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From Bad Behaviour to Bad Biology: Pitfalls and Promises in the Management of Resistant Hypertension
Canadian Journal of Cardiology 29 (2013) 549e556
Review
From Bad Behaviour to Bad Biology: Pitfalls and Promises in the Management of Resistant Hypertension Ross D. Feldman, MD,a,b and Eric P. Brass, MD, PhDc a
Departments of Medicine and of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Ontario, Canada b c
Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada
Department of Medicine, Harbor-UCLA Medical Center, Torrance, California, United States
ABSTRACT
RESUM E
Control rates for hypertension have dramatically improved during the past 2 decadesdespecially in Canada. However, hypertension remains one of the top risk factors for premature death globally. Furthermore, one-third of Canadians with hypertension have not obtained adequate blood pressure control. Most of these patients have resistant hypertension with uncontrolled blood pressure despite therapy. The etiology of resistant hypertension is multifactorial but includes both behavioural and biological factors. Among behavioural factors, nonadherence on the part of patients and especially clinical inertia on the part of health care professionals are contributing causes. An understanding of the root causes underlying the failure to control an individual’s blood pressure is central to optimal subsequent management. Further advances in blood pressure control rates in this group of patients will depend on improvements in health care delivery systems and the further development of innovative therapies. Drugs combining multiple antihypertensive agents in a single pill and the development of new technologies to lower blood pressure, primarily by disruption of the sympathetic nervous system, have the potential to be useful strategies in this effort.
rielle se sont conside rableLes taux de maîtrise de l’hypertension arte liore s au cours des 2 dernières de cennies, particulièrement au ment ame Canada. Cependant, l’hypertension demeure l’un des principaux faccès pre mature dans le monde. De plus, un tiers des teurs de risque de de de façon Canadiens souffrant d’hypertension n’ont pas maîtrise rielle. La plupart de ces patients ont une acceptable leur pression arte rielle re fractaire non maîtrise e en de pit du traitement. hypertension arte tiologie de l’hypertension re fractaire est multifactorielle, mais inclut L’e les facteurs comportementaux et les facteurs biologiques. Parmi les facteurs comportementaux, la non-observance par les patients et par sont des ticulièrement l’inertie clinique des professionnels de la sante hension des causes fondamentales causes qui y contribuent. La compre es à l’incapacite à maîtriser la pression arte rielle d’un individu est lie quente. De nouvelles primordiale à la prise en charge optimale subse es sur les taux de maîtrise de la pression arte rielle de ce groupe avance pendront de l’ame lioration des systèmes de prestations de patients de et du de veloppement de traitements innovateurs. Les de soins de sante dicaments combinant plusieurs agents antihypertensifs en une seule me veloppement de nouvelles technologies pour abaisser la pilule et le de rielle, principalement par la perturbation du système nerpression arte gies utiles en ce sens. veux sympathique, ont le potentiel d’être des strate
Significant progress has been made in the management of hypertension. While hypertension on a global basis remains among the top risk factors for attributable death1 and morbidity,2 the first decade of the millennium has seen unprecedented gains in blood pressure control rates. In Canada control rates have increased more than 4-fold since the1990s,3 with an overall control rate of almost two-thirds among patients diagnosed with hypertensiondthe highest national rate of control globally.4 Furthermore, the improved blood pressure control rates have paralleled an increase in prescription of antihypertensive drugs5 and an acceleration in the decline of hypertension-related cardiovascular complications.6
Notwithstanding these advances, important gaps remain in our ability to control blood pressure. This review outlines the current challenges in improving blood pressure control for the remaining one-third of patients with hypertension whose blood pressure is not controlled. New management options are also reviewed, both those now available and those on the horizon, that offer promise for further gains against a cornered but still dangerous disease adversary.
Received for publication December 20, 2012. Accepted February 12, 2013. Corresponding author: Dr Ross D. Feldman, Robarts Research Institute, 100 Perth Dr, London, Ontario N6A 5K8, Canada. E-mail: [email protected] See page 554 for disclosure information.
The “Other” Third Why are one-third of those almost 8 million Canadians with hypertension not at blood pressure targets? The patient population making up those whose hypertension remains uncontrolled hypertension comprise those with multiple contributing etiologies (Fig. 1). They include patients unaware of their hypertension7 and those with resistant hypertension, ie, those patients whose blood pressure remains uncontrolled despite pharmacologic treatment. These patients include those with
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.02.009
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so-called biologically resistant hypertension (see below). However, the largest subset in this grouping may be patients who are inadequately treateddwhose resistant hypertension is related to behavioural factors. These factors are both patient related and health care provider related. Using medical audit approaches, Garg and colleagues attempted to define the etiologies for resistant hypertension in a US population.8 They reported a number of familiar etiologies for uncontrolled hypertension, including nonadherence (16%); white coat hypertension (6%); secondary forms of hypertension (5%); and substances that interfere with blood pressure control or antihypertensive drug effectiveness, such as NSAIDs (1%). However, by far the largest identified etiology for poor blood pressure control was “drug related” causes (58%). Of those, a suboptimal medical regimen was cited as the primary factor. A suboptimal medical regimen might result from drugs being used at submaximal doses, failure to add a second (or third) drug when initial therapy is ineffective, or use of drug combinations with redundant mechanisms of actions (eg, an angiotensin converting enzyme [ACE] inhibitor and an angiotensin receptor antagonist [ARB]9). Thus, key factors in the development of resistant hypertension include those relating to both patient and health care provider behaviour patterns (Table 1). Patient Behaviours Contributing to Resistant Hypertension The patient is the central member of the team required to adequately control blood pressure. Lifestyle approaches to
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blood pressure control, including diet and exercise, can be implemented only by a motivated and educated patient. Failure to implement lifestyle changes may also compromise the pharmacologic management of hypertension. Specifically, failure to control sodium intake will compromise the effectiveness of any diuretic-based or renin-angiotensin system (RAS) inhibitor pharmacotherapy prescribed.10 An optimal prescribed pharmacologic regimen requires the patient to fill the prescription, comply with the directions, and adhere to the regimen over time. Nonadherence to a prescribed regimen remains the most commonly identified patientrelated behaviour associated with blood pressure control. Notably, the Canadian Hypertension Education Recommendations outline a number of approaches shown to be effective in improving adherence and blood pressure control, including the use of home blood pressure monitoring11 and single-pill combination therapy (discussed below).12 While less of an issue in Canada than in other parts of the world, cost of medications may be a substantial barrier to compliance.13 Clinical Inertia as a Determinant of BehaviourRelated Resistant Hypertension Clinical inertia, ie, the failure of health care providers to prescribe adequate antihypertensive therapy and/or to advance therapy when blood pressure remains above target, has been suggested to be an important contributing factor to the risk of uncontrolled hypertension.14 Furthermore, clinical inertia has been implicated as an important causal factor in
Figure 1. The spectrum of patients with uncontrolled hypertension. Some patients with poorly controlled blood pressure are unaware of their hypertension. Patients with diagnosed hypertension may have uncontrolled blood pressures due to behavioural etiologies. Nonoptimal behaviour may be observed in patients (eg, nonadherence to prescribed therapy) or health care systems (eg, irrational prescribing). In some patients a true biologic basis for their uncontrolled blood pressure is present.
