Abstract
Arterial hypertension is a very complex disease characterized by a sustained rise in systolic and/or diastolic blood pressure (BP) levels and a significantly increased risk of developing major adverse cardiovascular and renal outcomes. Although BP-lowering treatment reduces the hypertension-related burden of disease, BP control continues to be poorly achieved worldwide. A major factor contributing to this therapeutic failure is represented by resistant (or refractory) hypertension. The diagnosis of 'resistant hypertension' is very common in clinical practice, yet it is often used to improperly define patients with difficult or challenging forms of hypertension. An incorrect use of this definition by physicians may lead to clinical behaviors that do not help to improve BP control; on the other hand, correct diagnosis of resistant hypertension may facilitate the successful treatment of hypertension. In this article, we will review and discuss the definition, pathophysiological mechanisms, diagnostic algorithms and potential new therapeutic options for treating resistant hypertension.Blood Pressure Control in the Hypertensive Population: Focus on Resistant Hypertension
Arterial hypertension is a very complex disease.[1] Its pathophysiology is characterized by the intervention of multiple factors, leading to a substantial and persistent increase in blood pressure (BP) levels, and higher susceptibility to develop organ damage and overt cardiovascular (CV) and renal complications, including myocardial infarction, stroke, heart failure and end-stage renal disease.[2] BP reduction is, in turn, paralleled by marked reductions in fatal and nonfatal outcomes in hypertensive patients with different degrees of global CV risk profile.[3,4]
In spite of the progressive and considerable improvements achieved in diagnostic options and therapeutic interventions, recent observational surveys continue to show persistently low rates of BP control in the general population of hypertensive patients.[5] The treatment of hypertension, in fact, usually requires a therapeutic approach based on the adherence to healthy lifestyle measures and use of antihypertensive drugs.[6–8] In approximately two-thirds of hypertensive patients, however, a combination therapy based on the association of multiple agents belonging to different antihypertensive drug classes is required.[9,10] Of note, even with the most updated therapeutic approach based on the use of lifestyle measures and combination drug strategies, BP levels remain elevated in the majority of patients.[11]
Numerous patients with poor BP control in clinical practice are improperly classified as having 'resistant hypertension'. This diagnosis is not always appropriate and often misused to define patients with difficult-to-treat or 'challenging' forms of hypertension.[12,13] A difficult control of BP levels in hypertensive patients may, indeed, be related to several factors, including doctors' inertia, patients' poor compliance, insufficient patient–doctor communication, inappropriate BP measurements, or inadequate or insufficient antihypertensive interventions. These conditions obviously do not represent true 'resistant' hypertension. They should rather be considered as 'uncontrolled hypertension', which may nevertheless lead to increased risk of major CV events related to hypertension.
As indicated in the most recent hypertension guidelines, hypertension is defined as resistant (or refractory) to treatment when a therapeutic plan that consists of adherence to healthy lifestyle measures and the prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower systolic and/or diastolic BP to goal, as defined by BP levels below 140/90 mmHg in the general population of hypertensive patients and below 130/80 mmHg in those hypertensive patients at high or very high global CV risk (e.g., diabetics).[6–8]
In this article, we will discuss epidemiological aspects of 'true resistant hypertension', and propose a diagnostic algorithm to properly identify and treat patients with this condition in clinical practice. Finally, we will address modern therapeutic approaches, including new pharmacological options and nonpharmacologic interventions, which may help to better control BP levels in patients with resistant forms of hypertension.
