Hypertension 1 New drugs, procedures, and devices for hypertension

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1 Hypertension 1 New drugs, procedures, and devices for hypertension Stéphane Laurent, Markus Schlaich, Murray Esler Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. In this paper, we discuss two promising therapeutic alternatives for patients with resistant hypertension: novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices, including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with promising preclinical results, the clinical development of novel antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, thus leading to a new era of outcome trials and evidence-based guidelines. Introduction Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug and strategies to tackle the effect of adverse lifestyle behaviours on blood pressure. 5 30% of the overall hypertensive population have resistant hypertension. 1 Causes of this disorder are well known and include reluctance of patients to adhere to lifelong drug treat ment, physician inertia, the white-coat effect, effects of conflicting drugs (eg, non-steroidal anti-inflammatory drugs), or poorly selected antihypertensive drugs. 2 Only about 10% of patients have true resistant hypertension. 1,2 Although this hypertension can mostly be managed with a combination of existing antihypertensive drugs, a substan tial subset of patients exists in whom adequate control of blood pressure cannot be achieved despite prescribing and taking of several appropriate anti hypertensive drugs. 2 Perhaps the underlying patho physiology of these patients is refractory to the most widely prescribed antihypertensive drugs: renin-angio tensin system antagonists, dihydropyridine calcium-channel blockers, and diuretics. 3 We review two promising therapeutic alternatives in patients Search strategy and selection criteria We searched the Cochrane library, Medline, and Embase, from January, 2006, to February, 2012, with the search terms Hypertension/drug effects OR Hyper tension/ pharmacology OR Hypertension/therapy, in combination with Neprilysin, Aldos terone, Endo thelins, Nitric Oxide Donors, and Glycosylation End Products, Advanced. Although we selected publications from the past 6 years, we did not exclude commonly referenced and highly regarded old publications. We included review articles to provide a more comprehensive overview than can be included in our report. We searched to identify which clinical trials have been, or are presently being, done with novel molecules. Our reference list was modified on the basis of comments from peer reviewers. with true resistant hypertension: novel drugs, including either novel pharmacological classes or new molecules from present pharmacological classes, and new procedures and devices. New drugs for hypertension New pharmalogical classes and molecules Several novel cell-signalling pathways and pathophysiological mechanisms have emerged in the past few years, providing new pharmacological targets to treat hypertension. Although initially indicated for hyper tension, some of these molecules are studied in other diseases, such as diabetes, congestive heart failure, chronic kidney disease, and pulmonary hypertension. Rather than providing an exhaustive list of molecules in development, we discuss specific pharmacological classes to explain the interactions between various patho physio logical mechanisms, assess the benefit-risk ratio, and thus express the complexity of drug development (table). Dual vasopeptidase inhibitors Besides angiotensin-converting enzyme, two other zinc metalloproteinases neprilysin (also called neutral endopeptidase) and endothelin-converting enzyme are pharma cological targets for hypertension. 4 Combined inhibition of these three enzymes aimed to not only improve blood-pressure control in patients with hypertension, particularly those with resistant hypertension, but also to reduce target organ damage through enhanced antiproliferative, antifibrotic, and anti-inflammatory effects. 5 Although several dual or triple neprilysin and angiotensin-converting enzyme inhibitors (ie, vasopeptidase inhibitors) were developed, 6 only a few reached the clinical development stage. Inhibition of neprilysin, the degradative enzyme for natriuretic peptides, was regarded as a potential target to reduce blood pressure in hypertensive states by potentiating the diuretic, natriuretic, and vasorelaxant effects of endogenous natriuretic peptides. 4 However, the Lancet 2012; 380: See Editorial page 538 See Comment page 539 This is the first in a Series of three papers about hypertension Department of Pharmacology, European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris, Paris, France (Prof S Laurent MD); Université Paris Descartes, Paris, France (Prof S Laurent); Institut National de la Santé et de la Recherche Médicale INSERM U970-PARCC, Paris, France (Prof S Laurent); and Neurovascular Hypertension and Kidney Disease and Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (Prof M Schlaich MD, Prof M Esler MBBS) Correspondence to: Prof Stéphane Laurent, Department of Pharmacology and INSERM U970, Hôpital Européen Georges Pompidou, Université Paris Descartes, Paris, France stephane.laurent@egp.aphp.fr Vol 380 August 11,