Feldman and Brass Management of Resistant Hypertension Table 1. Behavioural reasons for uncontrolled blood pressure Patient-based reasons Failure to lose weight High sodium intake Poor exercise habits Failure to fill prescription Poor compliance with label directions Poor adherence with therapy over time Health care system or practitioner-based reasons Coprescribing of drugs that interfere with antihypertensive efficacy Inadequate patient education and/or support Irrational prescribing Failure to diagnose hypertension Wrong drugs Wrong dose
the low control rates for other target-based chronic disease risk factors, including diabetes15,16 and dyslipidemia.17,18 The causes of clinical inertia are multifactorial and complex and include factors related to dysfunctional health care delivery systems, inadequate blood pressure monitoring techniques, and patient resistance.19 However, behaviours by members of the health care delivery team manifested as clinical inertia are likely the major root cause in the patients whose resistance was ascribed by Garg and colleagues8 to “drug-related factors.” Furthermore, much of the practice-to-practice variability in blood pressure control rates has been related to variability in the extent of clinical inertia. Okonofua and colleagues found that the differences in blood pressure control rates varied widely between surveyed practices, from less than 10% to greater than 80%.20 That extent of variability directly paralleled the extent of clinical inertia, as determined by the proportion of times a practitioner failed to uptitrate a patient’s antihypertensive regimen when faced with a blood pressure above target levels. Okonofua et al. reported that those practices with the most clinical inertia, based on this metric, demonstrated the lowest blood pressure control rates. Approaches to Uncontrolled Blood Pressure Due to “Bad Behaviour”: Role of Single-Pill Combination Antihypertensive Drugs The pharmacologic management of hypertension is based on the use of regimens consisting of multiple drugs. As demonstrated from such studies as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the average patient with hypertension needs 2 to 3 antihypertensive drugs for blood pressure control,21 and those whose target blood pressure is lower (ie, < 130/80 for patients with hypertension and diabetes22) need more than 3. However, the use of multiple medications is problematic from the perspectives of both patient and health care provider. From a patient perspective, increased dosing frequency and increased number of prescribed tablets each parallels a reduction in compliance.23 The practice of substituting antihypertensive drugs because of either perceived lack of efficacy or perceived adverse effects is an almost inevitable consequence of building a multiple-dose regimen. The manipulation of the prescribed regimen over time results in a further reduction in both adherence and consequent blood pressure controlda phenomenon termed “therapeutic turbulence.”24 From a health care provider perspective, the complexity inherent in
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making the choices between the 5 first-line antihypertensive drugs as recommended by the Canadian Hypertension Education Program (CHEP), any pair of which can potentially be combined as Step 2 therapy,12 may be a contributor to therapeutic inertia. To avoid this challenge and to facilitate treatment escalation, single-pill combinations (formerly known as “fixed-dose combinations”) have been suggested to be, if not a panacea, at least a significant advance in managing most patients with hypertension.25 The rationale for the greater use of single-pill combination in the management of hypertension is based on both pharmacologic and behavioural considerations. It has been well established that combining antihypertensive drugs, with each drug at a submaximal dose, is significantly more efficacious than doubling a previously prescribed medication.26 Whereas the addition of a new antihypertensive drug is generally associated with an approximate doubling of antihypertensive effect, doubling a previously prescribed drug will result in a substantially lesser effect (in the range of 20%-25% for thiazides, beta-adrenergic antagonists, or ACE inhibitors and 35% to 40% for calcium channel antagonists). Furthermore, most antihypertensive drugs have side effect rates that approximate those of placebo at low doses, and dose escalation may lead to intolerance and nonadherence.27 Based on this pharmacologic premise, a number of studies have examined the potential superior effectiveness of singlepill combinations (vs conventional single-drug formulations) in hypertension. Approaches based on single-pill combinations have been shown to be superior to sequential single-pill therapeutic strategies in regard to (1) patient adherence;28,29 (2) medical resource use;29 (3) blood pressure control rates, as in the Simplified Treatment Intervention to Control Hypertension (STITCH) study;30 and (4) rate of hypertension-related cardiovascular complications.31 Despite the established effectiveness of single-pill combinations, Canada has lagged somewhat behind Western Europe and the United States in both the use and the availability of single-pill combinations. Although combinations of diuretics and ACE inhibitors and of diuretics and ARBs have been available for decades in Canada, they are used to a lesser extent in Canada than in the United States or Europednotwithstanding the support for their use in the CHEP recommendations.12 Furthermore, nondiuretic 2-drug combinations are both less available and less used in Canada. Two combinations of calcium channel antagonists and RAS inhibitors are available in Canada (trandolopril-verapamil and telmisartan-amlodipine). However, neither has been broadly prescribed by Canadian health care providers. Somewhat paradoxically, the preferred 2-drug combination (as per CHEP recommendations) for patients with hypertension at high risk for atherosclerotic complications, ie, a combination of an ACE-inhibitor and a dihydropyridine calcium channel antagonist,12,32 has yet to be released in Canada despite wide availability outside Canada. As the components of these 2-drug combinations are now largely available as generic drugs, the probability of seeing these combination drugs in Canada is becoming less likely over time. Furthermore, the single-pill, 3-drug combinations (diuretic, RAS inhibitor, and calcium channel antagonist) now being introduced outside Canada are even less likely to become available in Canada for economic reasons, minimizing our potential to make further
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advances in blood pressure control in the behaviourally challenged segment of the uncontrolled hypertension population. Systems-Based Approaches to Improve Blood Pressure Control in Patients with BehaviourRelated Resistant Hypertension One can speculate that one of the factors leading to the higher blood pressure control rates seen in clinical trials regardless of treatment is related to the application of fixed algorithms in blood pressure management. The efficacy of algorithm-based clinical management has long been established in the acute care setting (as in the use of surgical checklists, heparin algorithms, etc). However, the potential role of introducing algorithm-based management to minimize therapeutic inertia in chronic disease management is being increasingly considered, as in the management of diabetes33 and in hypertension. Notably, whether the effectiveness of the STITCH program was related more to the early use of single-pill combinations or to the use of a simplified algorithm may never be differentiated.30 However, in observational studies, algorithm-based management has been shown to improve both the identification of the cause of resistant hypertension34 and its management.35 Furthermore, as illustrated by the KaiserPermanente Northern California Hypertension Management System (which features the use of algorithm-based therapy and the early use of single-pill combinations), blood pressure control rates approximating clinical trial rates (greater than 80%) are achievable.36 Part of the effectiveness of the Kaiser Permanente system also may be related to the incorporation of a team-based care approach including nurses and pharmacists, which has been shown to be an effective systems-based approach for improving blood pressure control rates.37 Update on Approaches for Blood Pressure Control in Patients With Biologically-Related Resistant Hypertension True refractory hypertension, or biologically-based resistant hypertension, is conventionally defined as blood pressure uncontrolled on 3 drugs including a diuretic, or controlled on effective doses of more than 4 medications including a diuretic where patient adherence has been established. Note that this definition does not exclude nonoptimal selection of the prescribed medications and thus may still include patients with uncontrolled blood pressure due to nonbiologic reasons. Resistant hypertension not related to “behavioural considerations” and thus presumably of biologic etiology probably comprises less than 20% of patients with uncontrolled hypertension. The prevalence of biologically based resistant hypertension in Canada has been estimated to be approximately 5% to 8% of the entire hypertensive population7 and approximately 10% in the United States.38 Multiple factors have been associated with the occurrence of resistance in patients with primary hypertension (Table 2). Age and obesity are probably the 2 principal independent risk factors that have been most consistently linked to biologically based resistant hypertension.38 Changing demographics related to these factors predict a growth in the numbers of patients with resistant
Canadian Journal of Cardiology Volume 29 2013 Table 2. Biologic reasons for resistant hypertension Primary hypertension-associated causes Older age (> 75 years) Female gender Obesity Dietary sodium excess Diabetes Associated target organ damage (left ventricular hypertrophy, chronic kidney disease, atherosclerosis) Interfering drugs, eg, nonsteroidal anti-inflammatory drugs; steroids; sympathomimetics; herbal supplements, eg, ephedra, bitter orange Secondary hypertension causes Hyperaldosteronism Renal artery stenosis Obstructive sleep apnea Pheochromocytomadepisodic palpitations, headaches, sweating Thyroid disease Cushing syndrome Coarctation of the aorta Intracranial tumours “Reproduced and modified from Myat et al.39 with permission from BMJ Publishing Group Ltd.
