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Drug treatment of hypertension 

Drug treatment of hypertension
Chapter:
Drug treatment of hypertension
Author(s):

Michel Burnier

, Sverre Kjeldsen

, Anthony Heagerty

, and Bryan Williams

DOI:
10.1093/med/9780198784906.003.0569_update_001

Update:

Updates added due to the publication of the 2018 European Society of Cardiology/European Society of Hypertension Guidelines for the management of arterial hypertension.

Updated on 23 April 2020. The previous version of this content can be found here.
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date: 03 March 2021

This chapter provides the background information and detailed discussion of the data for the following current ESC Guidelines on: Drug treatment of hypertension management of arterial hypertension - https://academic.oup.com/eurheartj/article/39/33/3021/5079119#133825593

Summary

The prescription of antihypertensive drugs to achieve the recommended target blood pressures remains the main step of the management of hypertensive patients. Today, there is strong evidence from randomized controlled trials that antihypertensive drug classes proposed to treat hypertension are superior to placebo in reducing cardiovascular mortality and morbidity. In terms of cardiovascular protection, differences between drug classes exist but they are relatively modest. Indeed, the reduction of blood pressure per se remains the prominent mechanism whereby antihypertensive drugs provide cerebral, cardiac, renal, and vascular benefits. According to more recent guidelines, three drug classes are recommended as first-line therapy: blockers of the renin–angiotensin system, diuretics, and calcium antagonists. The use of beta blockers has been restricted to the treatment of hypertension associated with cardiac co-morbidities such as post-myocardial infarction or coronary heart disease. Many studies have demonstrated that drug classes can be combined successfully and nowadays, it is strongly recommended to use single pill combinations containing two or three antihypertensive drugs. This simplifies the treatment regimen, increases the efficacy, and promotes the long-term adherence and persistence, this latter being the major challenge of drug therapy for hypertension.

Introduction

Besides the implementation of lifestyle modifications, drug therapy remains the cornerstone of the management of hypertensive patients in order to decrease blood pressure (BP) to the recommended targets and to prevent the occurrence of disabling cardiovascular events. Reduction of BP with antihypertensive drugs has been shown to be effective in preventing cardiovascular events in all forms of hypertension including isolated diastolic hypertension, combined systolic–diastolic hypertension, and isolated systolic hypertension, common in elderly patients.

Today it is well recognized that the benefits of antihypertensive treatment are due primarily to lowering of BP per se, and are largely independent of the specific properties of drugs employed. Thus, when compared to placebo, all classes of antihypertensive drugs are accompanied by significant reductions of major cardiovascular events provided they lower BP. Nevertheless, in some specific conditions and for some clinical endpoints, relevant differences between drug classes do exist. This has been confirmed in several meta-analyses including the most recent one by Thomopoulos and colleagues who examined all randomized controlled trials published since 1966.1,2,3,4 At this stage, however, one has to acknowledge that drug classes have not always been compared to all other classes and that comparisons are often not directly between two classes, but rather between two treatment regimens. In addition, meta-analyses do not always take into account small but non-negligible differences in achieved BP, which may play an important role in the incidence of events. Lastly, the clinical benefits of each class should always be balanced by the burden of side effects and adverse drug events that may develop which any antihypertensive class.

The main objectives of the pharmacological treatment of hypertension is to prescribe patients a treatment that is effective in achieving target BP, well tolerated, economically affordable, and simple to take, thus supporting long-term persistence. To this purpose, four major classes of antihypertensive drugs are available and commonly prescribed in most countries of the world: diuretics, calcium antagonists, blockers of the renin–angiotensin system (RAS), and beta blockers. In this chapter, we shall (1) review some of the characteristics of each class of hypertensive drugs in terms of efficacy and tolerability, (2) present the evidence-based impact of the drug classes on cardiovascular mortality and cardiovascular complications, and (3) discuss their usefulness in monotherapy or combination therapy. Finally, we shall discuss the various therapeutic approaches that can be considered in the medical management of essential and apparent resistant hypertension.

Antihypertensive drugs for the medical treatment of hypertension

Diuretics

Diuretics have been a cornerstone of antihypertensive treatment since the 1970s. They are used in preventing stroke and coronary artery disease and are particularly effective in reducing the risk of heart failure. Various subgroups of diuretics can be used in the management of hypertension, that is, hydrochlorothiazide, chlorthalidone, indapamide, aldosterone antagonists (see chapter 5.2), and loop diuretics. The use of the latter is generally limited to patients with a limited glomerular filtration rate (estimated glomerular filtration rate <45 mL/min/1.73m2).

In recent years, whether diuretics such as chlorthalidone or indapamide should be used in preference to conventional thiazide diuretics such as hydrochlorothiazide has been the subject of many discussions. A systematic review and network meta-analyses of randomized trials in which one arm was based on either hydrochlorothiazide or chlorthalidone, has suggested that chlorthalidone is superior to hydrochlorothiazide in preventing cardiovascular events.5 In a population-based cohort study involving 29,873 older hypertensive patients, chlorthalidone was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of hospitalization with hypokalaemia or hyponatremia.6 One has to mention that meta-analyses claiming that hydrochlorothiazide has a lesser ability to reduce clinical outcomes than chlorthalidone or ambulatory BP than other agents are confined to a limited number of trials, and do not include head-to-head comparisons of different diuretics (no large randomized study is available).5,7 In the MRFIT (Multiple Risk Factor Intervention Trial) study, chlorthalidone and hydrochlorothiazide were not compared by randomized assignment, and chlorthalidone was often used at higher doses than hydrochlorothiazide.8 Indapamide was found to be more effective in reducing BP and to have lesser metabolic side effects than hydrochlorothiazide in a systematic review of 14 trials comparing hydrochlorothiazide with indapamide and chlorthalidone on antihypertensive potency or metabolic effects.9 Unfortunately no data on clinical endpoints were available in these trials.