2 Drug Preclinical stage Phase 1 3 Pharmaceutical industry Dual vasopeptidase inhibitor Dual neprilysin-ace inhibitor Ilepatril (AVE7688) Phase 3 Sanofi-Aventis Dual neprilysin-ece inhibitor Daglutril (SLV306) Phase 2 Solvay Pharmaceuticals Dual ARNI LCZ696 Phase 3 Novartis Pharmaceuticals Aldosterone-synthase inhibitor LCI699 Phase 2* Novartis Pharmaceuticals Endothelin antagonist Bosentan Darusentan Phase 2 Phase 3* Actelion Pharmaceuticals Gilead Sciences Nitric oxide donor Nitric oxide-releasing drugs Nitrosyl-cobinamide Yes Nitrix oxide-releasing hybrids Nitric oxide-losartan Nitric oxide-telmisartan Yes Yes Cayman Chemicals Cayman Chemicals CINOD Naproxcinod Phase 3 NicOx Renin-prorenin blocker Yes ACE-2 activator Yes Aminopeptidase-A inhibitor QGC001 Yes Quantum Genomics Corp Vaccine Angiotensin 1 vaccine PMD3117 Phase 2 Protherics Inc Angiotensin 2 vaccine Cyt006-AngQb Phase 2 Cytos Biotechnology AG Dual AT1R/ETA antagonist PS Phase 2 Ligand Pharmaceuticals Novel dual ARB and partial PPAR-γ agonist Yes AGE breaker Alagebrium (ALT-711) Phase 2* Synvista Therapeutics We have only listed molecules described in the text. ACE=angiotensin-I converting enzyme. ARNI=dual-acting angiotensin receptor-neprilysin inhibitor. CINOD=cyclo-oxygenase-inhibiting nitric-oxide donator. ARB=angiotensin-receptor blocker. PPAR-γ=peroxisome proliferator-activated receptor-γ. AGE=advanced glycation end-product. *Development stopped. Table: New drugs for hypertension antihypertensive activity of pure neprilysin inhibitors was weak with at best, marginal effects 7 because inhibition of neprilysin also increased concentrations of several different vasoconstrictor peptides (eg, angio tensin-2 and endothelin-1), which are metabolised by neprilysin. Research on antihypertensive drugs subse quently focused on neprilysin inhibition combined with blockers of the renin-angiotensin system, particularly inhibitors of angiotensin-converting enzyme (figure 1). Investigators had two main reasons for this focus: (1) neprilysin and angiotensin-converting enzyme are both metallopeptidases sharing several structural similarities, catalytic mechanisms, and sub strates, which allowed for the design of dual vasopeptidase inhibitors that bore similar inhibitory activities against both enzymes in a molecule with a binding affinity in the nanomolar range; (2) these vasopeptidase inhibitors have complementary mechanisms of action for lowering blood pressure in various experimental models. 8 Omapatrilat was the first in a new class of highly specific, non-peptidergic, orally active, dual vasopep tidase inhibitors, and was more effective for lowering blood pressure than were angiotensin-converting enzyme inhib itors (eg lisinopril and enalapril) alone. 9 However, frequency of angio-oedema was three to four times higher with omapatrilat than with enalapril (274 [2%] of patients vs 86 [<1%] of patients). 10 This increase in angio-oedema was mainly attributed to accumulation of bradykinin and to a lesser extent substance P and neurokinin, in response to the synergistic inhibition of their degradation by dual vasopeptidase inhibition. 11 These deleterious effects might have been amplified by non-specific inhibition of other enzymes associated with bradykinin metabolism, such as aminopeptidase P (figure 1). 12 These findings urged the development of novel orally active vasopeptidase inhibitors with different profiles of enzyme inhibition, including less inhibition of aminopeptidase P, 13 and a higher inhibition of angiotensin-converting enzyme than of neprilysin. Particular focus was on long-term safety and tolerability, particularly for angio-oedema. One of those novel agents is ilepatril (Sanofi-Aventis), which is being investigated in phase 3 trials, 14,15 and is characterised by prolonged, intense inhibition of angiotensin-converting enzyme compared with other selective angiotensin-converting enzyme inhibitors, such as ramipril. 15 Endothelin-converting enzyme is a key peptidase in the endothelin system. This enzyme cleaves inactive big endothelin-1 to active endothelin-1, which binds to endothelin type-a receptors, and thus exerts its vasoconstrictor effect. Combined neprilysin and endothelinconverting enzyme inhibitors inhibitors have several theoretical advantages (figure 2). 16 First, they block the proinflammatory and profibrotic effects of endothelin-1 and enhance the plasma concentrations of natriuretic Vol 380 August 11, 2012

