Hypertension is the most common chronic disease in developed countries, with a prevalence of approximately 25% to 30% in adults. High blood pressure (BP) remains one of the leading risk factors influencing cardiovascular morbidity and mortality. The current management of hypertension is based on knowledge accumulated over more than a half a century, the availability of multiple orally active and potent antihypertensive drugs targeting different pathophysiological pathways, the cumulative evidence from several randomized controlled trials and meta-analyses, and hundreds of pages of guidelines regularly updated by experts from around the world. Nevertheless, hypertension remains poorly controlled worldwide, and its incidence is increasing, because of the aging of the population and the obesity epidemic. However, only some of the patients for whom the recommended BP thresholds are not reached actually have resistant hypertension (RHTN).
According to the joint European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines, hypertension is defined as resistant to treatment “when a therapeutic strategy that includes appropriate lifestyle measures plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses (but not necessarily including a mineralocorticoid receptor antagonist) fails to lower systolic BP (SBP) and diastolic BP (DBP) values to less than 140 and 90 mm Hg, respectively.” These guidelines do not specify which classes of antihypertensive drugs other than a diuretic should be used to define RHTN. The NICE-UK (National Institute for Health and Care Excellence-United Kingdom) guidelines recommend that the three-drug regimen should include a renin angiotensin system (RAS) blocker (i.e., an angiotensin-converting enzyme [ACE] inhibitor, or angiotensin II receptor blocker [ARB], but not both), a long-acting calcium channel blocker (CCB) and a thiazide (or thiazide-like) diuretic in the absence of renal insufficiency. The American Heart Association guidelines also include BP controlled by four or more drugs in the definition of RHTN ; this approach aims at identifying patients likely to benefit from particular (1) diagnostic procedures to screen for secondary hypertension or (2) treatment options. The BP goals generally recommended for all hypertensive patients are an SBP of less than 140 mm Hg and a DBP of less than 90 mm Hg. Some guidelines recommend lower BP targets for patients with diabetes or chronic kidney disease and higher thresholds for patients over the age of 80 years, as shown in Table 43.1 . The NICE-UK guidelines also suggest defining RHTN after confirmation by ambulatory BP monitoring in case of a mean daytime BP greater than 135/85 mm Hg despite treatment with the combination of a RAS blocker, a CCB and a diuretic.
| Year | Guideline | Population | Goal Office BP (Mm Hg) |
|---|---|---|---|
| 2015 | Canadian Hypertension Education Program recommendations | Adults <80 years | <140/90 |
| Adults ≥80 years | <150 | ||
| Adults with diabetes | <130/80 | ||
| Adults with CKD | <140/90 | ||
| 2014 | Eighth Joint National Committee (JNC 8) Hypertension Guidelines | Adults <60 years | <140/90 |
| Adults ≥60 years | <150/90 | ||
| Adults with diabetes | <140/90 | ||
| Adults with CKD | <140/90 | ||
| 2014 | American Society of Hypertension/International Society of Hypertension (ASH/ISH) Clinical practice guidelines | Adults <80 years | <140/90 |
| Adults ≥80 years | <150/90 | ||
| Adults ≥80 years with CKD or diabetes | <140/90 | ||
| Adults <80 years with CKD and albuminuria | <130/80 | ||
| 2013 | European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of arterial hypertension | Adults <80 years | <140/90 |
| Adults ≥80 years | <150/90 | ||
| Adults with diabetes | <140/85 | ||
| Adults with CKD without proteinuria | <140/90 | ||
| Adults with CKD with overt proteinuria | <130/90 | ||
| Adults with CHD | <140/90 | ||
| 2012 | Kidney Disease: Improving Global Outcomes Chronic Kidney Disease clinical practice guideline (KDIGO) | Adults with CKD and urine albumin <30 mg/24 h | <140/90 |
| Adults with CKD and urine albumin ≥30 mg/24 h | <130/80 | ||
| 2011 | National Institute for Health and Care Excellence-United Kingdom (NICE-UK) guidance | Adults <80 years | <140/90 |
| Adults ≥80 years | <150/90 |
The United States guidelines provide a list of the optimal/adequate doses of a limited number of antihypertensive drugs available in the U.S. that should be used to treat hypertensive patients. No such detailed list is available in other guidelines and the antihypertensive drugs used, together with their doses, vary considerably between countries. Moreover, the optimal/adequate doses of antihypertensive drugs may differ between individuals, not only in terms of efficacy, but also in terms of tolerability. Furthermore, none of the guidelines clearly stress that preferential use should be made of long-acting drugs, which are more forgiving in case of a missed dose, or of fixed-dose triple combination therapy in a single pill, to reduce the daily pill burden, thereby favoring adherence to treatment (see later). Finally, the publication of the PATHWAY2 (Prevention And Treatment of Hypertension With Algorithm based therapY) and SPRINT (Systolic blood PRessure INtervention Trial) studies in 2015 may influence the definition of RHTN by (1) including the combination of a low-dose spironolactone with the above-mentioned triple therapy, and (2) favoring the use of lower BP thresholds, respectively.