Spironolactone has been found to have beneficial effects in heart failure (37.23)10 and has never been tested in randomized controlled trials in uncomplicated essential hypertension. The PATHWAY-2 (Optimum Treatment for Drug-Resistant Hypertension) study conducted in patients with resistant hypertension has shown that spironolactone was superior to placebo, bisoprolol, and doxazosin, in lowering BP (Figure 44.7.1) and achieving BP targets.11 Thus, spironolactone can be used as a fourth-line drug in this clinical situation as will be discussed in ‘Treatment strategy in resistant hypertension’. Spironolactone is the drug of choice to treat patients with primary hyperaldosteronism. Eplerenone has also shown a protective effect in heart failure,12 and can be used as an alternative to spironolactone in case of intolerance or side effects. Diuretics can be combined with all other major classes of antihypertensive. Because of their natriuretic properties, they are particularly useful when combined with a blocker of the RAS as sodium depletion potentiates the antihypertensive efficacy of blockers of the RAS (see chapter 5.1). This is the reason why so many drug combinations associate a diuretic and a RAS blocker. Surprisingly the results of the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial showed that the association of hydrochlorothiazide with an angiotensin-converting enzyme (ACE) inhibitor is less effective in reducing cardiovascular outcomes than the association of the same ACE inhibitor with a calcium antagonist despite an almost identical BP control.13 So far, the interesting findings of the ACCOMPLISH trial have not been replicated in different populations. In the COLM trial, 5141 high-risk hypertensive patients aged 65–84 years were randomized to receive olmesartan combined with either a calcium channel blocker (amlodipine or azelnidipine) or a low-dose diuretic for at least 3 years.14 In this trial, the reduction in BP was comparable with the two arms and there was no difference in the occurrence of cardiovascular endpoints between the olmesartan/hydrochlorothiazide and the olmesartan/calcium antagonist combinations.

Figure 44.7.1 Comparative effect of spironolactone, doxazosin, and bisoprolol in resistant hypertension (PATHWAY-2 study). CI, confidence interval; SBP, systolic blood pressure.

Figure 44.7.1 Comparative effect of spironolactone, doxazosin, and bisoprolol in resistant hypertension (PATHWAY-2 study). CI, confidence interval; SBP, systolic blood pressure.

Thus, the evidence provided by ACCOMPLISH does not appear to bear sufficient weight to exclude diuretics from first-line choice alone or in combination with a blocker of the RAS.

Calcium antagonists

Calcium antagonists have been classified in different ways. The most widely used is based upon the structural differences distinguishing diltiazem, verapamil, and dihydropyridines. The major difference between dihydropyridines and non-dihydropyridines resides in their cardiac and vascular selectivity. As shown in Table 44.7.1, several generations of dihydropyridine calcium antagonists have been developed, the latest ones having a higher vascular selectivity and an improved tolerability profile leading to less frequent peripheral oedema. Today, the largest group of calcium antagonists used in the management of hypertension is represented by dihydropyridines. Because verapamil has a weaker vasodilator effect than diltiazem and dihydropyridines, its use in hypertension is less common although some trials with this agent have been conducted and the drug has a recognized indication for hypertension. Due to its negative inotropic and chronotropic effects, verapamil is more frequently prescribed in cardiac indications such as angina pectoris or atrial dysrhythmias. Diltiazem also has negative inotropic and chronotropic properties but has a greater vasodilator effect than verapamil. For these reasons, this compound is used equally in hypertension and in cardiac indications. In general, dihydropyridine calcium antagonists have a much higher selectivity for vascular smooth muscle cells than for cardiac myocytes. Therefore, they induce a major vasodilatation of vessels and hence are very effective in lowering BP. However, recent investigations have suggested that in addition to their ability to vasodilate vessels, dihydropyridine calcium antagonists have some pleiotropic effects such as improving endothelial function or reducing oxidative stress, which probably participate in the clinical benefits of calcium antagonists in large clinical trials.15

Table 44.7.1 Classification of calcium channel blockers

Class

Name

Half-life (h)

Clinical indication

Phenylalkylamine

Verapamil

6–8

Hypertension, angina pectoris

Slow-release forms

12–24

Atrial dysrhythmias

Benzothiazepine

Diltiazem

6–12

Hypertension, angina pectoris

Slow release forms

18–24

Atrial dysrhythmias

Dihydropyridines

First generation

Nifedipine

0.2–1

Hypertension, angina pectoris

Slow release forms

Up to 24

Second generation

Nicardipine

6–8

Hypertension

Slow release form

8–12

Isradipine

8–12

Hypertension

Slow release form

12–18

Felodipine

11–16

Hypertension

Amlodipine.