* Abstract and Introduction
* Blood Pressure Control in the Hypertensive Population: Focus on Resistant Hypertension
* Epidemiology & Clinical Relevance of Resistant Hypertension
* Pathophysiological & Clinical Aspects
* Therapeutic Approach to Resistant Hypertension
* Expert Commentary
* Five-year View
* References
* Sidebar
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Epidemiology & Clinical Relevance of Resistant Hypertension
A poor control of BP level is a very common situation in clinical practice, as it has been described in international,[14–16] regional[17] or clinical[18] settings. One of the most recent and largest analyses based on observational studies in hypertension conducted in Italy between 2000 and 2007 revealed that only 22% of approximately 53,000 hypertensive patients included in these surveys were under control, whereas 39% had BP levels exceeding 140/90 mmHg and approximately one third (32.9%) had diastolic BP levels above 100 mmHg. In addition, approximately 5% of patients, predominantly elderly individuals, had isolated systolic hypertension.[18] In a more specific project aimed at identifying the prevalence of resistant hypertension with automated ambulatory BP monitoring systems conducted in Spain, more than 1000 investigators, selected through primary care physicians and referral units, participated by including a cohort of approximately 52,000 patients with untreated hypertension or previously diagnosed hypertensive patients on pharmacological treatment.[19] Among these patients, more than 6000 were revealed to have resistant hypertension, since their BP levels were above 140/90 mmHg, in spite of using more than three concomitant antihypertensive drugs from different classes, including diuretics (either thiazide or loop diuretics).[20] Thus, the prevalence of resistant hypertension in this Spanish cohort was approximately 12%, with the remaining proportion of hypertensive patients having a satisfactory control of their BP levels.[20]
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) highlighted for the first time the potential impact of resistant hypertension among general practitioners.[20] In this large, interventional clinical trial performed in hypertensive patients with a high CV risk profile randomized to receive an antihypertensive treatment based on either a calcium channel blocker (CCB; amlodipine), a diuretic (chlorthalidone) or an ACE inhibitor (lisinopril), the percentages of patients achieving the recommended BP targets were approximately 61, 57 and 54%, respectively. It should be highlighted, however, that in this trial approximately one-third of the patients were receiving three or more antihypertensive agents, and in spite of that their BP levels remained above normal values.
The real prevalence of resistant hypertension in the clinical practice is, however, far from being definitely assessed. In fact, some physicians tend to classify those individuals in whom systolic and/or diastolic BP goals are difficult to achieve under multiple antihypertensive drug treatment as resistant hypertensive patients, and this may simply reflect a number of diagnostic problems that are not systematically addressed in routine practice, as well as the complexity of choosing the appropriate treatment in the individual hypertensive patient.
Failure to achieve a satisfactory BP control often results in physician's disappointment and resignation to accept persistently elevated BP levels. Alternatively, an excessive number of patients are referred to 'hypertension centers', which are overwhelmed by this type of referral. In fact, only a minority of general practitioners or specialists operating in outpatient clinics adhere to the definition proposed by current guidelines,[6–8] and identify 'true resistant' hypertension after all necessary diagnostic steps (including home BP evaluation and 24-h ambulatory BP monitoring, where appropriate) and therapeutic (pharmacological and nonpharmacological) measurements have been undertaken.[21]
Thus, efforts should be devoted to clearly identify patients with true resistant hypertension, as defined previously,[6–8] and to distinguish them from those with uncontrolled or 'challenging' forms of hypertension, since these latter patients may only require further diagnostic steps or therapeutic adjustments. This is of crucial relevance, especially to reduce the clinical inertia that may be based on the physician's erroneous assumption that the patient is resistant to treatment. As an example supporting this view, in the Reassessment of Antihypertensive Chronic Therapy (REACT) study, 42% of physicians decided not to modify the antihypertensive regimen, even though their hypertensive patients were not controlled after more than 1 year of follow-up.[22] This issue remains, in our opinion, a major problem in the clinical management of hypertension.
A closer look into major pathophysiological aspects, diagnostic options and available therapeutic interventions for treating this condition may be of help when managing patients with resistant hypertension.
* Abstract and Introduction
* Blood Pressure Control in the Hypertensive Population: Focus on Resistant Hypertension
* Epidemiology & Clinical Relevance of Resistant Hypertension
* Pathophysiological & Clinical Aspects
* Therapeutic Approach to Resistant Hypertension
* Expert Commentary
* Five-year View
* References
* Sidebar
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Pathophysiological & Clinical Aspects
Pseudo-resistant Hypertension
The diagnosis of resistant hypertension should begin with an initial fundamental clinical step, which is the identification of 'pseudo-resistant' hypertension. This condition, which is frequently confused with resistant hypertension, is characterized by BP levels persistently above normal values at clinic measurements in patients who do not have resistant hypertension.[6–8] Several factors may contribute to maintain elevated BP levels and induce the perception of resistant hypertension. The identification and removal of these factors may contribute to normalize BP levels and, thus, to rule out the diagnosis of resistant hypertension.