hypertension in the coming decades. Secondary forms of hypertension have also been overrepresented among those with biologically resistant hypertension (Table 2).39 Therapeutic approaches suggested in patients with biologically based resistant hypertension have generally focused on the reduction of intravascular volume and the use of aldosterone antagonism. Occult dietary salt excess was identified by Pimenta and colleagues40 as an important determinant of resistant hypertension, and sodium reduction in these patients paralleled a very significant reduction in blood pressure (> 20 mm Hg systolic) when combined with optimal pharmacologic therapy. Parenthetically, aerobic exercise, another important lifestyle modification shown to lower blood pressure in the general hypertensive population, has also been shown to lower blood pressure in patients with resistant hypertension.41 Aldosterone antagonism has also been suggested to be an important part of the management of patients with biologically based resistant hypertension.42 Elevated aldosterone levels are common in resistant hypertension.43 Although occasionally related to unrecognized primary hyperaldosteronism, increased plasma aldosterone concentrations are an almost inevitable consequence of multiple-drug antihypertensive therapy, especially related to the use of higherdose diuretics. High plasma aldosterone concentrations are often observed despite the use of ACE inhibitors or ARBsdwhich are usually associated with a degree of “aldosterone escape” with chronic therapy.44 Furthermore, aldosterone has vascular pressor effects beyond its actions on renal sodium retention,45,46 supporting the utility of aldosterone blockade, even in the absence of hyperaldosteronism. In this context, spironolactone has been shown to have beneficial effects in controlling blood pressure in patients with resistant hypertension, with average reductions in blood pressure of 1625/9-12 mm Hg, irrespective of baseline aldosterone levels.47 Notably, and especially for those unable to tolerate spironolactone, amiloride has also been shown to be an effective antihypertensive in the setting of resistant hypertension.48 For the management of those patients with hypertension not controlled by current preferred first-line therapeutic
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regimens (ie, RAS inhibitors, diuretics, and calcium channel blockers), health care providers are turning back to those therapies acting by sympathetic nervous system (SNS) inhibition, (ie, a-adrenergic antagonists, b-adrenergic antagonists, and centrally acting antihypertensive drugs such as clonidine). The importance of using these classes of drugs in the management of biologically based resistant hypertension is perhaps, in part, a consequence of their declining use as firstline drugs. Thus patients whose hypertension is characterized by sympathetic hyperactivity are less likely to be effectively treated by our currently recommended first-line therapies. This may be especially notable in those patient populations whose hypertension is more likely to be associated with SNS hyperactivity, such as those with renal injury and end-stage renal disease.49 However, in addition to conventional drug therapy for SNS inhibition, new technological advances are being used to control blood pressure by SNS inhibition, including renal denervation and carotid baroreceptor pacing.
Renal denervation The role of the sympathetic nervous system in resistant hypertension has been revisited with the availability of the technology for intra-arterial renal nerve ablation. A role for both renal efferent and afferent nerve activation in blood pressure regulation has long been recognized. Renal efferent activation is known to (1) increase renin release (and consequent activation of the RAS), (2) increase sodium retention, and (3) decrease renal blood flow. Renal afferent nerve activity is a key regulator of central sympathetic drive, with broad actions on peripheral resistance, cardiac output, and renal sodium handling. Renal nerves arise from the T10 through the L2 spinal segments and arborize around the renal arteries, residing primarily in the adventia.50 Prior to the advent of modern antihypertensive drugs, surgical ablation of the lumbar sympathetic chain was used in patients with malignant hypertension. Surgical ablation of the lumbar sympathetic chain often resulted in beneficial effects on blood pressure control but also a range of troubling side effects including orthostatic hypotension, intestinal disturbances, and sexual dysfunction.51 The interest in sympathetic nerve ablation as a therapeutic approach has increased with the development of new approaches for selective renal nerve sympathectomy. A catheter-based approach for renal denervation has recently been approved in Canada and is being used in several quaternary-level centres across Canada. Renal sympathetic ablation is achieved with a radiofrequency ablation catheter inserted through the femoral artery and into each renal artery sequentially (Symplicity, Ardian Inc, Palo Alto, CA, USA). Sustained blood pressure reductions (> 1 year) have now been seen both in initial proof of principle studies and in longerterm randomized studies of patients with resistant hypertension.52,53 Only minor adverse effects (eg, pseudoaneurysm at femoral artery insertion site) have been associated with the procedure, without long-term sequelae.52,53 The ultimate effectiveness of this therapy in patients with resistant hypertension is currently being studied in the double-masked, randomized Symplicity 3 study, assessing the treatmentrelated reduction in both clinic and ambulatory blood
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pressures; its expected completion date is the third quarter of 2013.54 Important questions remain before the utility of catheterbased renal denervation can be determined. First, the antihypertensive effect of this technology has been reported to be greater when assessed on the basis of clinic blood pressure measurements rather than 24-hour blood pressure control rates.55 It has been suggested that this discrepancy between clinic-based and ambulatory-based measures of antihypertensive effectiveness has been a recurring theme in antihypertensive drug therapies, although perhaps not to the same extent as that seen in renal denervation studies.56 Thus, the results of the Symplicity-3 study, which includes assessment by ambulatory blood pressure monitoring, will be important in establishing the true antihypertensive effectiveness of this therapy. Second, more data are needed regarding the safety of catheter-based renal denervation. Renal nerve activation may be especially important in maintaining blood pressure in settings of conditions characterized by reduced peripheral resistance and/or reduced intravascular volume, such as with hemorrhage and septic shock. How well patients post renal nerve denervation will respond to these vascular challenges