>44

Hypertension

Angina pectoris

Nitrendipine

10–22

Hypertension

Nisoldipine

7–12

Hypertension

Third generation

Lercanidipine

8–10

Hypertension

Lacidipine

12–19

Hypertension

Manidipine

5

Hypertension

Cilnidipine

2.5

Hypertension

Benidipine

2

Hypertension

Nilvadipine

15–20

Hypertension

Nimodipine

1–2

Subarachnoid haemorrhage

Clevidipine

0.25

Hypertensive emergencies

According to the latest comprehensive meta-analyses, calcium antagonists are more effective than placebo in preventing stroke, cardiovascular death, and all-cause mortality.2,3 For the prevention of stroke they appear to be superior to beta blockers and blockers of the RAS such as ACE inhibitors and angiotensin receptor blockers (ARBs). However, they appear to be clearly inferior to other classes in preventing heart failure. In a previous meta-analysis,16 calcium antagonists reduced new-onset heart failure by about 20% compared with placebo. Of note, in all trials17,18,19,20 in which the design permitted or prescribed the simultaneous use of diuretics, beta blockers, or ACE inhibitors, calcium antagonists were not inferior to comparative therapies in preventing heart failure.

Most randomized controlled trials have been performed using dihydropyridine calcium antagonists and only few of them were done with non-dihydropyridines (diltiazem and verapamil). In the meta-analysis by Thomopoulos and colleagues, a specific analysis was done to compare the two subclasses of calcium antagonists.3 The higher risk of heart failure was significant with either subclasses, and quantitatively similar. Yet, the lower risk of stroke, cardiovascular, and all-cause death was significant only with dihydropyridines.

Blockers of the renin–angiotensin system

RAS blockers include ACE inhibitors, ARBs, and renin inhibitors (see chapter 5.1). Today, they are among the most widely used antihypertensive drugs, at least in developed countries. The results of several meta-analyses have indicated that RAS blockers may be somewhat inferior to calcium antagonists and diuretics in preventing stroke.2,21,22 There have been also many discussions based on meta-analyses on possible differences between ACE inhibitors and ARBs in their abilities to reduce the risk of coronary heart disease and cardiovascular mortality in favour of ACE inhibitors.23 The results of ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint trial), the only direct head-to-head comparison of an ACE inhibitor (ramipril) and an ARB (telmisartan), actually failed to demonstrate any statistical between the ACE inhibitor and the angiotensin receptor antagonist as far as incidence of major cardiac outcomes, stroke, and all-cause death is concerned.24 The only significant difference reported in this trial was the better tolerability profile of the ARB. Among well-known, ancillary properties of ACE inhibitors and ARBs, are the peculiar effectiveness in reducing proteinuria25,26,27 retarding CKD progression,26,28,29 improving outcomes in chronic heart failure,30 and preventing new-onset heart failure.31

Aliskiren, a direct inhibitor of renin, is also available for treating hypertensive patients both as monotherapy and in a combination with a diuretic or a calcium antagonist. When used alone aliskiren lowers systolic BP and diastolic BP in younger and elderly hypertensive patients32; it has a greater antihypertensive effect when given in combination with a thiazide diuretic, or a calcium channel blocker and that prolonged administration in combination treatment can have a favourable effect on asymptomatic organ damage such as urinary protein excretion or on a prognostic biomarkers for heart failure such as B-type natriuretic peptides.33 No trial is available on the effect of aliskiren on cardiovascular or renal morbid and fatal events in hypertension.

After the results of the ONTARGET24 and ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) trials,34 RAS blockers (ACE inhibitor, ARB, or direct renin inhibitor) should not be combined because of a higher risk of adverse events such as renal complications (such as end-stage renal disease and renal death), hyperkalaemia, and hypotension. Therefore any combinations of two RAS blockers remain a formal contraindication.

Beta blockers

Since the availability of propranolol, which represents the prototype of beta blockers for clinical studies, several generations of beta blockers with various pharmacological properties have been developed and are now available on the market. As summarized in Table 44.7.2, beta blockers can now be classified into three generational categories according to their pharmacological characteristics (see also chapter 5.3).

Table 44.7.2 Classification of beta blockers according to their main properties

Generation

Properties

Drugs

First

Non-selective

Propranolol, timolol, pindolol

No vasodilatation

Nadolol, sotalol, penbutolol

Second

β‎1-selective without vasodilatation

Atenolol, bisoprolol, metoprolol, betaxolol, esmolol

β‎1-selective with vasodilatation

Acebutolol

Third

β‎1-selective with vasodilatation

+ alpha blocking

Bucindolol, labetalol, carvedilol

+ nitric oxide donation

Nebivolol, carvedilol

In recent years, beta blockers have been disregarded as first-line therapy of hypertension in many guidelines essentially because they were found to be less effective than other classes in preventing stroke and this was confirmed in the latest meta-analyses.2 This lower effectiveness of beta blockers2,16 has been attributed to their lower ability to reduce central systolic BP and pulse pressure.35 Nevertheless, the meta-analysis by Law and colleagues16 has shown beta blocker-initiated therapy to be (1) equally effective in preventing coronary outcomes as the other major classes of antihypertensive agents and (2) highly effective in preventing cardiovascular outcomes in patients with a recent myocardial infarction and those with heart failure. A similar incidence of cardiovascular outcomes between beta blockers and other drug classes has now been reported in several meta-analyses.3,36 Results of a cohort study have suggested that beta blockers may lower mortality in patients with chronic obstructive pulmonary disease and cardiovascular diseases.37