3 peptides, which have vasodilatory, antihypertrophic, and antifibrotic effects. Second, they overcome a limitation of sole neprilysin inhibition, which can lead to some vasoconstriction because neprilysin degrades endothelin-1. Third, the natriuretic action of neprilysin can oppose the salt and fluid retention caused by non-selective blockade of endothelin receptors. Daglutril (Solvay Pharmaceuticals), a potent inhibitor of combined neprilysin and endothelinconverting enzyme, is pres ently in phase 2 clinical development in patients with hypertension. Dual-acting angiotensin receptor-neprilysin inhibitors To overcome the risk of angio-oedema, neprilysin inhibitors have been combined with angio tensin-2 type-1 receptor blockers, which have no effect on metallopeptidases that participate in bradykinin breakdown (figure 3). LCZ696 (Novartis Pharmaceuticals), a first-inclass inhibitor of dual-acting angiotensin-2 type-1 receptor and neprilysin inhibitors, was developed as a molecule composed of molecular moieties of valsartan and neprilysin inhibitor prodrug AHU377 in a 1:1 ratio. 17 Several phase 2 randomised clinical trials have been done or are underway in patients with hypertension. In a proofof-concept randomised trial, 18 LCZ696 was compared with valsartan in 1328 patients with mild-to-moderate hyper tension, and provided fully additive reduction of blood pressure. No cases of angio-oedema were reported in the 8 week treatment period. This tolerance should be confirmed, particularly in black patients, for whom omapatrilat resulted in a higher occurrence of angiooedema than in white patients. 10 Indeed, in the proof-ofconcept trial only about 8% of patients were black. Aldosterone synthase inhibitors Mineralocorticoid receptor-blocking drugs (also called aldosterone antagonists), such as spironolactone and eplerenone, are increasingly prescribed, not only for patients with primary aldosteronism, but also for those with resistant hypertension. Both drugs are effective for resistant hypertension. However, the poor selectivity of spironolactone for mineralocorticoid receptors is often associated with progesterone-dependent and testosterone-dependent adverse effects, such as gynaecomastia. Eplerenone is a more selective inhibitor of mineralocorticoid receptors and has fewer sexual side-effects than does spironolactone. Both spirono lactone and eplerenone can lead to development of hyper kalaemia (particularly in patients with renal impairment with or without Vasopeptidase inhibitors (dual NEP-ACE inhibitors) NEP inhibition ACE inhibition NEP ACE Natriuretic peptides (ANP, BNP) Angiotensin 2 < Angiotensin 2 Angiotensin 1 Vasodilatation Sodium excretion Antihypertrophic effect Antifibrotic effect Vasoconstriction Sodium retention Pro-hypertrophic effect Pro-fibrotic effect Synergistic effect on blood-pressure lowering and reduction of target organ damage Risk of angio-oedema Bradykinin Aminopeptidase P Figure 1: Synergistic antihypertensive effect of dual NEP-ACE inhibitors Combined inhibitors of NEP and ACE block the vasoconstrictive, prohypertrophic, and profibrotic effects of angiotensin 2, and enhance the plasma concentrations of natriuretic peptides, which are known for their vasodilatory, antihypertrophic, and antifibrotic effects. These inhibitors overcome a limitation of sole NEP inhibition: because NEP also degrades angiotensin 2, its inhibition can lead to some vasoconstriction though increased circulating concentrations of angiotensin 2; however this effect is largely compensated (indicated by <) by the reduction in angiotensin 2 in response to ACE inhibition. Furthermore, the natriuretic action of NEP can oppose the salt and fluid retention attributed to AT1R activation by angiotensin 2 (and aldosterone secretion). The synergistic effect on lowering of blood pressure and reduction on target organ damage is compensated by an increased risk of angio-oedema caused by the accumulation of bradykinin in response to synergistic inhibition of its degradation by dual NEP-ACE inhibition. NEP=neprilysin. ACE=angiotensin-converting enzyme. ANP=atrial natriuretic peptide. BNP=brain natriuretic peptide. AT1R=angiotensin-2 type-1 receptor. Vol 380 August 11,

4 Vasopeptidase inhibitors (dual NEP-ECE inhibitors) NEP inhibition ECE inhibition NEP ECE Natriuretic peptides (ANP, BNP) Endothelin 1 < Endothelin 1 Big endothelin 1 Vasodilatation Antihypertrophic effect Antifibrotic effect Vasoconstriction Pro-inflammatory effect Pro-fibrotic effect Non-selective blockade of endothelin Sodium excretion Sodium and fluid retention Synergistic effect on blood-pressure lowering and reduction of target organ damage Risk of angio-oedema Bradykinin Aminopeptidase P Figure 2: Synergistic antihypertensive effect of dual NEP-ECE inhibitors Combined inhibitors of NEP and ECE block the pro-inflammatory and pro-fibrotic effects of endothelin 1 and enhance the plasma concentrations of natriuretic peptides, which are known for their vasodilatory, antihypertrophic, and antifibrotic effects. They overcome a limitation