remains to be determined. Furthermore, the longer-term (> 5 years) durability of the effects of renal denervation has yet to be established. Notwithstanding, this modality may well be a very important addition to the armamentarium for patients with truly resistant hypertension. Carotid sinus stimulation Carotid baroreflex stimulation has been appreciated to have significant depressor effects on blood pressure via decreasing sympathetic outflow and enhancing parasympathetic activity. Based on this premise, a baroreflex activation system has been developed (Rheos, CVRx, Minneapolis, MN, USA). In this approach, following implantation of a pulse generator, baroreflex activation leads are wrapped around the carotid bifurcation bilaterally. Antihypertensive efficacy of baroreflex activation 12 months post implantation has been shown using this system.57 However, complications of the insertion of the device, both acute and long-term (including permanent nerve injury), have dampened enthusiasm for this otherwise promising technology.56 Whether a new generation of leads that are inserted unilaterally and have a much smaller footprint will minimize adverse effects while maintaining effectiveness has yet to be determined. New Antihypertensive Drug Classes Still on the Horizon Although the pipeline for new antihypertensive drug classes has been diminishing during the past 30 years, there is ongoing development of new classes of antihypertensive drugs that may be available during the next 5 to 10 years. These include safer dual vasopeptidase inhibitors and more effective nitric oxide donors (for a more comprehensive review of new drug development, the reader is referred to a recent comprehensive review;58 see Table 3). The first dual vasopeptidase (ie, inhibiting both the ACE and the neutral endopeptidase) to reach phase-3 testing, omepatrilat was withdrawn related to angioedema risks.59
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Table 3. New drugs for hypertension Drug class Dual vasopeptidase inhibitors Dual neprilysin-ACE inhibitor Dual neprilysin-ECE inhibitor Dual ARNI Aldosterone-synthase inhibitor Endothelin antagonists Nitric oxide donors Nitric oxide-releasing drugs Nitrix oxide-releasing hybrids CINOD Renin-prorenin blocker ACE-2 activator Aminopeptidase-A inhibitor Vaccines Angiotensin 1 vaccine Angiotensin 2 vaccine Dual ARB/ETA-RB AGE breaker
Drug name
Drug discovery phase
Ilepatril (AVE7688) Daglutril (SLV306) LCZ696 LCI699 Bosentan Darusentan
3 2 3 2* 2 3
Nitrosyl-cobinamide Nitric oxide-losartan Nitric oxide-telmisartan Naproxcinod NA NA QGC001
P P P 3 P P P
PMD3117 Cyt006-AngQb PS-433540 Alagebrium (ALT-711)
2 2 2 2*
ACE, angiotensin-I converting enzyme; AGE, advanced glycation end-product; ARB, angiotensin-receptor blocker; ARNI, dual-acting angiotensin receptorneprilysin inhibitor; CINOD, cyclo-oxygenase-inhibiting nitric-oxide donator; ETA-RB, Endothelin A receptor blocker; PPAR-g, peroxisome proliferator-activated receptor-g; P, preclinical. * Development stopped. Reprinted and modified from Laurent et al.58, Copyright 2012, with permission from Elsevier.
Newer vasopeptidases without obvious increased risk of angioedema are being developed, including those with additional endothelin-1 converting enzyme inhibitory effects60 (Table 3). Whether a member of this class will ever be commercially available and whether it will offer any advantage to combination therapy (as above) remains unclear. Pharmacologic hybrid molecules, combining nitric oxidee releasing compounds with angiotensin receptor blockers, have been developed (Table 3). However, neither their utility nor their safety has yet been determined. Other previously promising drugs with targets like aldosterone synthase and endothelin receptors have been shown to be either ineffective (endothelin receptor antagonists) or insufficiently specific (as in the aldosterone synthase inhibitors) to be carried forward in clinical testing (Table 3). Summary Very significant advances have been made during the past 2 decades in the control of hypertension and hypertension-related complications. Further advances to improve control for the remaining one-third of patients with hypertension whose blood pressure remains elevated will be dependent on innovations in many areas: health care delivery systems, further development of single-pill combination drugs, and the refinement of new technologies to control blood pressure in patients with biologically resistant hypertension. Disclosures Dr Brass is a consultant to several pharmaceutical companies on issues related to drug development and regulation but not on projects related to antihypertensive products. Dr Feldman has served as a consultant with Abbott, Boehringer-Ingleheim, Medtronics, Novartis, Pfizer, and Servier. He has been supported for CME events by Abbott, Boehringer-Ingleheim, Pfizer, and Servier.
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31. Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. Hypertension 2011;58:566-72.
14. Faria C, Wenzel M, Lee KW, Coderre K, Nichols J, Belletti DA. A narrative review of clinical inertia: focus on hypertension. J Am Soc Hypertens 2009;3:267-76. 15. Harris SB, Kapor J, Lank CN, Willan AR, Houston T. Clinical inertia in patients with T2DM requiring insulin in family practice. Can Fam Physician 2010;56:e418-24. 16. Zafar A, Davies M, Azhar A, Khunti K. Clinical inertia in management of T2DM. Prim Care Diabetes 2010;4:203-7. 17. Lazaro P, Murga N, Aguilar D, Hernandez-Presa MA. Therapeutic inertia in the outpatient management of dyslipidemia in patients with ischemic heart disease: the inertia study. Rev Esp Cardiol 2010;63: 1428-37. 18. Goldberg KC, Melnyk SD, Simel DL. Overcoming inertia: improvement in achieving target low-density lipoprotein cholesterol. Am J Manag Care 2007;13:530-4. 19. Redón J, Coca A, Lázaro P, et al. Factors associated with therapeutic inertia in hypertension: validation of a predictive model. J Hypertens 2010;28:1770-7. 20. Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension 2006;47: 345-51. 21. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393-404. 22. Bakris GL. The importance of blood pressure control in the patient with diabetes. Am J Med 2004;116(suppl 5A):30S-8S. 23. Fung V, Huang J, Brand R, Newhouse JP, Hsu J. Hypertension treatment in a Medicare population: adherence and systolic blood pressure control. Clin Ther 2007;29:972-84. 24. Caro JJ, Speckman JL, Salas M, Raggio G, Jackson JD. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. CMAJ 1999;160:41-6. 25. Cowart JB, Taylor AA. Should two-drug initial therapy for hypertension be recommended for all patients? Curr Hypertens Rep 2012;14:324-32. 26. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med 2009;122:290-300. 27. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:1427. 28. Khan NA, Hemmelgarn B, Herman RJ, et al. The 2008 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2dtherapy. Can J Cardiol 2008;24:465-75.