Box 1 reports a number of potential causes that might be involved in the genesis of pseudo-resistant hypertension. Among these causes, inaccurate BP measurements[23] or the use of inadequate dosages or inappropriate combinations of drugs[24] probably represent the most common. White-coat hypertension may represent another possible cause of pseudo-resistant hypertension, which needs to be properly identified.[25] The prognostic significance of this condition, however, is still debated. Some authors have reported that patients with white-coat hypertension may develop sustained forms of hypertension over the years.[26]
In this latter regard, studies published in the last few years have shown that the presence of true resistant hypertension in cohorts of hypertensive patients has been better defined by using 24-h ambulatory BP monitoring, which can also be of help in characterizing the BP profile of this clinical condition. In a study published by Veglio et al. in 2001, the use of ambulatory BP monitoring allowed the detection of the presence of true resistant hypertension in approximately 2% of the overall hypertensive outpatients referred to that hypertension unit.[27] In this subgroup, patients with true resistant hypertension were significantly younger, and had significantly higher sodium and alcohol intake than those recorded in patients with white-coat resistant hypertension.[25] Another analysis performed by Brown et al. in 2001 substantially confirmed the use of 24-h ambulatory BP monitoring as an appropriate step to be undertaken before further investigating or treating patients with apparently resistant hypertension.[28]
Secondary Hypertension
An important diagnostic step is to exclude a secondary cause of hypertension.[29] Among the potential causes of impaired or insufficient response to multiple antihypertensive drug therapy, renal parenchimal disease,[30,31] renal artery disease[32,33] and hyperaldosteronism[34,35] may be viewed as the most frequently reported in large observational databases. The estimated prevalence of these conditions, however, varies between 1.8% for renal parenchimal disease, 3.4% for renal artery disease and 8% (range: 5–13%) for hyperaldosteronism according to an analysis published in 2006 by Moser and colleagues.[36]
Indeed, the presence of primary hyperaldosteronism should be always considered in patients who have developed a 'challenging' form of hypertension.[37] In a study by Veglio and colleagues performed in 2001 in a population of more than 1500 patients with so-called 'resistant hypertension', it was found that 11.3% of these patients had, indeed, primary hyperaldosteronism.[27] Other studies report that primary aldosteronism accounts for up to 20% of resistant hypertension.[34,38,39] It should be noted that this population was mostly recruited among hypertensive patients with BP levels above 140/90 mmHg, despite a drug regimen of three antihypertensive drugs, including a diuretic.[27]
Lack of sleep or sleep apnea syndrome, which represent growing problems in modern society, have recently been proposed as emerging causes of moderate-to-severe forms of hypertension, including masked hypertension (e.g., elevated BP levels at home and normal office BP levels)[40] and resistant hypertension.[39]
Drug-induced Hypertension
Another aspect that should be considered when excluding potential causes of poor BP control in the presence of multiple and appropriate antihypertensive therapy is drug-induced hypertension.[41] A list of drugs potentially involved in the genesis and maintenance of resistant hypertension is reported in Box 2. Among these, NSAIDs (e.g., cyclooxygenase-2 inhibitors) and sympathomimetic agents, including anorectics, appear to be the most frequent causes of drug-induced sustained BP elevation. Abuse of cocaine, amphetamines and other illicit drugs, as well as oral contraceptive hormones, also represent emerging problems. Other potential substances that may render the treatment of hypertension more difficult include herbal principles, energizing drinks, androgens and anabolizing hormones. Finally, immunosuppressant agents, which are commonly used in patients undergoing organ transplantation or suffering from immune diseases, should be considered as potential causes of resistant hypertension.
The mechanisms by which the different drugs may induce a persistent rise in BP levels are multiple and not fully elucidated, sharing several common pathways that are schematically reported in Figure 1. In particular, three major pathophysiological mechanisms have been advocated. They include:
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(Enlarge Image)
Figure 1.