of sole NEP inhibition: because NEP likewise degrades endothelin 1, inhibition can lead to some vasoconstriction through increased concentrations of endothelin 1; however, this effect is largely compensated (indicated by <) by the reduction in endothelin 1 in response to ECE inhibition. The natriuretic action of NEP can oppose the salt and fluid retention attributed to non-selective blockade of endothelin receptors. The synergistic effect on lowering of blood pressure and reduction on target organ damage is compensated by an increased risk of angio-oedema, caused by the accumulation of bradykinin in response to the inhibition of its degradation by NEP inhibition. NEP=neprilysin. ECE=endothelin-converting enzyme. ANP=atrial natriuretic peptide. BNP=brain natriuretic peptide. diabetes), but hyperkalaemia is less frequent with eplerenone. Finally, use of aldosterone antagonists is associated with reactive increase in plasma concentrations of aldosterone, which could inflate the actions of aldosterone that are mediated independently of effects on gene transcription. However, the clinical role of these non-genomic effects is unclear. 19 To reduce aldosterone concentration but avoid sideeffects, a new therapeutic option is inhibition of aldosterone synthase to prevent activation of both genomic and non-genomic pathways. LCI699 (Novartis Pharmaceuticals) was the first-in-class orally admin istered inhibitor of aldosterone synthase. 20,21 In 524 patients with primary hypertension, 1 0 mg LCI699 given once-daily for 4 weeks, significantly reduced 24 h ambulatory systolic blood pressure compared with placebo (p=0 046), 21 and with a similar magnitude as eplerenone 50 mg twicedaily. However, adreno corticotropic hor mone stimulation of cortisol was suppressed in about 20% of patients receiving 1 0 mg LCI699. This effect is probably because of partial inhibition of 11-β-hydroxylase, which catalyses con version of 11-deoxycortisol to cortisol. Development of LCI699 was stopped in 2010, and research focused more on aldosterone synthase inhibitors, which have heightened selectivity for aldosterone synthase, thus leaving normal adrenocorticotropic hormone stimu lation of cortisol release intact. Endothelin antagonists Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide that acts through endothelin-a and endothelin-b receptors, and in particular mediates vasoconstriction and inflammation. 22 Bosentan (Actelion Pharmaceuticals) was the first-in-class of highly spe cific, non-peptidergic, orally active, mixed endothelin-a and endothelin-b receptor antagonists (eg, avosentan, enrasentan, tesozentan), that was suitable for long-term treatment. 23 Although endothelin-1 an tagonists were only marketed to treat pulmonary artery hypertension, some have been investigated in patients with resistant hypertension. Compared with placebo, bosentan sig nificantly reduced clinic blood pressure. 24 Because of side-effects mainly increases in values of liver trans aminase, oedema, and water retention subsequent randomised trials were Vol 380 August 11, 2012

5 Dual-acting ARNI NEP inhibition AT1R blockade NEP Natriuretic peptides (ANP, BNP) Angiotensin 2 AT1R Angiotensin 1 Vasodilatation Sodium excretion Antihypertrophic effect Antifibrotic effect Vasoconstriction Sodium retention Pro-hypertrophic effect Pro-fibrotic effect Synergistic effect on blood-pressure lowering and reduction of target organ damage Risk of angio-oedema Bradykinin Aminopeptidase P Figure 3: Dual-acting ARNI Combined inhibitors of NEP and AT1R blocker block the vasoconstrictive, prohypertrophic, and profibrotic effects of angiotensin 2 and enhance the plasma concentrations of natriuretic peptides, which are known for their vasodilatory, antihypertrophic, and antifibrotic effects. They overcome a limitation of sole NEP inhibition: because NEP likewise degrades angiotensin 2, its inhibition can lead to some vasoconstriction. The natriuretic action of NEP can oppose the salt and fluid retention caused by AT1R activation by angiotensin 2 (and aldosterone secretion). The synergistic effect on lowering of blood pressure and reduction on target organ damage is compensated by an increased risk of angio-oedema due to the accumulation of bradykinin in response to the inhibition of its degradation by NEP inhibition. ARNI=angiotensin receptor-neprilysin inhibitor. NEP=neprilysin. AT1R=angiotensin-2 type-1 receptor. ANP=atrial natriuretic peptide. BNP=brain natriuretic peptide. restricted to patients with resistant hyper tension. In such patients, darusentan, a mixed endothelin-a and endothelin-bantagonist that is presently in phase 3 trials (Gilead Sciences), was more effective than placebo for lowering clinic and ambulatory blood pressure in addition to treatment with three or more antihypertensive drugs. 25 Although 20 (25%) of 81 patients receiving darusentan had oedema or fluid retention compared with only 19 (14%) of 132 on placebo, the investigators managed this issue by increasing the dose of diuretics. 