Prevalence and Incidence of Resistant Hypertension
It is difficult to estimate the prevalence of true RHTN. This prevalence is clearly lower than that of “apparent” RHTN, which may be attributed to inadequate office BP measurement, white coat hypertension, the use of nonoptimal combinations of drugs at nonadequate doses, or nonadherence to treatment. Its estimation thus depends on multiple factors, including the clinical setting (general population, tertiary referral center, clinical trial), the time frame of evaluation, the classes and optimal doses of antihypertensive treatment used, the exclusion or retention of patients not complying with treatment, the method of BP measurement, and the BP threshold selected. In the 2003 to 2008 National Health and Nutrition Examination Surveys (NHANES) survey, 8.9% of the U.S. adults with hypertension included in the survey (12.8% of those treated) were classified as resistant because their office BP was 140/90 mm Hg and they reported using antihypertensive drugs from three different classes, or because they reported using antihypertensive drugs from four different classes regardless of BP. The prevalence of apparent RHTN increased from 15.9% of treated patients in 1998 to 2004 to 28% of treated patients in 2005 to 2008. An analysis of electronic record data from more than 200 community-based clinics in the U.S. between 2007 and 2010 showed that 31.5% of 468,877 hypertensive patients had uncontrolled BP (office BP >140/90 mm Hg), but that only 9.5% were treated with three or more antihypertensive drugs. The triple-drug combination therapy was considered optimal in only 4.7% of the total study population.
Unsurprisingly, the prevalence of RHTN is higher in tertiary referral centers than elsewhere. RHTN was confirmed by ambulatory BP monitoring (ABPM) in 19.3% of the 1034 patients aged 18 to 80 years hospitalized at a university hospital tertiary referral center in Paris. Another way of estimating the prevalence of RHTN is to analyze the results of randomized controlled trials. A meta-analysis of 20 observational studies and randomized controlled trials estimated the prevalence of RHTN at 13.72% (95% confidence interval [CI]:11.19% −16.24%) for the observational studies and 16.32% (95% CI: 10.68% −21.95%) for the randomized controlled trials. Finally, the prevalence of RHTN is highest in patients with a low glomerular filtration rate (GFR) and albuminuria (i.e., chronic kidney disease), in which it may be as high as 50%. In a population-based cohort, the prevalence of refractory hypertension, the extreme phenotype of RHTN, defined as uncontrolled BP (≥140/90 mm Hg) on five or more antihypertensive drugs, was 3.6% in participants with RHTN (n = 2144) and 41.7% in participants taking drugs from five or more antihypertensive drug classes. In all these settings, the prevalence of RHTN is probably overestimated because it is generally defined on the basis of office BP measurements. The systematic use of ABPM in a Spanish registry including more than 8000 patients with RHTN defined on the basis of an office BP of at least 140/90 mm Hg despite treatment with three antihypertensive drugs showed that 37.5% of these patients actually had pseudoresistant hypertension (HTN) because of (1) a “white coat phenomenon” causing isolated office HTN or (2) a poor method of office BP measurement. These results suggest that out-of-office BP measurements (i.e., ABPM or self-BP measurement at home) should be used systematically for the definition and confirmation of RHTN, to exclude pseudoresistance.