Pathophysiological mechanisms involved in the genesis of drug-induced arterial hypertension.
BP: Blood pressure; NO: Nitric oxide; RAS: Renin–angiotensin system.
[ CLOSE WINDOW ]
Figure 1.
Pathophysiological mechanisms involved in the genesis of drug-induced arterial hypertension.
BP: Blood pressure; NO: Nitric oxide; RAS: Renin–angiotensin system.
* Increased vascular tone
* Salt and water retention with volume expansion
* Abnormal activation of the sympathetic nervous system or renin–angiotensin system
In addition, an imbalance between nitric oxide production and vasoconstricting agents at the endothelial level may be involved in the pathogenesis of these situations. In some circumstances, such as the use of cyclosporine, the increase in renin production also appears to play a major role.
On the basis of these considerations, the importance of an accurate collection of patient's personal clinical history appears to be a fundamental step for identifying any potential cause of resistant hypertension, especially when this has not been taken into sufficient account in previous visits. Thus, even in patients not responding to three or more antihypertensive drugs, an accurate collection of information on drug consumption or alcohol abuse may be extremely important.
Difficult Control of Blood Pressure in Specific Clinical Conditions
Patients' clinical characteristics associated with the presence of resistant hypertension include older age (increased arterial stiffness), baseline BP levels in the upper range (grade 2–3 hypertension) at diagnosis, obesity, excessive dietary salt ingestion, black race, female gender and residence in specific geographical areas. In particular, with regard to the presence of obesity, any effort should be undertaken to properly control it, as well as any other potentially modifiable risk factor, in order to better manage high BP levels.
Other clinical conditions can be found in patients with resistant hypertension. These include severe left ventricular hypertrophy, cardiomyopathies, diabetes mellitus with proteinuria, and chronic kidney disease. Finally, aortosclerosis and insufficiency of the aortic valve are frequently associated with forms of isolated systolic hypertension, which may not benefit an aggressive antihypertensive drug therapy.Therapeutic Approach to Resistant Hypertension
With regard to the therapeutic approach to resistant hypertension, besides the appropriate use of the five major classes of antihypertensive drugs in combination, as recommended by the current European and North-American guidelines, new therapeutic options are becoming available (Box 2).[6–8] It must be highlighted, however, that appropriate lifestyle interventions, such as salt restriction, weight loss, physical activity, smoking cessation and alcohol abstention, should be always considered in any therapeutic plan aimed at reducing BP levels to goal. Accumulating evidence, in fact, supports the role of these interventions in improving BP control and reducing the incidence of major CV events in high-risk hypertensive patients. Thus, they must be viewed as a fundamental step when treating patients with either essential or resistant hypertension.
Aldosterone Antagonists & Potassium-sparing Diuretics
Aldosterone antagonists represent a well-established pharmacological tool for managing patients with resistant hypertension, even when true hyperaldosteronism is difficult to identify clinically or after performing sophisticated investigations.
Besides the established use of these drugs, which have proven to be effective in previous clinical trials,[42,43] eplerenone, canrenone and potassium canreonate may represent alternatives for treating resistant hypertension, in view of the lesser incidence of drug-related side effects (e.g., gynecomastia).[44,45] Amiloride may represent another potential option,[46] although the efficacy of this compound is controversial in treating patients with resistant hypertension.[43] It should be also highlighted, however, that some of these compounds (mostly canrenone and potassium canreonate) are not available in all countries.
A recent analysis of the results of the Anglo–Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT–BPLA) has adopted an antihypertensive treatment algorithm to control resistant hypertension in both the amlodipine- and atenolol-based regimen using the α-blocker doxazosin or other antihypertensive drugs, mostly spironolactone.[47] In this population, the use of spironolactone was able to reduce BP in those patients who were not responding to multiple drug combinations. This therapeutic approach reduced systolic BP levels from 156.9/85.3 to 135.1/75.8 mmHg.[47] In another study by Nishizaka looking at the effect of spironolactone, the average reduction in systolic and diastolic BP levels in patients with resistant hypertension was approximately 25 mmHg after 6 months.[48] More recently, preliminary evidence has demonstrated that treatment with spironolactone significantly reduces ambulatory and clinic BP levels, and ameliorates the severity of obstructive sleep apnea syndrome in patients with resistant hypertension, although an increase in serum creatinine levels and plasma renin activity has been reported.[49]
Finally, it should be mentioned that sometimes (thiazide or loop) diuretics are underused or underdosed in the treatment of difficult forms of hypertension owing to clinical inertia or fear of the side effects. One of the common features of patients with resistant hypertension may be the presence of 'subclinical hypervolemia', which should be carefully considered in each patient with persistently elevated BP levels.