Beta blockers appear to be somewhat less effective than RAS blockers and calcium antagonists in regressing or delaying organ damages, such as left ventricular hypertrophy, carotid intima–media thickness, aortic stiffness, and small artery remodelling.38 Finally, the limitations of traditional beta blockers may not be shared by the newer beta blockers with vasodilating or alpha-blocking properties, such as celiprolol, carvedilol, and nebivolol. These latter drugs lower BP by reducing systemic vascular resistances rather than decreasing cardiac output.

They were found to reduce central pulse pressure and aortic stiffness39,40,41 and to have less impact on metabolic and lipid parameters than earlier beta blockers even when added to hydrochlorothiazide.42,43,44 Yet, there is no clear evidence today that these newer beta blockers are superior to earlier beta blockers or to other drug classes in preventing cardiovascular events in hypertension as randomized controlled trials with these agents have been conducted essentially in heart failure and not in arterial hypertension.

Other antihypertensive agents

Centrally active agents and alpha-receptor blockers are also effective antihypertensive agents (see also chapter 5.3). Today they are most often used in multiple drug combinations as fifth or sixth line of therapy. The alpha blocker doxazosin has effectively been used as third line therapy in the ASCOT trial but the trial design differed significantly from clinical practice.20 This will be further discussed in the section on resistant hypertension.

Tolerability profile of antihypertensive drugs

Besides their ability to lower BP and to reduce cardiovascular outcomes, it is important to consider the tolerability profile of antihypertensive drugs as tolerability is the major determinant of the long-term persistence on therapy. Actual antihypertensive agents have a much better tolerability profile than earlier drugs with the development of new generations within classes. For most classes, the incidence of adverse effects is dose dependent. This is true for diuretics, beta blockers, and calcium antagonists. Therefore, increasing the dose may not always be the right strategy to adapt therapy. One exception is blockers of the RAS (ACE inhibitors and ARBs). With these agents, the incidence of side effects is not dose dependent. The major side effects of antihypertensive drugs are summarized in Table 44.7.3. In one meta-analysis by Thomopoulos and colleagues,45 all classes of drugs significantly increased discontinuations for adverse events over those occurring on placebo and ARBs were the only ones to be equivalent to placebo.

Table 44.7.3 More frequent side effects of antihypertensive drugs:

Drug class

Changes in laboratory values

Clinical signs/symptoms

Diuretics

Thiazides

Hyponatraemia, hypokalaemia, hyperuricaemia, increase in cholesterol and LDL (not with indapamide) Increase in serum creatinine/urea Increased risk of diabetes

Weakness, muscle cramps, impotence, gout attacks, signs of hypovolaemia,

Antialdosterone diuretics

Hyperkalaemia

Gynaecomastia, dizziness, drowsiness, allergic reactions, sexual disturbances, nausea, vomiting

ACE inhibitors

Hyperkalaemia, increased serum creatinine

Persistent dry cough, angio-oedema dry mouth, nausea, rash

Angiotensin receptor blockers

Hyperkalaemia, increased serum creatinine

Nausea, dry mouth, abdominal pain

Calcium antagonists

Dihydropyridines

Peripheral oedema, headache, flushing, palpitations, constipation, nausea, gingival hyperplasia

Non-dihydropyridines

Bradycardia, headache, nausea (diltiazem), constipation (verapamil), arrhythmia, peripheral oedema

Beta blockers

Increased risk of diabetes (first- and second-generation beta blocker)

Increase triglycerides, decrease high density lipoprotein

Aggravation of asthma (with some BB), bradycardia, fatigue, insomnia, nightmares, reduced ability to exercise, rash, cold extremities, weight gain

Effects of antihypertensive drugs on morbidity and mortality based on randomized clinical trials

Trials based on mortality and morbidity endpoints comparing active treatment with placebo

Recommendations about pharmacological therapy must be supported by the analysis of the available evidence (as provided by large randomized trials based on fatal and non-fatal events) of the benefits obtained by antihypertensive therapy and of the comparative benefits obtained by the various classes of agents. This is the strongest type of evidence available. It is commonly recognized, however, that event-based randomized therapeutic trials have some limitations; among these, the special selection criteria of the subjects included, the frequent selection of high-risk patients in order to increase the power of the trial, so that the vast majority of uncomplicated and lower risk hypertensives are rarely represented; the therapeutic programmes that often diverge from usual therapeutic practice; and the stringent follow-up procedures enforcing patients’ compliance well beyond that obtained in common medical practice. The most important limitation is perhaps the necessarily short duration of a controlled trial, in most cases 4–5 years, whereas additional life expectancy and hence expectancy of therapeutic duration for a middle-aged hypertensive is of 20–30 years.46, 47

Long-term therapeutic benefits and long-term differences between benefits of various drug classes may also be evaluated by using intermediate endpoints (i.e. subclinical organ damage changes), as some of these changes have predictive value of subsequent fatal and non-fatal events. Several of the recent event-based trials have also used ‘softer’ endpoints, such as congestive heart failure (certainly clinically relevant, but often based on subjective diagnosis), hospitalization, angina pectoris, and coronary revascularization (highly subjected to local clinical habits and facilities). Treatment-induced alterations in metabolic parameters, such as serum low- or high-density lipoprotein cholesterol, serum potassium, glucose tolerance, induction or worsening of the metabolic syndrome, or diabetes, although they can hardly be expected to affect cardiovascular event incidence during the short term of a trial, may have some impact during the longer course of the patient’s life.

