a novel therapeutic strategy for diastolic heart failure. Clin Res Cardiol 2011; 100: 249-251 DOI: 10.1007/s00392-010-0249-0.
• 82 Bisognano JD, Kaufman CL, Bach DS et al. Improved cardiac structure and function with chronic treatment using an implantable device in resistant hypertension: results from European and United States trials of the Rheos system. J Am Coll Cardiol 2011; 57: 1787-1788 DOI: 10.1016/j.jacc.2010.11.048.
• 83 Bertog SC, Kolmer C, Kleschnew S et al. Percutaneous femoral arteriovenous shunt creation for advanced chronic obstructive pulmonary disease: a single-center safety and efficacy study. Circ Cardiovasc Interv 2012; 5: 118-126 DOI: 10.1161/CIRCINTERVENTIONS.111.964494.
• 84 Burchell AE, Lobo MD, Sulke N et al. Arteriovenous anastomosis: is this the way to control hypertension?. Hypertension 2014; 64: 6-12 DOI: 10.1161/HYPERTENSIONAHA.114.02925.
• 85 Lobo MD, Sobotka PA, Stanton A et al. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. The Lancet 2015; 385: 1634-1641 DOI: 10.1016/s0140-6736(14)62053-5.
• 86 Mahfoud F, Bohm M. Hypertension: Arteriovenous anastomosis - next panacea for hypertension?. Nat Rev Cardiol 2015; 12: 197-198 DOI: 10.1038/nrcardio.2015.24.