Combination Therapy
Clinical studies have revealed that an effective way to control resistant hypertension can be based on an early initiation of antihypertensive treatment with two-drug combinations, as suggested by current guidelines.[6–8] Combination strategy should be based on the use of drugs with synergistic mechanisms. Available evidence demonstrated a better BP control by combining drugs able to modulate the abnormal activation of the renin–angiotensin system, including ACE inhibitors or ARBs, with vasodilating agents, such as CCBs,[50–52] α-blockers[53,54] or diuretic (thiazide) drugs.[55,56] In this latter regard, it should be mentioned that in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial,[57] only one-third of high-risk hypertensive patients were under control on routine antihypertensive therapy at the beginning of the study, while more than 80% were under control with both study drug combination regimens, including an ACE inhibitor and either a CCB or a thiazide diuretic at the end of the study. Interesting results have been obtained with the ARB olmesartan medoxomil combined with either the CCB amlodipine or a thiazide diuretic, or both,[50,51] or with the ACE inhibitor enalapril combined with the CCB lercanidipine.[58] In these clinical studies the percentage of responders in difficult-to-treat patients was up to 80–90%, which is a very encouraging result.[50,51,58]
Direct Renin Inhibition
Among the potential new pharmacological options, the use of the direct renin inhibitor, aliskiren, has been revealed to be effective in patients who are not under control on multiple antihypertensive drug therapy, including other drugs blocking the renin–angiotensin system.[59,60] No specific study has been performed with aliskiren in patients with resistant hypertension, although this would be highly recommended. At this time, aliskiren may only be considered as a promising option in this clinical setting. Preliminary analysis, performed in a large observational database of prescriptions collected in the 'real world' of clinical practice in Italy, showed a high rate of responders among hypertensive patients with resistant or challenging hypertension, who were already treated with at least three antihypertensive drugs.[101]
Novel Antihypertensive Agents
Aldosterone synthase inhibitors are currently being tested as an option to treat resistant hypertension.[61] Other potential effective tools include a new formulation of clonidine with extended release, endothelin antagonists and neutral endopeptidase inhibitors, particularly omapatrilat. This compound has not been admitted for hypertension treatment, owing to side effects observed in specific populations, although it could be reconsidered in the future for compassionate use in patients with resistant hypertension.[62–64] Among potentially novel antihypertensive agents, darusentan, a specific endothelin antagonist, has recently been tested in a randomized clinical trial performed in hypertensive patients with established diagnosis of resistant hypertension.[65] Although the results of this study demonstrated that this strategy may provide additional reduction in BP levels in patients who did not attain their treatment goals with three or more antihypertensive drugs,[65] the future inclusion of this drug in the therapeutic armamentarium of hypertension is still under debate.
Nonpharmacological Agents
Several nonpharmacologic therapeutic approaches to treat patients with resistant hypertension are under development or evaluation. Among these, preliminary data have recently demonstrated the efficacy, safety and tolerability of implantable pulse generators in both experimental and human studies.[66] This system consists of a surgically and chronically implanted pulse generator and bilateral perivascular carotid sinus leads, and is being evaluated in prospective clinical trials for the treatment of drug-resistant hypertension.[66] Pilot studies support the efficacy of renal artery denervation in treating patients with true resistant hypertension, in which a renal origin of the disease has been established.[67,68] Furthermore, neurovascular decompensation has recently been evaluated as a potential treatment option in patients with uncontrolled or true resistant hypertension, although recent studies indicate it may only be useful temporarily.[69] As well as for the implantation of carotid pulse generators, it should be highlighted, however, that these procedures are invasive and irreversible, and that nowadays they should be strictly recommended to those patients with uncontrolled BP levels despite optimal pharmacological strategy, following a rigorous clinical evaluation of the patient, the exclusion of any reasonable alternative and a presumably unfavorable prognosis of the disease.