Data on the incidence of RTHN are scarce. A single retrospective cohort study of two integrated health plans evaluated the incidence of RHTN in a population of 205,750 patients with newly diagnosed hypertension. The incidence of RHTN was 16.2% (1.9% of the initial cohort) after a median follow-up of 1.5 years among the patients taking three or more antihypertensive drugs for at least 1 month for whom follow-up office BP measurements were available (n = 24,499). In a randomized controlled trial assessing the BP-lowering efficacy of single-pill, fixed-dose, triple combination therapy, 29% of the patients treated with the highest daily dose (25 mg hydrochlorothiazide/320 mg valsartan/10 mg amlodipine) for 8 weeks still had an office BP above 140/90 mm Hg.
Factors Contributing to Resistant Hypertension
Characteristics of Patients With Resistant Hypertension
RHTN is significantly associated with older age, being male, African origin, initial BP at the diagnosis of hypertension, highest BP ever reached during the patient’s lifetime, frequent outpatient visits, obesity, diabetes, a Framingham 10-year coronary risk greater than 20%, chronic kidney disease, and the presence of target organ damage. Obstructive sleep apnea (OSA) is also frequently associated with hypertension, particularly in obese patients, and is almost four times more frequent in patients with RHTN than in patients with controlled hypertension. This higher prevalence may reflect the higher frequency of obesity, excess aldosterone, or sympathetic overdrive in these patients. OSA should be suspected in obese patients with a short neck who snore and present daytime sleepiness and frequent night-time awakenings, in whom apnea is witnessed. The Epworth questionnaire is used to screen for OSA, which is diagnosed by polysomnography.
RHTN is also associated with a higher prevalence of end-organ damage, including left ventricular hypertrophy (LVH) carotid intima–media thickening, microalbuminuria, and retinal lesions, than well-controlled hypertension. The frequent association of target organ damage and the clustering of cardiovascular risk factors in patients with RHTN accounts for the higher risk of a major cardiovascular event in these patients and, thus, of a poor short-term prognosis. Indeed, after a median follow-up of 3.8 years, patients with incident RHTN had a higher risk of cardiovascular events (adjusted hazard ratio [HR], 1.47; 95% CI, 1.33 to 1.62) than those with controlled hypertension. The long-term risk of major adverse events, including death, is much higher in women displaying signs of myocardial ischemia and RHTN (HR, 1.77; 95% CI, 1.26 to 2.49) than in those with controlled hypertension. In patients with chronic kidney disease, RHTN is also associated with a higher cardiovascular risk (HR: 1.98, 95% CI: 1.14 to 3.43) and renal events (HR: 2.66, 95% CI: 1.62 to 4.37).
Consequently, patients with RHTN report a higher degree of concern about their high BP levels and a greater emotional burden, including a poorer perception of their overall health, than patients with uncontrolled hypertension.
Lifestyle Factors
Excessive salt consumption promotes hypervolemia, which is frequently observed in patients with RHTN, and decreases the effectiveness of diuretics and RAS blockers. The effects of excessive salt consumption are particularly marked in elderly patients, in those of African origin and in those with chronic kidney disease. Daily salt intake can be assessed by food records, questionnaires or by measuring sodium excretion over a 24-hour period.
Alcohol abuse is also a major factor underlying poor BP control through a direct vasoconstrictive effect mediated, at least in part, by sympathetic overdrive (see later). It is also associated with being overweight and low compliance with treatment, both of which also contribute to RHTN (see later).
Finally, BP increases steadily with body mass index (BMI). Being overweight or obese is associated with significantly poorer BP control. Overweight and obesity are frequently observed in patients with RHTN.