25 De velopment stopped after a subsequent trial in patients with resistant hypertension showed that darusentan did not decrease sitting systolic blood pressure more than placebo, although it did provide a greater reduction in systolic blood pressure at ambulatory blood-pressure monitoring. 26 Nitric oxide donors Nitric oxide is a powerful vasodilator. However, clinical use of nitrates for treating hypertensive patients in the long term is limited by their short duration of action; the tolerance event tachyphylaxia; and their side-effects, such as headache. To overcome the occurrence of tolerance, which develops because of the biotransformation of organic nitrates to an active form, research focuses on drugs that directly release nitric oxide eg, nitrosyl-cobinamide (presently in preclinical stage); 27 nitric oxide-releasing pharmacodynamic hybrids of losartan 28 and telmisartan; 29 non-peptidic renin inhibitors nitroderiv atives; and naproxcinod, a cyclooxygenaseinhibiting donator of nitric oxide, which is being developed (NicOx) to treat patients with hypertension and arthritis, 30 in phase 3 trials. Novel drugs in preclinical development Novel drugs include non-peptide antagonists of the (pro) renin receptor (ie, renin-prorenin receptor blocker, 31,32 and activators of angiotensin-converting enzyme-2, which breaks down angiotensin-2 while generating angiotensin-(1 7), a putative cardioprotective peptide. 33 Orally active aminopeptidase-a inhibitors are a novel class of centrally acting antihypertensive drugs. These inhibitors, eg, QGC001 (Quantum Genomics Corp oration), 34 target aminopeptidase-a, the enzyme that generates angiotensin-3 in the brain, one of the major effector peptides of the brain renin-angiotensin system in the control of arginine vasopressin release and blood pressure. Vaccines Although tested in animals two decades ago, 35 vaccines for hypertension are in the early phase in human beings. Vol 380 August 11,

6 Two angiotensin-based vaccines are in development. In a phase 2a study, 36 CYT006-AngQb, an angiotensin-2 vaccine (Cytos Biotechnology AG), significantly reduced blood pressure in hypertensive patients compared with placebo (p=0 015 for systolic and for diastolic), 36 but a similar effect was not reproducible with more frequent dosing. PMD3117, an angiotensin-1 vaccine (Protherics Inc), lowered blood pressure in preclinical studies of rats, but not in a subsequent placebo-controlled clinical study in patients with hypertension. Further studies with modified immunogen or adjuvant are needed to boost antibody titres. Pharmacological classes: new versus old molecules The dual angiotensin-2 type-1 receptor and endothelin-a receptor antagonists are either at pre-clinical 37 or phase-2 stage (PS , Ligand Pharmaceuticals). The dual angiotensin receptor-neprilysin inhibitor LCZ696 is in phase 2 study. 18 Some novel angiotensin-receptor blockers increase gene expression or receptor activity of peroxisome proliferator-activated receptor-γ, which has promising antidiabetic and antiatherosclerotic properties. 38 For example, a new series of imidazo[4,5-b] pyridines have been reported with dual activities at angiotensin-2 type-1 receptor and peroxisome proliferator-activated receptor-γ. 39 Although therapeutic progress might seemingly originate only from new molecules, existing pharmacological classes or drugs can provide important therapeutic advances. For example, marketed angiotensin receptor blockers telmisartan and azilsartan have shown partial peroxisome proliferator-activated receptor-γ agonist proper ties. Furthermore, optimising of therapeutic combinations is important, particularly for prevention of major cardiovascular events. For instance, the ACCOMPLISH trial 40 showed that amlodipine combined with a renin-angiotensin system blocker was more effect for cardiovascular and renal protection than was a thiazide plus renin-angiotensin system combination. New molecules targeting vascular ageing and isolated systolic hypertension Inhibitors or breakers of advanced glycation end-products (AGE), which target the molecular components of the aortic wall responsible for arterial stiffening, might be of particular interest, not only for isolated systolic hypertension, but also for hypertensive patients with diabetes or chronic kidney disease. 41 AGE inhibitors (eg, aminoguanidine, pyridoxamine) can prevent the forma tion of AGE crosslinks between proteins, and breakers (alagebrium and pyridinium analogues TRC4186 and TRC4149) can catalytically break these crosslinks; however, both act mainly as chelators that inhibit metal-catalysed oxidation reactions that accelerate AGE for mation. Thiazolium derivative alagebrium (Synvista Therapeutics) was regarded as a promising molecule to reduce aortic stiffness independently of blood pressure in patients with isolated systolic hypertension. 