The results of trials performed in mostly systolic–diastolic hypertension and in elderly patients with isolated systolic hypertension have been included in meta-analyses.47,48,49,50,51,52 Antihypertensive treatment resulted in significant and similar reductions of cardiovascular and all-cause mortality in both types of hypertension. With regard to cause-specific mortality, Collins and colleagues observed a significant 45% reduction in fatal stroke (45%, p <0.001), but not in fatal coronary heart disease (−11%, not significant).53 This could be related to age, because coronary mortality was significantly reduced by 26% (p <0.01) in a meta-analysis on elderly with systolic–diastolic hypertension.54 Fatal and non-fatal strokes combined and all coronary events were significantly reduced in the two types of hypertension. The BPLTTC (Blood Pressure Lowering Treatment Trialists Collaboration)1 performed separate meta-analyses of placebo-controlled trials in which active treatment was initiated by a calcium antagonist or by an ACE inhibitor and showed the reductions in cardiovascular endpoints were similar to those found in the trials in which active treatment was based on diuretics or beta blockers. The proportional reduction of the cardiovascular risk appears to be similar in women and in men.55

Placebo-controlled trials have also addressed the effect of the ARBs losartan26 and irbesartan28 in hypertensive patients with type 2 diabetes and nephropathy. The studies concluded that the drug treatment was renoprotective but that there was no evidence of benefit in secondary cardiovascular endpoints (for the evaluation of which, however, these trials had insufficient power). It can be concluded from these placebo-controlled trials that BP lowering by angiotensin antagonists can also be beneficial, particularly in stroke prevention, and, in patients with diabetic nephropathy, in slowing down progression of renal disease. Similar results have been obtained with ACE inhibitors in non-diabetic nephropathy.56

The HYVET (Hypertension in the Very Elderly) Trial was the most recent placebo-controlled trial, performed in otherwise healthy old people above the age of 80 (averaging 83.6 years) with baseline BP of 173/91 mmHg.57 People with orthostatic hypotension were excluded, and then the active treatment arm was titrated with diuretic ± ACE inhibitor towards 140 mmHg, on average 15/6 mmHg lower than the placebo arm. The study was stopped early because all-cause mortality, stroke, and heart failure were lowered by active treatment.

Trials based on mortality and morbidity endpoints comparing treatments initiated by different drug classes

During the last decade, a large number of controlled randomized trials have compared antihypertensive regimens initiated with different classes of antihypertensive agents, most often comparing older (diuretics and beta blockers) with newer ones (calcium antagonists, ACE inhibitors, angiotensin receptor antagonists, alpha blockers), and occasionally comparing newer drug classes. Several trials with over 67,000 randomized patients compared calcium antagonists with older drugs.58 For none of the outcomes considered in this analysis, including all-cause and cardiovascular mortality, all cardiovascular events, stroke, myocardial infarction, and heart failure, did the p-values for heterogeneity reach statistical significance (0.12≤ p ≤0.95). The pooled odds ratios expressing the possible benefit of calcium antagonists over old drugs were close to unity and non-significant for total mortality, cardiovascular mortality, all cardiovascular events, and myocardial infarction.

Calcium antagonists provided slightly better protection against fatal and non-fatal stroke than old drugs. For the trials combined, the odds ratio for stroke reached formal significance (0.90, 95% confidence interval 0.82–0.98; p = 0.02) after CONVINCE (Controlled Onset Verapamil INvestigation of Cardiovascular Endpoints),59 the only large trial based on verapamil, was excluded. For heart failure, calcium antagonists appeared to provide less protection than conventional therapy, regardless of whether or not the CONVINCE trial was incorporated in the pooled estimates and this was confirmed in one of the meta-analysis by Thomopoulos and colleagues.3

Six trials with over 47,000 randomized patients compared ACE inhibitors with older drugs.60,61,62,63 The pooled odds ratios expressing the possible benefit of ACE inhibitors over conventional therapy were close to unity, and non-significant for total mortality, cardiovascular mortality, all cardiovascular events, and myocardial infarction. Compared with old drugs, ACE inhibitors provided slightly less protection against stroke, heart failure, and all cardiovascular events. For all-cause and cardiovascular mortality, stroke, and myocardial infarction, p-values for heterogeneity among the trials of ACE inhibitors were non-significant (0.16≤ p ≤ 0.90). In contrast, for all cardiovascular events and heart failure, heterogeneity was significant due to the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) findings.60 Compared with chlorthalidone, ALLHAT patients allocated to lisinopril had a greater risk of stroke, heart failure, and hence combined cardiovascular disease.60 Similar findings were previously reported for the comparison of the alpha-blocker doxazosin with chlorthalidone, an ALLHAT arm that was interrupted prematurely. Although ALLHAT stands out as the largest double-blind trial undertaken in hypertensive patients, interpretation of its results is difficult in several aspects, which may account for the heterogeneity of ALLHAT results with respect to those of the other trials.