Nonadherence to Antihypertensive Treatment
Nonadherence to antihypertensive medications and lifestyle measures is a key factor underlying resistance to treatment and this remains a major public health challenge. Nonadherence is associated with poor cardiovascular prognosis. Several disease-related, physician-related, treatment-related, and patient-related factors, either alone or in combination, promote nonadherence to treatment and are common to all chronic diseases, including hypertension. These factors include (1) a lack of symptoms in patients with hypertension; (2) inadequate patient education leading to a poor understanding of the BP goal to be achieved, the treatment strategy, the balance between the benefits and risk of treatment, and the need for life-long treatment; (3) cognitive impairment, particularly in elderly patients or in patients with a history of stroke or other causes of dementia; (4) the use of complex antihypertensive drug regimens, particularly if combined with treatments for diabetes, dyslipidemia, or other comorbid conditions, increasing the pill burden and the number of drug intakes per day ; (5) illegible prescriptions; (6) the occurrence of drug-related side effects, which can alter quality of life, particularly in patients who were previously asymptomatic (e.g., coughing with ACE inhibitors, flushing or leg edemas with CCBs, sexual dysfunction with diuretics or beta-blockers, gout with diuretics, symptomatic hypotension etc.); and (7) a poor health care provider-patient relationship including (a) too little time spent with patients, (b) a lack of explanation about hypertension and the benefits of treatment, or (c) a lack of consideration of the patient’s complaints about drug-related side effects on the part of the physician. Psychosocial factors, perceptions of treatment concerns, depression, excessive alcohol consumption, a lack of belief in the efficacy of the treatment, practical barriers to treatment and poor access to busy nonempathetic physicians, high drug and appointment costs, a lack of health insurance, unemployment, low income, and poor compliance with lifestyle changes have also been associated with poor compliance with drug treatment. It is important to take the patient’s viewpoint and beliefs about the causes and effects of hypertension and its treatment into account. A systematic review of 53 studies from 16 countries showed that a large proportion of patients (1) felt that their hypertension was principally caused by stress and, therefore, did not believe that treatment was required once the stress had been relieved, (2) were reluctant to use antihypertensive treatment, and (3) had concerns about side effects and the risk of drug addiction.
Various direct and indirect methods for assessing adherence to drug treatments have been developed. The direct methods include the direct observation of treatment intake in a medicalized setting, such as a BP clinic, the detection of a drug or its metabolite in blood or urine, or the determination of a pharmacodynamic marker. Indirect methods include patient questionnaires such as the eight-item Morisky questionnaire (MMAS-8), self-reports, patient diaries, pill counts, prescription refill rates, the assessment of patient clinical response, electronic drug monitoring systems, and the determination of physiological markers. Pharmacodynamic markers of exposure to a given antihypertensive treatment include, for example, bradycardia in patients on beta-blockers, hyperuricemia or gout in patients on diuretics, increases in plasma renin concentration in patients on diuretics or RAS blockers, increases in urine N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) concentration in patients on ACE inhibitors, and drug-related side effects.
The prevalence of nonadherence to antihypertensive treatment in patients with RHTN remains high when assessed by toxicological analyses based on high-performance or ultra-high-performance liquid chromatography with tandem mass spectrometry (HP LC-MS/MS) to detect the presence of a given prescribed drug in plasma or urine samples. About 50% of patients attending specialized BP clinics for RHTN have been found not to be complying with the prescribed drug regimen on the basis of a lack of detection of one or more of the multiple antihypertensive drugs prescribed in plasma or urine. However, the nondetection of a drug is not sufficient to conclude with certainty that the patient is not complying with antihypertensive treatment. Alterations or between-subject variability in drug pharmacokinetics (absorption, distribution, metabolism, or elimination) related to (1) associated comorbid conditions (e.g., gastrointestinal bypass, etc.), (2) genetic factors, including polymorphisms of genes encoding drug-metabolizing enzymes or transporters, (3) drug-drug interactions (involving transport proteins, the inhibition or induction of enzymes, such as cytochromes P450, especially CYP3A4, or of drug transporters, such as P-glycoprotein, etc.), or (4) interference with food (e.g., high sodium intake, grapefruit juice, herbal teas ) may strongly influence the pharmacokinetics of antihypertensive drugs, resulting in their nondetection in biological samples. Conversely, the detection of significant quantities of drugs in plasma or urine is not sufficient to confirm optimal adherence to treatment on a daily basis. Indeed, patients often display better adherence to treatment during the week before and the week immediately after medical visits. This phenomenon, known as “the toothbrush effect,” may be amplified if the patients are aware that regular drug monitoring is carried out at each visit.
In conclusion, each method for measuring treatment adherence has advantages and disadvantages, and the method chosen depends on availability in the clinical setting. Some methods are easy to use (standardized questionnaire, determination of physiological variables), whereas others, such as drug detection or the direct observation of treatment intake, are much more difficult to implement.