42 How ever, several clinical trials did not show benefit in patients with hypertension or chronic heart failure, and the development was stopped in the late 2000s. New procedures and treatment devices Devices and surgical procedures are being increasingly assessed in view of failures encountered in the conventional pharmacological treatment of hypertension. 2 Although the device revolution in cardiovascular medicine has now reached hypertension, surgical procedures, and to a lesser extent devices, have long been used in hypertensive patients. In fact, surgery has been the preferred treatment method for some forms of secondary hypertension for decades. Furthermore, before effective drug treatment of hypertension was possible, surgical resection of the sympathetic chain and splanchnic nerves was commonly used. 43 An implantable device to lower blood pressure by stimu lating the arterial baroreceptors was first developed and tested more than 40 years ago. 44 But recently, a flurry of activity has occurred with the testing of device-guided respiration to lower blood pressure in hypertensive patients, 45 use of continuous positive airway pressure devices in hypertensive patients with obstructive sleep apnoea, 46 direct electrical stimulation of brain regions to change blood pressure, 47 reassessment of a device to stimulate the arterial baroreceptors, 48 surgical neuro vascular depression of the brainstem to overcome presumed vascular compression of bulbar regions that control sympathetic outflow and blood pressure, 49 and development and testing of a radiofrequency catheter to ablate the renal nerves. 50 The sympathetic nervous system is the forgotten pathway in hypertension treatment, which is surprising in view of its importance in the pathogenesis hypertension. 3,51 National and international society guidelines for treatment of hypertension typically relegate antiadrenergic drugs to the third or fourth tier. Although many of the procedures and devices listed do target the sympathetic nervous system, the extent to which they effectively and safely lower blood pressure in patients with hypertension varies widely. Devices and procedures that are effective, but not primarily antihypertensive, newly discredited, or of questionable clinical relevance Continuous positive airway pressure Hypertension in obese people has often been attributed to obstructive sleep apnoea, because the two disorders are closely linked. 46,52 Maintenance of continuous posi tive pressure in the upper airways with proprietary facemasks and pumps is the main treatment for obstructive sleep apnoea. 53,54 Benefits of this treatment are wide-ranging and include blood-pressure reduction, which is attributed to removal of chronic sympathetic activation. 45,52 54 In the face of claims linking hyper tension in obese people to Vol 380 August 11, 2012

7 obstructive sleep apnoea, the magnitude of this reduction in blood pressure (roughly 5 mmhg systolic 53,54 ) is less than expected, but certainly helpful. When anti hypertensive drugs, are needed, patients seem to respond best to mineralocorticoid antagonists. 55,56 Deep brain stimulation Stimulating electrodes permanently placed in the brain are increasingly used in neurological disorders, such as Parkinsonism and chronic pain syndromes. In patients with comorbid hypertension, this placement has been used to stimulate brain regions that can lower blood pressure 47,57 eg, with stimulation of CNS depressor regions or electrical inhibition of pressor regions. Although this application has no general therapeutic use, it illuminates various mechanisms of brain control of blood pressure. 57 Device-guided respiration Brain centres controlling respiration and blood pressure are functionally connected. 58 This association seems to be the guiding rationale for development of an investigative technique to slow respiration, with an aim to reduce blood pressure in parallel. The strong claims made for lowering of blood pressure with device-guided respiration 44 have been disputed, 59 and are not substantiated in studies of rigorous design. Brainstem neurovascular decompression Studies in animals have identified regions in the medulla oblongata, which can increase sympathetic nervous outflow and blood pressure. 60 The clinical counterpart of this finding is the suggestion that human hypertension is often due to compression of the medulla by tortuous arteries, mainly the posterior inferior cerebellar artery. 49 Surgical techniques have aimed to eliminate this vascular compression, and findings have suggested substantial reductions in blood pressure; 49,61 however, no adequately controlled clinical trials have been done. Renal artery stenting Previously, recommended and standard treatment for renal artery stenosis in hypertension was vascular bypass surgery, guided by measurements of renal vein renin. 