  • In ALLHAT, 90% of the patients at randomization were already on antihypertensive treatment, most often diuretics, thus ALLHAT tested ‘continuing a diuretic’ versus ‘switching drug classes’. Patients on diuretics with latent or compensated heart failure were deprived of their needed therapy when they were not randomized to chlorthalidone.

  • The achieved systolic BP was higher on doxazosin, amlodipine, and lisinopril than on chlorthalidone. Presumably, these factors (i.e. lack of diuretic with subsequent fluid retention) explain why the Kaplan–Meier curves started to diverge immediately after randomization for heart failure, and difference in achieved BP approximately 6 months later for stroke.

  • The sympatholytic agents used for step-up treatment (atenolol, clonidine, and/or reserpine at the physician’s discretion) led to a somewhat artificial treatment regimen, which does not reflect modern clinical practice, is not usually recommended, and is known to potentiate the BP response to diuretics much more than to ACE inhibitors or alpha blockers.

  • ALLHAT did not include systematic endpoint evaluation, which may have particularly affected evaluation of ‘softer’ endpoints, such as congestive heart failure.

These limitations notwithstanding, ALLHAT60 either alone or in combination with the other trials, supports the conclusion that the benefits of antihypertensive therapy largely depend on BP lowering, thus being in line with the findings of the meta-analysis of the BPLTTC64 and the meta-analysis by Thomopoulos and colleagues.3 The conclusion that a substitution of portion of the benefit of antihypertensive treatment depends on BP reduction per se is also supported by the findings of INVEST (INternational VErapamil SR-Trandolapril) Study,65 in which cardiovascular disease was similarly frequent in patients treated with verapamil compared with those treated with atenolol (± hydrochlorothiazide). It is not entirely supported by the data of the Second Australian Blood Pressure study,66 in which ACE inhibitor-based treatment was found to be more protective against cardiovascular disease than diuretic-based treatment. The difference was modest, however, and significant only when the second morbid event in the same patient was included in the analysis. The conclusion of the paramount importance of BP control for prevention of cardiovascular complications is supported by the results of the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial,67,68 in which cardiac disease (the primary endpoint) was similarly frequent in high-risk hypertensive patients who were treated with valsartan or amlodipine. Amlodipine reduced BP to a greater degree in the months that followed randomization than using the other drug regimen, and this was accompanied by a lower risk of events.67

The LIFE (Losartan Intervention For Endpoint reduction in hypertension) study69 compared the ARB losartan with the beta blocker atenolol in hypertensive patients with left-ventricular hypertrophy for an average of 4.8 years, and found a significant 14.6% reduction in major cardiovascular events, mostly due to a significant 25% reduction in stroke incidence. There were no BP differences between the treatment groups. The SCOPE (Study on Cognition and Prognosis in the Elderly) study70 was initiated as a comparison of elderly patients receiving candesartan or placebo but, because of ethical reasons 85% of the placebo-initiated patients received antihypertensive therapy (mostly diuretics, beta blockers, or calcium antagonists), the study is a comparison of antihypertensive treatment with or without candesartan. After 3.7 years of treatment there was a non-significant 11% reduction in major cardiovascular events, and a significant 28% reduction in non-fatal strokes among candesartan-treated patients, with a lower achieved BP (3.2/1.6 mmHg) in the candesartan group.

In a meta-analysis of the BPLTTC that included angiotensin receptor antagonist treatment,64 it was concluded that angiotensin receptor antagonist-based regimens showed a greater effect than other control regimens on the risk of stroke, heart failure, and major cardiovascular events, but not on coronary heart disease, cardiovascular death, and total mortality. However, angiotensin receptor antagonist treatment compared to calcium antagonist treatment with amlodipine is balanced when assessing the VALUE trial68 and the CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan) study.71

Two large outcome trials have randomized patients to different combination regimens rather than strict head-to-head comparison of two drugs. The ASCOT (Anglo Scandinavian Cardiac Outcomes) Trial compared the calcium antagonist amlodipine ± the ACE inhibitor perindopril with atenolol ± bendroflumethiazide in over 19,000 patients free of coronary heart disease at the outset. The amlodipine–perindopril combination (in most patients) was superior to the atenolol–thiazide combination for all-cause mortality, most cardiovascular endpoints, renal disease and new diabetes.20 The benefit could partly be explained by lower BP.

ACCOMPLISH used a forced titration protocol in about 11,500 patients to compare the ACE inhibitor benazepril either combined with hydrochlorothiazide or amlodipine.13 The latter combination lowered the composite cardiovascular endpoint by 20% for the same level of BP control. Sixty per cent of ACCOMPLISH participants had diabetes and the benefit was statistically significant in groups with and without diabetes and in those with diabetes and particularly high risk of cardiovascular events.