* Abstract and Introduction
* Blood Pressure Control in the Hypertensive Population: Focus on Resistant Hypertension
* Epidemiology & Clinical Relevance of Resistant Hypertension
* Pathophysiological & Clinical Aspects
* Therapeutic Approach to Resistant Hypertension
* Expert Commentary
* Five-year View
* References
* Sidebar
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Expert Commentary
Worldwide prevalence of hypertension is high and increasing, and BP control in hypertensive populations remains unacceptably poor. This has dramatic consequences for public health, because the benefit of antihypertensive treatment is mostly related to the degree of systolic or diastolic BP reduction. The situation is even more dramatic in perspective owing to the continuing rise in the prevalence of hypertension and other comorbidities at a global level.
The lack of BP control may be related to several factors, including doctors' inertia, patients' poor compliance, insufficient patient–doctor communication, inappropriate measurements of BP, or inadequate or insufficient antihypertensive interventions. The diagnosis of resistant hypertension is often advocated as a major cause.
Although the diagnosis of 'resistant hypertension' is very common in the clinical practice, it is often used to improperly define patients with difficult or challenging forms of hypertension. According to current guidelines, the definition of resistance (or refractory) to treatment should be limited to those hypertensive patients in whom adherence to lifestyle measures and prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower systolic and/or diastolic BP to goal.[6–8]
Correct diagnosis and management of resistant hypertension is a fundamental step when approaching patients with difficult-to-treat or challenging hypertension, and it should be carried out in careful, mandatory clinical steps as schematically shown in Figure 2. First, it is important to consider the diagnosis of pseudo-resistant hypertension and hypertension related to concomitant diseases, use of drugs or other substances, and secondary hypertension. The treatment of resistant hypertension should include optimization of dosages and more frequent use of rational combination therapy in order to increase the synergistic effects on BP lowering. Novel pharmacological and nonpharmacological interventions can be considered as alternative options to treat patients with resistant hypertension.
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(Enlarge Image)
Figure 2.
How to properly diagnose true resistant hypertension in daily clinical practice.
†Diagnose and treat any concomitant conditions that may affect high blood pressure levels, including: renal parenchimal disease, renovascular disease, aldosteronism, thyroid disease, Cushing's syndrome, pheocromocytoma, aortic coarctation, severe aortic atherosclerosis (aortosclerosis) and sleep apnea syndrome. BP: Blood pressure.
* Abstract and Introduction
* Blood Pressure Control in the Hypertensive Population: Focus on Resistant Hypertension
* Epidemiology & Clinical Relevance of Resistant Hypertension
* Pathophysiological & Clinical Aspects
* Therapeutic Approach to Resistant Hypertension
* Expert Commentary
* Five-year View
* References
* Sidebar
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Five-year View
Over the last few decades, control of BP levels has been poorly achieved in worldwide general practice. Resistant hypertension has represented a major factor contributing to the lack of BP control. Beside the appropriate use of appropriate lifestyle interventions and the use of five major classes of antihypertensive drugs in rational combination strategies, new therapeutic options are becoming available. They mostly include drugs able to counteract the deleterious effects of abnormal activation of the renin–angiotensin system or the sympathetic nervous system at different levels than previously adopted (e.g., renin or prorenin inhibition, aldosterone synthase inhibitors, and so on), or novel combination strategies. In addition, nonpharmacological tools, such as carotid implantable pulse generators, renal artery denervation and neurovascular decompensation, will soon become available for treating patients with uncontrolled BP levels or resistant hypertension. Preliminary data from clinical trials showed promising results of these additional strategies in terms of BP-lowering efficacy and increasing responder's rates to antihypertensive strategies. Further research and clinical studies are needed in order to better clarify the main pathophysiological aspects and optimal therapeutic approaches to be applied in patients with resistant hypertension.