62 Nowadays, renal artery stenting for atherosclerotic renal artery stenosis is commonplace. Despite some disagreement, a meta-analysis 63 and a randomised trial 64 suggest that for lowering of blood pressure or preservation of renal function, little of no benefit is gained from insertion of a stent in an atherosclerotic renal artery in patients with hypertension. Arterial baroreceptor stimulation Devices to stimulate the carotid baroreflex have been developed to treat patients with hypertension, and are undergoing clinical testing. In models of hypertension, 65 activation of central baroreflex pathways by continuous electrical stimulation of the nerves of carotid sinus baroreceptors reduced sympathetic outflow from the CNS and reduced blood pressure. This effect persisted in the long term with no change. The Rheos implantable carotid sinus stimulator (CVRx, Minneapolis, MN, USA) has been studied in patients with severe drug-resistant hypertension. 48,66,67 During implantation, both carotid sinuses are surgically exposed and electrodes are placed bilaterally on the carotid adventitial surfaces. The leads run subcutaneously to an implantable stimulation generator, which is placed subcutaneously on the anterior chest wall. Short-term sympathetic inhibition and lowering of blood pressure are evident with this technique. 66 Studies are being done to assess the efficacy and safety of the procedure for refractory hypertension. In a large-scale, double-blind study, 67 the Rheos device was implanted in 265 patients who were subsequently randomised (2:1) to immediate arterial baroreceptor stimulation for the first 6 months (n=181), or deferred stimulation after month 6 (n=84). The smaller group was the control group. At 6 months, blood pressure fell in the group receiving immediate treat ment, but the primary efficacy endpoint was not reached, partly because it likewise decreased in many control patients. Additionally, the trial did not meet criteria for procedural safety. 67 Therefore, the future of this procedure is uncertain. Recent investigation of the long-term safety of device implantation in sheep and in patients does not indicate carotid artery injury or stenosis. 68 Clinical trials are now being done to establish whether the benefit of bloodpressure lowering is sufficient to outweigh the cost and invasive nature of the procedure, with less cumbersome electrodes than are used presently, and with unilateral stimulation of the carotid sinus. Catheter-based renal denervation A revolutionary treatment principle, which has recently been tested, uses ablation of the renal sympathetic nerves with a radiofrequency-emitting catheter inserted percutaneously via the femoral into the lumen of both renal arteries. 50,69 Howard Levin and Mark Gelfand first showed the feasibility of catheter-based renal denervation for hyper tension (US provisional patents 60/ [April, 2002], 60/ [October, 2002] and 60/ [January, 2003]). Sympathetic nerves enter the human kidneys in the walls of the renal arteries, 70 within reach of ablative energy delivered from the artery lumen. Before the availability of antihypertensive drugs, extensive surgical sympathectomy was used to treat severe hypertension to negate the vasoconstrictive in fluence of the pressor sympathetic nerves. 43 Although survival benefit was shown, rates of surgical complication were high, as was morbidity from the extensive denervation, which did not specifically target the renal sympathetic nerves. Renal nerves were not then thought to be the culprit. Vol 380 August 11,

8 See Online for appendix In many models of hypertension, sympathetic outflow to the kidneys is activated, and renal sympathectomy typically prevents development of hypertension (appendix pp 1 2). 71 Initi ation of the endovascular renal denervation treatment was based on these observations, and the demonstration that the renal sympathetic outflow is activated in essential hypertension. 72 For inclusion in a randomised trial 69 with the Symplicity R radiofrequency catheter (Ardian, Mountainview, CA, USA), patients had to meet criteria for uncontrolled essential hypertension that were stricter than the international standard (clinic blood pressure in excess of 160/90 mm Hg, rather than >140/90 mm Hg, and receiving three or more anti hypertensive drugs). Radiofrequency energy is delivered in 90 degree quadrants in a stepwise fashion to the full circumference of both renal arteries (appendix p 3). Both efferent and afferent renal nerves traverse the renal arteries, lying mainly in, or just outside, the adventitia. Studies in pigs 73 have shown that radiofrequency energy emission in the renal artery lumen, at a sufficient and optimised level, could selectively ablate the renal nerves with minimum damage to the vessel wall, the nerves being more thermally sensitive than the rest of the artery wall. The randomised trial 69 and a pilot study 50 aimed to establish that catheter-based renal denervation can produce renal sympathectomy in human beings, is safe, and that blood pressure is lowered; all aims have been confirmed. Measurement of noradrenaline release from the kidneys (spillover of the sympathetic neurotransmitter) indicated that sympathetic denervation does in fact occur. 