In the most recent meta-analysis by Thomopoulos and colleagues,3 significant reductions of stroke, major cardiovascular events, and cardiovascular and all-cause death were obtained with calcium antagonists; stroke, coronary heart disease, heart failure, and major cardiovascular events by ACE inhibitors; and stroke, heart failure, and major cardiovascular events by ARBs. When compared with all other classes, diuretics are advantageous for the prevention of heart failure; beta blockers have disadvantages in preventing stroke (+23% higher risk); calcium antagonists are associated with a 20% higher risk of heart failure but have advantages to prevent stroke and all-cause mortality; and ACE inhibitors are associated with a 8% increase in stroke risk but reduce the risk of CHD and ARBs slightly increase the risk of CHD.

Randomized trials based on intermediate endpoints

The studies that have tested the effects of various antihypertensive agents on hypertension-associated left ventricular hypertrophy, mostly evaluated as left-ventricular mass at the echocardiogram, are almost innumerable, but only a few of them have followed strict enough criteria to provide reliable information. The very few studies adhering to these strict criteria do not yet provide uncontroversial answers, although meta-analyses suggest that, for a similar BP reduction, newer agents (ACE inhibitors, calcium antagonists, and ARBs) may be more effective than conventional drugs.72 The large and long-term (over 5 years of follow-up) LIFE study is particularly relevant, as the greater regression of electrocardiographically (ECG) determined left ventricular hypertrophy with losartan compared to atenolol was accompanied by a reduced incidence of cardiovascular events.69 The benefit of losartan was statistically significant for interaction with prespecified subgroups of patients with isolated systolic hypertension and diabetes. The LIFE study is the only head-to-head comparison of two drugs that has favoured one drug over the comparator in the treatment of hypertension. Even more importantly, a series of publications from the LIFE study have documented that, independent of choice of treatment, regression of ECG-left ventricular hypertrophy was related to reduction of numerous incident cardiovascular endpoint (cardiovascular mortality, myocardial infarction, stroke, sudden cardiac death, heart failure, atrial fibrillation, cardiac and peripheral revascularization, and diabetes). The same key findings were obtained in a LIFE substudy in which left ventricular hypertrophy was determined by echocardiography. Future studies should investigate treatment-induced effects on indices of collagen content of the ventricular wall rather than on its mass only.

A number of randomized trials have compared the long-term (over a follow-up period of 2–4 years) effects of different antihypertensive regimens on carotid artery wall intima–media thickness. The most convincing evidence has been obtained for calcium antagonists, which comes from trials with different agents, concluding with a long-term study on more than 2000 patients.73,74 The data show that for a similar reduction in BP these drugs slow down carotid artery wall thickening and plaque formations more than conventional drugs.73,74,75,76 Evidence of a greater benefit is also available for ACE inhibitors although less consistently.77 However, data released from the PROG IMT (Progression Intima–Media Thickness) consortium78 on almost 40,000 participants showed no prognostic effect of following the intima–media thickness with ultrasound of the carotid artery.

The most abundant evidence concerns renal function in diabetic patients.79 Progression of renal dysfunction can be retarded by adding an ARB in diabetic patients with advanced nephropathy.26,28,80 Consistent effects of more intensive BP lowering were found on urinary protein, both overt proteinuria and microalbuminuria. Of several studies in diabetic patients comparing treatments initiated by different agents, some63,81,82 did not show a difference in the renal protective effect of the drugs that were being compared, whereas one indicated the ARB irbesartan to be superior to the calcium antagonist amlodipine in retarding development of renal failure,80 and the other indicated the ARB losartan to reduce incidence of new overt proteinuria better than the beta blocker atenolol.83

As for patients with non-diabetic renal disease, a meta-analysis of 11 randomized trials comparing antihypertensive regimens including or excluding an ACE inhibitor84 indicates a significantly slower progression in patients achieving a BP of 139/85 mmHg rather than 144/87 mmHg particularly in those with a high proteinuria (>3 g/24h). It is not clear, however, whether the benefit should be ascribed to ACE inhibition or to the lower BP achieved. Some light on the matter is shed by the AASK (African American Study of Kidney Disease and Hypertension) study.85 ACE inhibitors were shown to be somewhat more effective than beta blockers85 or a calcium antagonist86 in slowing glomerular filtration rate decline. It appears, therefore, that in patients with diabetic and non-diabetic renal disease, the use of an ACE inhibitor may be more important than an aggressive BP reduction.

Several studies have also investigated the combination of an ARB with an ACE inhibitor (compared with monotherapies). A meta-analysis concluded that the combination in patients with chronic proteinuric renal disease was safe and confirmed greater antiproteinuric action, at least in the short term.87 However, the results of the ONTARGET and ALTITUDE trials24,27 have demonstrated that the combination of two blockers of the RAS is associated with an increased risk of acute kidney injury, hyperkalaemia, and no real impact on renal disease progression.

Diabetes and hypertension are often associated and awareness that several antihypertensive agents may exert undesirable metabolic effects has prompted investigation of the incidence of new diabetes in antihypertensive treatment trials.88 Almost all trials of antihypertensive therapy using new-onset diabetes as an endpoint have shown a significantly greater incidence in patients treated with diuretics and/or beta blockers compared with ACE inhibitors, ARBs, or calcium antagonists60,70,82,83,89 with a few exceptions61,90 (Figure 44.7.2). The ARBs valsartan and candesartan have been more beneficial on this endpoint than amlodipine.68,71 There are thus differences between different antihypertensive drugs on this endpoint. This is likely to be clinically relevant because, in the long term, treatment-induced diabetes is accompanied by an increased incidence of cardiovascular disease similar to native diabetes.91,92,93

Figure 44.7.2 Prevention of new-onset diabetes. * 2 years; ** 4 years; ¶ non-significant. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor antagonist; BB, beta blockers; Conv; conventional treatment (BB/D); D, diuretics; PL, placebo.