32. Rabi DM, Daskalopoulou SS, Padwal RS, et al. The 2011 Canadian Hypertension Education Program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy. Can J Cardiol 2011;27:415-33, e411-2. 33. White RO, DeWalt DA, Malone RM, Osborn CY, Pignone MP, Rothman RL. Leveling the field: addressing health disparities through diabetes disease management. Am J Manag Care 2010;16:42-8. 34. Limonta LB, Valandro Ldos S, et al. Causes of resistant hypertension detected by a standardized algorithm. Int J Hypertens 2012;2012: 392657. 35. Mann SJ, Parikh NS. A simplified mechanistic algorithm for treating resistant hypertension: efficacy in a retrospective study. J Clin Hypertens (Greenwich) 2012;14:191-7. 36. Jaffe MG, Young JD. The Kaiser Permanente Northern California Hypertension Project 2001-2009: how an integrated care delivery system increased blood pressure control rates from 44% to 80% in 8 years. J Clin Hypertens 2011;13:A6. 37. Carter BL, Bosworth HB, Green BB. The hypertension team: the role of the pharmacist, nurse, and teamwork in hypertension therapy. J Clin Hypertens (Greenwich) 2012;14:51-65. 38. Roberie DR, Elliott WJ. What is the prevalence of resistant hypertension in the United States? Curr Opin Cardiol 2012;27:386-91. 39. Myat A, Redwood SR, Qureshi AC, Spertus JA, Williams B. Resistant hypertension. BMJ 2012;345:e7473. 40. Pimenta E, Gaddam KK, Oparil S, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 2009;54:475-81. 41. Dimeo F, Pagonas N, Seibert F, Arndt R, Zidek W, Westhoff TH. Aerobic exercise reduces blood pressure in resistant hypertension. Hypertension 2012;60:653-8. 42. Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med 2013;64:233-47. 43. Xanthakis V, Vasan RS. Aldosterone and the risk of hypertension. Curr Hypertens Rep 2013;15:102-7. 44. Sato A, Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001;29:13-21. 45. Gros R, Ding Q, Sklar LA, et al. GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. Hypertension 2011;57:442-51. 46. Feldman RD, Gros R. Unraveling the mechanisms underlying the rapid vascular effects of steroids: sorting out the receptors and the pathways. Br J Pharmacol 2011;163:1163-9. 47. Clark D III, Ahmed MI, Calhoun DA. Resistant hypertension and aldosterone: an update. Can J Cardiol 2012;28:318-25.
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48. Saha C, Eckert GJ, Ambrosius WT, et al. Improvement in blood pressure with inhibition of the epithelial sodium channel in blacks with hypertension. Hypertension 2005;46:481-7. 49. Masuo K, Lambert GW, Esler MD, Rakugi H, Ogihara T, Schlaich MP. The role of sympathetic nervous activity in renal injury and end-stage renal disease. Hypertens Res 2010;33:521-8. 50. Atherton DS, Deep NL, Mendelsohn FO. Micro-anatomy of the renal sympathetic nervous system: a human postmortem histologic study. Clin Anat 2012;25:628-33. 51. Grimson KS, Orgain ES, Anderson B, D’Angelo GJ. Total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy for hypertension. Ann Surg 1953;138:532-47. 52. Esler MD, Krum H, Schlaich M, Schmieder RE, Bohm M, Sobotka PA. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the symplicity HTN-2 randomized, controlled trial. Circulation 2012;126:2976-82. 53. Investigators, Symplicity HTN-1. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911-7.
Canadian Journal of Cardiology Volume 29 2013 54. Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol 2012;35:528-35. 55. Prochnau D, Figulla HR, 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. 56. Doumas M, Anyfanti P, Bakris G. Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension: a perspective. J Hypertens 2012;30:874-6. 57. 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;58:765-73. 58. Laurent S, Schlaich M, Esler M. New drugs, procedures, and devices for hypertension. Lancet 2012;380:591-600. 59. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103-11. 60. Cuculi F, Erne P. Combined neutral endopeptidase inhibitors. Expert Opin Investig Drugs 2011;20:457-63.
Review
From Bad Behaviour to Bad Biology: Pitfalls and Promises in the Management of Resistant Hypertension Ross D. Feldman, MD,a,b and Eric P. Brass, MD, PhDc a
Departments of Medicine and of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Ontario, Canada b c
Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada
Department of Medicine, Harbor-UCLA Medical Center, Torrance, California, United States
ABSTRACT
RESUM E
Control rates for hypertension have dramatically improved during the past 2 decadesdespecially in Canada. However, hypertension remains one of the top risk factors for premature death globally. Furthermore, one-third of Canadians with hypertension have not obtained adequate blood pressure control. Most of these patients have resistant hypertension with uncontrolled blood pressure despite therapy. The etiology of resistant hypertension is multifactorial but includes both behavioural and biological factors. Among behavioural factors, nonadherence on the part of patients and especially clinical inertia on the part of health care professionals are contributing causes. An understanding of the root causes underlying the failure to control an individual’s blood pressure is central to optimal subsequent management. Further advances in blood pressure control rates in this group of patients will depend on improvements in health care delivery systems and the further development of innovative therapies. Drugs combining multiple antihypertensive agents in a single pill and the development of new technologies to lower blood pressure, primarily by disruption of the sympathetic nervous system, have the potential to be useful strategies in this effort.
rielle se sont conside rableLes taux de maîtrise de l’hypertension arte liore s au cours des 2 dernières de cennies, particulièrement au ment ame Canada. Cependant, l’hypertension demeure l’un des principaux faccès pre mature dans le monde. De plus, un tiers des teurs de risque de de de façon Canadiens souffrant d’hypertension n’ont pas maîtrise rielle. La plupart de ces patients ont une acceptable leur pression arte rielle re fractaire non maîtrise e en de pit du traitement. hypertension arte tiologie de l’hypertension re fractaire est multifactorielle, mais inclut L’e les facteurs comportementaux et les facteurs biologiques. Parmi les facteurs comportementaux, la non-observance par les patients et par sont des ticulièrement l’inertie clinique des professionnels de la sante hension des causes fondamentales causes qui y contribuent. La compre es à l’incapacite à maîtriser la pression arte rielle d’un individu est lie quente. De nouvelles primordiale à la prise en charge optimale subse es sur les taux de maîtrise de la pression arte rielle de ce groupe avance pendront de l’ame lioration des systèmes de prestations de patients de et du de veloppement de traitements innovateurs. Les de soins de sante dicaments combinant plusieurs agents antihypertensifs en une seule me veloppement de nouvelles technologies pour abaisser la pilule et le de rielle, principalement par la perturbation du système nerpression arte gies utiles en ce sens. veux sympathique, ont le potentiel d’être des strate
Significant progress has been made in the management of hypertension. While hypertension on a global basis remains among the top risk factors for attributable death1 and morbidity,2 the first decade of the millennium has seen unprecedented gains in blood pressure control rates. In Canada control rates have increased more than 4-fold since the1990s,3 with an overall control rate of almost two-thirds among patients diagnosed with hypertensiondthe highest national rate of control globally.4 Furthermore, the improved blood pressure control rates have paralleled an increase in prescription of antihypertensive drugs5 and an acceleration in the decline of hypertension-related cardiovascular complications.6
Notwithstanding these advances, important gaps remain in our ability to control blood pressure. This review outlines the current challenges in improving blood pressure control for the remaining one-third of patients with hypertension whose blood pressure is not controlled. New management options are also reviewed, both those now available and those on the horizon, that offer promise for further gains against a cornered but still dangerous disease adversary.
Received for publication December 20, 2012. Accepted February 12, 2013. Corresponding author: Dr Ross D. Feldman, Robarts Research Institute, 100 Perth Dr, London, Ontario N6A 5K8, Canada. E-mail: [email protected] See page 554 for disclosure information.