50 The mean level of reduction of clinic blood pressure in the randomised trial was 32/12 mm Hg at 6 months (p<0 001). A longer follow up of 2 years, has been possible in patients in the pilot and registry studies. The reduction in blood pressure is durable with no reduction in time, and averages 32/14 mm Hg at 24 months. 74 This longevity suggests that renal sympathetic reinnervation, if it has occurred, cannot cancel out the benefit of reductions in blood pressure. Results for ambulatory blood-pressure monitoring were avail able for only 40% of trial patients, a deficiency being addressed in a continuing US trial, which likewise includes a sham procedure in the control group to ascertain whether a placebo effect on blood pressure might have existed in earlier trials of renal denervation. The importance of destruction of renal afferent nerves in the antihypertensive effect is uncertain. Without analgesia, the procedure causes moderately severe abdom inal pain during delivery of radiofrequency energy due to stimulation of the renal sensory nerves before their destruction. Protection against pain is now ensured with use of opiates and sedatives. 50,69,74 Unexpectedly, the procedure reduces sympathetic outflow from the brain from ablation of afferent renal nerves, which is evident in lowering of whole-body spillover of noradrenaline to plasma (measured by isotope dilution), and in reduction of sympathetic nerve traffic to the skeletal muscle vasculature measured by microneurography 75 Renal sensory nerves, which are sensitive to renal injury, through their projection to the hypothalamus can stimulate sympathetic outflow, this CNS input from renal afferent nerves being crucical in production of both the sympathetic activation and hypertension noted in patients with end-stage renal disease. 78 A recent report 79 documents substantial blood-pressure lowering with renal denervation in patients with renal hyper tension. Radiofrequency destruction of the afferent nerves of the kidneys might contribute to the decrease in blood pressure noted in essential hyper tension. 75 Because very little regeneration of renal afferent nerves occurs, 80 any blood-pressure reduction caused by ablation of renal sensory nerves is likely to be permanent. Despite the renal denervation procedure previously being confined to patients with drug-resistant hypertension who have substantial cardiovascular risk, safety has been of paramount importance. Few procedural complications are noted, and these have been mainly restricted to infrequent haematomas at the access site to the femoral artery (roughly 2% incidence) and two reported instances of renal artery dissection (<1% in overall experience) that needed renal artery stenting. 50,69,74 No identified stenoses, aneurysms or new athero sclerotic lesions at the sites of energy delivery have been noted, with maximum follow-up now beyond 3 years. Renal function does not deteriorate acutely with denervation, and shows minimum decline in time in parallel with that occurring in the drug-treated control groups. 50,69,74 Safety and effectiveness of blood-pressure lowering have been established; we now need clinical outcome data. Contributors SL drafted the section on new drugs, and MS and ME drafted the sections on new procedures and devices. All authors revised the manuscript. Conflicts of interest SL has received fees for consultancy and speaking, and honoraria from the drug companies AstraZeneca, Boehringer Ingelheim, Chiesi, Daiichi-Sankyo, Menarini, Negma, Novartis, Recordati, and Servier, and manufacturers Esaote-Pie Medical and Omron; and research funding from AstraZeneca, Atcor, Daiichi-Esaote-Pie Medical, Sankyo, Novartis, and Servier. MS has received fees for consultancy and speaking, and honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Medtronic, Novartis, and Servier; research funding from Abbott and Medtronic. ME received relevant consultancies, and honoraria or speaker s fees from Abbott, AstraZeneca, Boehringer Ingelheim, Kona Medical, Medtronic, Cardiosonic and Novartis; and research funding from Medtronic and Servier. Acknowledgments SL thanks Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance-Publique Hôpitaux de Paris, Université Paris Descartes. MS and ME are supported by research fellowships from the NHMRC of Australia and are both prinicipal investigators in clinical trials of renal denervation sponsored by Medtronic. References 1 Mancia G, de Backer G, Cifkova R, et al. Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Cardiology (ESC) and of the European Society of Hypertension (ESH). J Hypertens 2007; 25: Vol 380 August 11, 2012

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