Multiple modes of intervention are required to improve compliance, but their long-term efficacy has yet to be clearly established. These modes of intervention include improving the physician-patient relationship, empathy on the part of the physician when the patients are describing their complaints, patient education, the provision of reminders in the packaging of the drugs, frequent clinic visits, the self-monitoring of BP, patient empowerment and self-management, text messaging, the use of single-pill combination treatments, and assistance from other health care providers and families. However, the complexity of these interventions may make them difficult to implement in everyday practice, in which physicians are subject to a number of constraints potentially limiting the time available.
Self-BP monitoring at home may improve the patient’s compliance with drug treatment, but clinical trials have reported mixed benefits. In 6 of 11 randomized controlled trials included in a systematic review, the use of “multimodal complex” interventions involving self-BP measurement was associated with significant improvements in adherence to treatment. Treatment adherence was measured by pill-counting, pharmacy refill rates, self-reporting, and electronic monitoring devices, but not by LC-MS/MS. A meta-analysis of 23 randomized controlled trials including 7037 patients showed that the teletransmission of self-BP measurements resulted in a lower BP (SBP lower by 4.7 mm Hg and DBP lower by 3.3 mm Hg) than usual care. This approach thus improved BP control, despite the absence of a significant influence on adherence to treatment.
Self-BP management coupled to self-BP monitoring may improve adherence to treatment further, as shown in the TASMIN-SR randomized controlled trial. This trial compared self-BP management with the self-titration of antihypertensive medication, using a precise treatment algorithm with usual care in 450 patients with a high cardiovascular risk. After 12 months, a difference in BP of 9.2/3.1 mm Hg in favor of the self-management group was reported.
These studies did not specifically include patients with RHTN or monitor compliance with treatment, but it seems likely that the teletransmission of self-monitoring BP measurements and the self-titration of medication improve BP control through better compliance with treatment. However, the long-term efficacy of this approach and its external applicability to all patients remains questionable. This approach probably requires the active and motivated participation of well-educated and trained patients without cognitive deficiencies.
Support from health professionals, including pharmacists and nurses, counseling, motivational support or cognitive behavioral therapy, and additional help from the family may also increase compliance with treatment. Technological interventions for education, counseling, self-monitoring, feedback, and electronic reminders are increasingly being used, but the evidence concerning their efficacy for improving compliance with treatment is inconsistent.
The use of once-daily single-pill double or triple combination therapies reduces pill burden, simplifies treatment regimens without increasing the incidence of side effects, and has been shown to improve compliance with treatment. All of this should, in turn, help patients to reach and maintain their target BP and to achieve the short-term and long-term treatment goal of cardiovascular risk reduction. Finally, the use of electronic pill monitors improves BP control, probably by improving compliance with treatment, but these devices are expensive and not readily available outside of clinical trials.
Clinical Inertia
Clinical inertia is defined as a lack of treatment intensification in a patient whose treatment goals have not been attained. This inertia is another major factor contributing to inadequate BP control and other associated risk factors. It was first assessed in 1998, in a Veterans Administration study, in which the clinical inertia rate reached 75%. Clinical inertia is, unfortunately, frequent. In the nationally representative CardioMonitor 2004 survey, treatment was intensified for uncontrolled hypertension at 32% of patient visits in the U.S., and at 14% to 26% of patient visits in European countries. An analysis of electronic record data for patients at 200 U.S. clinical sites showed that only 4.7% of the hypertensive patients included in the analysis were prescribed optimal triple therapy including a diuretic and at least two other BP drugs at a dose at least 50% the maximum dose recommended for hypertension. This low proportion highlights deficiencies in the prescription of optimal triple therapy to hypertensive patients by health care providers, despite the need for this treatment.
There are many reasons for this clinical inertia and a systematic review identified 293 potential barriers to compliance with guidelines for physicians. The most frequently cited reasons for an absence of antihypertensive treatment intensification related to (1) physicians being satisfied with the change in BP achieved with their prescription, despite the persistence of systolic BP above the threshold in their patients ; (2) the number of associated cardiovascular risk factors and comorbid conditions to be taken into account simultaneously ; (3) the side effects of antihypertensive treatments reported by the patients during the visit ; and (4) the lack of time to find a well-tolerated drug regimen.