The “Other” Third Why are one-third of those almost 8 million Canadians with hypertension not at blood pressure targets? The patient population making up those whose hypertension remains uncontrolled hypertension comprise those with multiple contributing etiologies (Fig. 1). They include patients unaware of their hypertension7 and those with resistant hypertension, ie, those patients whose blood pressure remains uncontrolled despite pharmacologic treatment. These patients include those with
0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.02.009
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so-called biologically resistant hypertension (see below). However, the largest subset in this grouping may be patients who are inadequately treateddwhose resistant hypertension is related to behavioural factors. These factors are both patient related and health care provider related. Using medical audit approaches, Garg and colleagues attempted to define the etiologies for resistant hypertension in a US population.8 They reported a number of familiar etiologies for uncontrolled hypertension, including nonadherence (16%); white coat hypertension (6%); secondary forms of hypertension (5%); and substances that interfere with blood pressure control or antihypertensive drug effectiveness, such as NSAIDs (1%). However, by far the largest identified etiology for poor blood pressure control was “drug related” causes (58%). Of those, a suboptimal medical regimen was cited as the primary factor. A suboptimal medical regimen might result from drugs being used at submaximal doses, failure to add a second (or third) drug when initial therapy is ineffective, or use of drug combinations with redundant mechanisms of actions (eg, an angiotensin converting enzyme [ACE] inhibitor and an angiotensin receptor antagonist [ARB]9). Thus, key factors in the development of resistant hypertension include those relating to both patient and health care provider behaviour patterns (Table 1). Patient Behaviours Contributing to Resistant Hypertension The patient is the central member of the team required to adequately control blood pressure. Lifestyle approaches to
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blood pressure control, including diet and exercise, can be implemented only by a motivated and educated patient. Failure to implement lifestyle changes may also compromise the pharmacologic management of hypertension. Specifically, failure to control sodium intake will compromise the effectiveness of any diuretic-based or renin-angiotensin system (RAS) inhibitor pharmacotherapy prescribed.10 An optimal prescribed pharmacologic regimen requires the patient to fill the prescription, comply with the directions, and adhere to the regimen over time. Nonadherence to a prescribed regimen remains the most commonly identified patientrelated behaviour associated with blood pressure control. Notably, the Canadian Hypertension Education Recommendations outline a number of approaches shown to be effective in improving adherence and blood pressure control, including the use of home blood pressure monitoring11 and single-pill combination therapy (discussed below).12 While less of an issue in Canada than in other parts of the world, cost of medications may be a substantial barrier to compliance.13 Clinical Inertia as a Determinant of BehaviourRelated Resistant Hypertension Clinical inertia, ie, the failure of health care providers to prescribe adequate antihypertensive therapy and/or to advance therapy when blood pressure remains above target, has been suggested to be an important contributing factor to the risk of uncontrolled hypertension.14 Furthermore, clinical inertia has been implicated as an important causal factor in
Figure 1. The spectrum of patients with uncontrolled hypertension. Some patients with poorly controlled blood pressure are unaware of their hypertension. Patients with diagnosed hypertension may have uncontrolled blood pressures due to behavioural etiologies. Nonoptimal behaviour may be observed in patients (eg, nonadherence to prescribed therapy) or health care systems (eg, irrational prescribing). In some patients a true biologic basis for their uncontrolled blood pressure is present.
Feldman and Brass Management of Resistant Hypertension Table 1. Behavioural reasons for uncontrolled blood pressure Patient-based reasons Failure to lose weight High sodium intake Poor exercise habits Failure to fill prescription Poor compliance with label directions Poor adherence with therapy over time Health care system or practitioner-based reasons Coprescribing of drugs that interfere with antihypertensive efficacy Inadequate patient education and/or support Irrational prescribing Failure to diagnose hypertension Wrong drugs Wrong dose
the low control rates for other target-based chronic disease risk factors, including diabetes15,16 and dyslipidemia.17,18 The causes of clinical inertia are multifactorial and complex and include factors related to dysfunctional health care delivery systems, inadequate blood pressure monitoring techniques, and patient resistance.19 However, behaviours by members of the health care delivery team manifested as clinical inertia are likely the major root cause in the patients whose resistance was ascribed by Garg and colleagues8 to “drug-related factors.” Furthermore, much of the practice-to-practice variability in blood pressure control rates has been related to variability in the extent of clinical inertia. Okonofua and colleagues found that the differences in blood pressure control rates varied widely between surveyed practices, from less than 10% to greater than 80%.20 That extent of variability directly paralleled the extent of clinical inertia, as determined by the proportion of times a practitioner failed to uptitrate a patient’s antihypertensive regimen when faced with a blood pressure above target levels. Okonofua et al. reported that those practices with the most clinical inertia, based on this metric, demonstrated the lowest blood pressure control rates. Approaches to Uncontrolled Blood Pressure Due to “Bad Behaviour”: Role of Single-Pill Combination Antihypertensive Drugs The pharmacologic management of hypertension is based on the use of regimens consisting of multiple drugs. As demonstrated from such studies as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the average patient with hypertension needs 2 to 3 antihypertensive drugs for blood pressure control,21 and those whose target blood pressure is lower (ie, < 130/80 for patients with hypertension and diabetes22) need more than 3. However, the use of multiple medications is problematic from the perspectives of both patient and health care provider. From a patient perspective, increased dosing frequency and increased number of prescribed tablets each parallels a reduction in compliance.23 The practice of substituting antihypertensive drugs because of either perceived lack of efficacy or perceived adverse effects is an almost inevitable consequence of building a multiple-dose regimen. The manipulation of the prescribed regimen over time results in a further reduction in both adherence and consequent blood pressure controlda phenomenon termed “therapeutic turbulence.”24 From a health care provider perspective, the complexity inherent in
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making the choices between the 5 first-line antihypertensive drugs as recommended by the Canadian Hypertension Education Program (CHEP), any pair of which can potentially be combined as Step 2 therapy,12 may be a contributor to therapeutic inertia. To avoid this challenge and to facilitate treatment escalation, single-pill combinations (formerly known as “fixed-dose combinations”) have been suggested to be, if not a panacea, at least a significant advance in managing most patients with hypertension.25 The rationale for the greater use of single-pill combination in the management of hypertension is based on both pharmacologic and behavioural considerations. It has been well established that combining antihypertensive drugs, with each drug at a submaximal dose, is significantly more efficacious than doubling a previously prescribed medication.26 Whereas the addition of a new antihypertensive drug is generally associated with an approximate doubling of antihypertensive effect, doubling a previously prescribed drug will result in a substantially lesser effect (in the range of 20%-25% for thiazides, beta-adrenergic antagonists, or ACE inhibitors and 35% to 40% for calcium channel antagonists). Furthermore, most antihypertensive drugs have side effect rates that approximate those of placebo at low doses, and dose escalation may lead to intolerance and nonadherence.27 Based on this pharmacologic premise, a number of studies have examined the potential superior effectiveness of singlepill combinations (vs conventional single-drug formulations) in hypertension. Approaches based on single-pill combinations have been shown to be superior to sequential single-pill therapeutic strategies in regard to (1) patient adherence;28,29 (2) medical resource use;29 (3) blood pressure control rates, as in the Simplified Treatment Intervention to Control Hypertension (STITCH) study;30 and (4) rate of hypertension-related cardiovascular complications.31 Despite the established effectiveness of single-pill combinations, Canada has lagged somewhat behind Western Europe and the United States in both the use and the availability of single-pill combinations. Although combinations of diuretics and ACE inhibitors and of diuretics and ARBs have been available for decades in Canada, they are used to a lesser extent in Canada than in the United States or Europednotwithstanding the support for their use in the CHEP recommendations.12 Furthermore, nondiuretic 2-drug combinations are both less available and less used in Canada. Two combinations of calcium channel antagonists and RAS inhibitors are available in Canada (trandolopril-verapamil and telmisartan-amlodipine). However, neither has been broadly prescribed by Canadian health care providers. Somewhat paradoxically, the preferred 2-drug combination (as per CHEP recommendations) for patients with hypertension at high risk for atherosclerotic complications, ie, a combination of an ACE-inhibitor and a dihydropyridine calcium channel antagonist,12,32 has yet to be released in Canada despite wide availability outside Canada. As the components of these 2-drug combinations are now largely available as generic drugs, the probability of seeing these combination drugs in Canada is becoming less likely over time. Furthermore, the single-pill, 3-drug combinations (diuretic, RAS inhibitor, and calcium channel antagonist) now being introduced outside Canada are even less likely to become available in Canada for economic reasons, minimizing our potential to make further
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advances in blood pressure control in the behaviourally challenged segment of the uncontrolled hypertension population. Systems-Based Approaches to Improve Blood Pressure Control in Patients with BehaviourRelated Resistant Hypertension One can speculate that one of the factors leading to the higher blood pressure control rates seen in clinical trials regardless of treatment is related to the application of fixed algorithms in blood pressure management. The efficacy of algorithm-based clinical management has long been established in the acute care setting (as in the use of surgical checklists, heparin algorithms, etc). However, the potential role of introducing algorithm-based management to minimize therapeutic inertia in chronic disease management is being increasingly considered, as in the management of diabetes33 and in hypertension. Notably, whether the effectiveness of the STITCH program was related more to the early use of single-pill combinations or to the use of a simplified algorithm may never be differentiated.30 However, in observational studies, algorithm-based management has been shown to improve both the identification of the cause of resistant hypertension34 and its management.35 Furthermore, as illustrated by the KaiserPermanente Northern California Hypertension Management System (which features the use of algorithm-based therapy and the early use of single-pill combinations), blood pressure control rates approximating clinical trial rates (greater than 80%) are achievable.36 Part of the effectiveness of the Kaiser Permanente system also may be related to the incorporation of a team-based care approach including nurses and pharmacists, which has been shown to be an effective systems-based approach for improving blood pressure control rates.37 Update on Approaches for Blood Pressure Control in Patients With Biologically-Related Resistant Hypertension True refractory hypertension, or biologically-based resistant hypertension, is conventionally defined as blood pressure uncontrolled on 3 drugs including a diuretic, or controlled on effective doses of more than 4 medications including a diuretic where patient adherence has been established. Note that this definition does not exclude nonoptimal selection of the prescribed medications and thus may still include patients with uncontrolled blood pressure due to nonbiologic reasons. Resistant hypertension not related to “behavioural considerations” and thus presumably of biologic etiology probably comprises less than 20% of patients with uncontrolled hypertension. The prevalence of biologically based resistant hypertension in Canada has been estimated to be approximately 5% to 8% of the entire hypertensive population7 and approximately 10% in the United States.38 Multiple factors have been associated with the occurrence of resistance in patients with primary hypertension (Table 2). Age and obesity are probably the 2 principal independent risk factors that have been most consistently linked to biologically based resistant hypertension.38 Changing demographics related to these factors predict a growth in the numbers of patients with resistant
Canadian Journal of Cardiology Volume 29 2013 Table 2. Biologic reasons for resistant hypertension Primary hypertension-associated causes Older age (> 75 years) Female gender Obesity Dietary sodium excess Diabetes Associated target organ damage (left ventricular hypertrophy, chronic kidney disease, atherosclerosis) Interfering drugs, eg, nonsteroidal anti-inflammatory drugs; steroids; sympathomimetics; herbal supplements, eg, ephedra, bitter orange Secondary hypertension causes Hyperaldosteronism Renal artery stenosis Obstructive sleep apnea Pheochromocytomadepisodic palpitations, headaches, sweating Thyroid disease Cushing syndrome Coarctation of the aorta Intracranial tumours “Reproduced and modified from Myat et al.39 with permission from BMJ Publishing Group Ltd.
hypertension in the coming decades. Secondary forms of hypertension have also been overrepresented among those with biologically resistant hypertension (Table 2).39 Therapeutic approaches suggested in patients with biologically based resistant hypertension have generally focused on the reduction of intravascular volume and the use of aldosterone antagonism. Occult dietary salt excess was identified by Pimenta and colleagues40 as an important determinant of resistant hypertension, and sodium reduction in these patients paralleled a very significant reduction in blood pressure (> 20 mm Hg systolic) when combined with optimal pharmacologic therapy. Parenthetically, aerobic exercise, another important lifestyle modification shown to lower blood pressure in the general hypertensive population, has also been shown to lower blood pressure in patients with resistant hypertension.41 Aldosterone antagonism has also been suggested to be an important part of the management of patients with biologically based resistant hypertension.42 Elevated aldosterone levels are common in resistant hypertension.43 Although occasionally related to unrecognized primary hyperaldosteronism, increased plasma aldosterone concentrations are an almost inevitable consequence of multiple-drug antihypertensive therapy, especially related to the use of higherdose diuretics. High plasma aldosterone concentrations are often observed despite the use of ACE inhibitors or ARBsdwhich are usually associated with a degree of “aldosterone escape” with chronic therapy.44 Furthermore, aldosterone has vascular pressor effects beyond its actions on renal sodium retention,45,46 supporting the utility of aldosterone blockade, even in the absence of hyperaldosteronism. In this context, spironolactone has been shown to have beneficial effects in controlling blood pressure in patients with resistant hypertension, with average reductions in blood pressure of 1625/9-12 mm Hg, irrespective of baseline aldosterone levels.47 Notably, and especially for those unable to tolerate spironolactone, amiloride has also been shown to be an effective antihypertensive in the setting of resistant hypertension.48 For the management of those patients with hypertension not controlled by current preferred first-line therapeutic
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regimens (ie, RAS inhibitors, diuretics, and calcium channel blockers), health care providers are turning back to those therapies acting by sympathetic nervous system (SNS) inhibition, (ie, a-adrenergic antagonists, b-adrenergic antagonists, and centrally acting antihypertensive drugs such as clonidine). The importance of using these classes of drugs in the management of biologically based resistant hypertension is perhaps, in part, a consequence of their declining use as firstline drugs. Thus patients whose hypertension is characterized by sympathetic hyperactivity are less likely to be effectively treated by our currently recommended first-line therapies. This may be especially notable in those patient populations whose hypertension is more likely to be associated with SNS hyperactivity, such as those with renal injury and end-stage renal disease.49 However, in addition to conventional drug therapy for SNS inhibition, new technological advances are being used to control blood pressure by SNS inhibition, including renal denervation and carotid baroreceptor pacing.