The use of strict protocol-based treatment algorithms may overcome clinical inertia by providing health care providers with simple, accessible prescription rules, as shown in the Canadian Simplified Treatment Intervention To Control Hypertension (STITCH) cluster-randomized, controlled trial. Indeed, this trial showed that a simplified antihypertensive algorithm including (1) initial low-dose fixed-dose combination therapy with a diuretic and a RAS blocker; (2) the uptitration of combination therapy; (3) the addition and uptitration of a calcium channel blocker, and (4) the addition of a non–first-line antihypertensive agent, was superior to guideline-based practice for achieving a target office BP < 140/90 mm Hg after 6 months of follow-up (64.7% versus 52.7%; respectively, p = 0.026). Such algorithms can be incorporated into clinical support decision tools to reduce clinical inertia, but the resulting hypothetical improvement in BP control in patients with RHTN is uncertain. Indeed, in the Renal Denervation for Hypertension (DENERHTN) trial, only 18% of the patients with RHTN on standardized triple therapy randomized to the control group achieved BP control (<130/80 mm Hg on 24-hour ABPM) despite treatment according to a strict algorithm including the sequential addition of 25 mg spironolactone, 10 mg bisoprolol, 5 mg prazosin, and 1 mg rilmenidine at monthly visits, according to home BP results.
Screening for Secondary Hypertension
The prevalence of secondary hypertension is much higher in patients with RHTN. The frequency of secondary hypertension has been estimated at 5% in the general population, but may be as high as 10% to 20% in patients with RHTN. Up to 50% of patients with RTHN referred for renal denervation may have secondary hypertension.
Patients with confirmed RHTN should thus be screened for secondary hypertension. Additional reasons to screen for secondary hypertension are:
- 1.
Early hypertension onset (i.e., before the age of 30 years) in patients without other risk factors (family history, obesity, etc.)
- 2.
Grade III hypertension (>180/110 mm Hg) or hypertensive emergencies
- 3.
Sudden increase in BP in a previously stable patient
- 4.
Nondipping or reverse dipping during 24-hour ambulatory BP monitoring
- 5.
Presence of target organ damage (LVH, hypertensive retinopathy, etc.)
Some etiologies of secondary hypertension are common, whereas others are much less common as indicated in Table 43.2 .
| Common Causes | |
| Primary hyperaldosteronism (reported prevalence: 7% to 20%) |
|
| Renal artery stenosis (reported prevalence: 2% to 24%) |
|
| Renal parenchymal disease (reported prevalence: 1% to 2%) |
|
| Uncommon (Reported Prevalence: <1%) | |
| Pheochromocytoma |
|
| Thyroid diseases |
|
| Cushing syndrome |
|
| Other rare causes of endocrine hypertension |
|
| Urological causes |
|
| Coarctation of the thoracic or abdominal aorta |
|
| Intracranial tumor |
|
Screening for Drug-Induced Hypertension
Drug-induced RHTN is often underestimated. Several drugs prescribed for conditions other than hypertension can increase BP per se or blunt the BP-lowering effect of antihypertensive treatments ( Table 43.3 ). Some drugs induce sodium retention associated with extracellular volume expansion. Others directly or indirectly activate the sympathetic nervous system, act directly on arterial smooth muscle tone, or have no clear mechanism of action (for review, see references ). Finally, some drugs may directly or indirectly interfere with the pharmacokinetic and/or pharmacodynamic profile of the antihypertensive drug. A systematic examination of the recommendations in 12 UK national clinical guidelines revealed 32 potentially serious drug-disease interactions between drugs recommended for type 2 diabetes and the other 11 conditions considered: 6 for drugs recommended for depression and 10 for drugs recommended for heart failure. Careful evaluation of the drugs taken by patients for conditions other than cardiovascular diseases, through the completion of a standardized questionnaire or the use of drug-drug interaction-checking websites, can help to identify drug-related hypertension.
| Drugs or substances associated with apparent mineralocorticoid excess or activation of the renin angiotensin system |
|
| Drugs or substances with direct vasopressor properties |
|
| Drugs or substances activating the sympathetic nervous system |
|
| Drugs or substances with diverse mechanisms of action |
|
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