Renal denervation The role of the sympathetic nervous system in resistant hypertension has been revisited with the availability of the technology for intra-arterial renal nerve ablation. A role for both renal efferent and afferent nerve activation in blood pressure regulation has long been recognized. Renal efferent activation is known to (1) increase renin release (and consequent activation of the RAS), (2) increase sodium retention, and (3) decrease renal blood flow. Renal afferent nerve activity is a key regulator of central sympathetic drive, with broad actions on peripheral resistance, cardiac output, and renal sodium handling. Renal nerves arise from the T10 through the L2 spinal segments and arborize around the renal arteries, residing primarily in the adventia.50 Prior to the advent of modern antihypertensive drugs, surgical ablation of the lumbar sympathetic chain was used in patients with malignant hypertension. Surgical ablation of the lumbar sympathetic chain often resulted in beneficial effects on blood pressure control but also a range of troubling side effects including orthostatic hypotension, intestinal disturbances, and sexual dysfunction.51 The interest in sympathetic nerve ablation as a therapeutic approach has increased with the development of new approaches for selective renal nerve sympathectomy. A catheter-based approach for renal denervation has recently been approved in Canada and is being used in several quaternary-level centres across Canada. Renal sympathetic ablation is achieved with a radiofrequency ablation catheter inserted through the femoral artery and into each renal artery sequentially (Symplicity, Ardian Inc, Palo Alto, CA, USA). Sustained blood pressure reductions (> 1 year) have now been seen both in initial proof of principle studies and in longerterm randomized studies of patients with resistant hypertension.52,53 Only minor adverse effects (eg, pseudoaneurysm at femoral artery insertion site) have been associated with the procedure, without long-term sequelae.52,53 The ultimate effectiveness of this therapy in patients with resistant hypertension is currently being studied in the double-masked, randomized Symplicity 3 study, assessing the treatmentrelated reduction in both clinic and ambulatory blood
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pressures; its expected completion date is the third quarter of 2013.54 Important questions remain before the utility of catheterbased renal denervation can be determined. First, the antihypertensive effect of this technology has been reported to be greater when assessed on the basis of clinic blood pressure measurements rather than 24-hour blood pressure control rates.55 It has been suggested that this discrepancy between clinic-based and ambulatory-based measures of antihypertensive effectiveness has been a recurring theme in antihypertensive drug therapies, although perhaps not to the same extent as that seen in renal denervation studies.56 Thus, the results of the Symplicity-3 study, which includes assessment by ambulatory blood pressure monitoring, will be important in establishing the true antihypertensive effectiveness of this therapy. Second, more data are needed regarding the safety of catheter-based renal denervation. Renal nerve activation may be especially important in maintaining blood pressure in settings of conditions characterized by reduced peripheral resistance and/or reduced intravascular volume, such as with hemorrhage and septic shock. How well patients post renal nerve denervation will respond to these vascular challenges remains to be determined. Furthermore, the longer-term (> 5 years) durability of the effects of renal denervation has yet to be established. Notwithstanding, this modality may well be a very important addition to the armamentarium for patients with truly resistant hypertension. Carotid sinus stimulation Carotid baroreflex stimulation has been appreciated to have significant depressor effects on blood pressure via decreasing sympathetic outflow and enhancing parasympathetic activity. Based on this premise, a baroreflex activation system has been developed (Rheos, CVRx, Minneapolis, MN, USA). In this approach, following implantation of a pulse generator, baroreflex activation leads are wrapped around the carotid bifurcation bilaterally. Antihypertensive efficacy of baroreflex activation 12 months post implantation has been shown using this system.57 However, complications of the insertion of the device, both acute and long-term (including permanent nerve injury), have dampened enthusiasm for this otherwise promising technology.56 Whether a new generation of leads that are inserted unilaterally and have a much smaller footprint will minimize adverse effects while maintaining effectiveness has yet to be determined. New Antihypertensive Drug Classes Still on the Horizon Although the pipeline for new antihypertensive drug classes has been diminishing during the past 30 years, there is ongoing development of new classes of antihypertensive drugs that may be available during the next 5 to 10 years. These include safer dual vasopeptidase inhibitors and more effective nitric oxide donors (for a more comprehensive review of new drug development, the reader is referred to a recent comprehensive review;58 see Table 3). The first dual vasopeptidase (ie, inhibiting both the ACE and the neutral endopeptidase) to reach phase-3 testing, omepatrilat was withdrawn related to angioedema risks.59
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Table 3. New drugs for hypertension Drug class Dual vasopeptidase inhibitors Dual neprilysin-ACE inhibitor Dual neprilysin-ECE inhibitor Dual ARNI Aldosterone-synthase inhibitor Endothelin antagonists Nitric oxide donors Nitric oxide-releasing drugs Nitrix oxide-releasing hybrids CINOD Renin-prorenin blocker ACE-2 activator Aminopeptidase-A inhibitor Vaccines Angiotensin 1 vaccine Angiotensin 2 vaccine Dual ARB/ETA-RB AGE breaker
Drug name
Drug discovery phase
Ilepatril (AVE7688) Daglutril (SLV306) LCZ696 LCI699 Bosentan Darusentan
3 2 3 2* 2 3
Nitrosyl-cobinamide Nitric oxide-losartan Nitric oxide-telmisartan Naproxcinod NA NA QGC001
P P P 3 P P P
PMD3117 Cyt006-AngQb PS-433540 Alagebrium (ALT-711)
2 2 2 2*
ACE, angiotensin-I converting enzyme; AGE, advanced glycation end-product; ARB, angiotensin-receptor blocker; ARNI, dual-acting angiotensin receptorneprilysin inhibitor; CINOD, cyclo-oxygenase-inhibiting nitric-oxide donator; ETA-RB, Endothelin A receptor blocker; PPAR-g, peroxisome proliferator-activated receptor-g; P, preclinical. * Development stopped. Reprinted and modified from Laurent et al.58, Copyright 2012, with permission from Elsevier.
Newer vasopeptidases without obvious increased risk of angioedema are being developed, including those with additional endothelin-1 converting enzyme inhibitory effects60 (Table 3). Whether a member of this class will ever be commercially available and whether it will offer any advantage to combination therapy (as above) remains unclear. Pharmacologic hybrid molecules, combining nitric oxidee releasing compounds with angiotensin receptor blockers, have been developed (Table 3). However, neither their utility nor their safety has yet been determined. Other previously promising drugs with targets like aldosterone synthase and endothelin receptors have been shown to be either ineffective (endothelin receptor antagonists) or insufficiently specific (as in the aldosterone synthase inhibitors) to be carried forward in clinical testing (Table 3). Summary Very significant advances have been made during the past 2 decades in the control of hypertension and hypertension-related complications. Further advances to improve control for the remaining one-third of patients with hypertension whose blood pressure remains elevated will be dependent on innovations in many areas: health care delivery systems, further development of single-pill combination drugs, and the refinement of new technologies to control blood pressure in patients with biologically resistant hypertension. Disclosures Dr Brass is a consultant to several pharmaceutical companies on issues related to drug development and regulation but not on projects related to antihypertensive products. Dr Feldman has served as a consultant with Abbott, Boehringer-Ingleheim, Medtronics, Novartis, Pfizer, and Servier. He has been supported for CME events by Abbott, Boehringer-Ingleheim, Pfizer, and Servier.
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