Figure 44.7.2 Prevention of new-onset diabetes. * 2 years; ** 4 years; non-significant. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor antagonist; BB, beta blockers; Conv; conventional treatment (BB/D); D, diuretics; PL, placebo.

Two large hypertension trials (VALUE94 and LIFE95) have shown that ARBs are associated with a relative risk reduction of new atrial fibrillation of 33% compared with a beta blocker in LIFE and 23% compared with a calcium antagonist in VALUE, respectively. A lower incidence of new atrial fibrillation has also been observed in heart failure trials using ACE inhibitors, ARBs, and aldosterone antagonists, and some smaller studies have shown effects of ARBs on recurrent atrial fibrillation in patients with previous episodes of arrhythmia when used in addition to amiodarone.96 No significant difference was seen between the ACE inhibitor ramipril, the ARB telmisartan, or the combination of both (ACE inhibitor plus ARB) in case of new-onset atrial fibrillation in the ONTARGET trial.24 Possible mechanisms for the reduction of atrial fibrillation seen after treatment with blockers of the RAS may in addition to the BP reduction per se be prevention of left atrial dilatation, cardiac fibrosis, and dysfunction as well as a possible direct antiarrhythmic effect.96

Therapeutic strategies

Principles of drug treatment: monotherapy versus combination therapy

In most, if not all, hypertensive patients, therapy should be started gently, and target BP values achieved progressively through several weeks (see also chapter 44.5). In grade 1 hypertension, monotherapy is likely to be successful in 40–60% of patients. However, it is impossible to predict with a specific degree of confidence the BP response to a given antihypertensive drug. If the priority is to normalize BP at the first attempt, results of some clinical trials have suggested that the best choice may be a diuretic or a calcium antagonist in older patients and in patients of African or African American origin, and a blocker of the RAS in younger patients and in non-African patients as recommended by British Hypertension Society.97 However, the distinction between younger and older patients for the choice of the first-line therapy is not supported by a meta-analysis64 and is not proposed by the 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC)38 or American guidelines.98

Drug treatment of hypertension To reach target BP rapidly, a larger proportion of patients will respond to a combination therapy. The proportion of patients responding to a combination therapy will also depend on baseline BP values. In patients with a higher cardiovascular risk and more severe hypertension (grade 2 and 3 hypertension), the likelihood to control BP with a monotherapy is very low. Therefore, the new 2018 ESC/ESH guidelines recommend to start immediately with a combination therapy in all hypertensive patients except frail elderly patients and patients with a low cardiovascular risk.99 For example, in trials on diabetic patients, the vast majority of patients were on at least two drugs, and in two trials on diabetic nephropathy26,80 an average of 2.5 and 3.0 non-study drugs were required in addition to the ARBs used as study drug. There are many good pathophysiological reasons why multiple-mechanism therapies have a greater efficacy in controlling BP in hypertensive patients. Firstly, the probability to lower BP is higher if one attacks more than one BP control mechanism. Secondly, when combining therapeutic strategies, each component has the potential to neutralize counter-regulatory mechanisms. Hence, the BP reductions that result are often additive. Thirdly, the side effects of one compound are sometimes blunted by the addition of another class. This is the case, for example, of the association of a calcium antagonist and a blocker of the RAS, which provokes less peripheral oedema than calcium antagonists alone.

Drug treatment of hypertension In conclusion, according to the most recent guidelines (2018 ESC/ESH Guidelines),99 it appears reasonable to initiate therapy with a combination of two agents as first step therapy in most patientsand monotherapy can be reserved for low cardiovascular risk patients and frail elderly patients (Figure 44.7.3). If a monotherapy is chosen and BP control is not achieved, the next step is to switch to a single-pill combination therapy. If therapy has been initiated by a single-pill combination of two drugs and BP is not controlled, a single-pill combination associating three antihypertensive classes (diuretics, RAS blocker, and calcium antagonist) is now recommended.

Figure 44.7.3 Monotherapy versus combination strategies. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor antagonist; BP, blood pressure; CA, calcium antagonist; CV, cardiovascular; D, diuretic.

Figure 44.7.3 Monotherapy versus combination strategies. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor antagonist; BP, blood pressure; CA, calcium antagonist; CV, cardiovascular; D, diuretic.

Fixed-dose combinations

Today, several fixed-dose combinations or single pill combinations combining two or three antihypertensive classes have been developed and are now available for the management of hypertension. Fixed-dose combinations have the same efficacy and tolerability profile as conventional therapeutic combinations but they do lower the pill burden.100 Consequently, one major advantage of fixed-dose combinations is an improvement in drug adherence and persistence. In meta-analyses, adherence or persistence on therapy was improved by about 20% in patients receiving a fixed-dose combination versus free-drug combinations.101,102 With the development of ARBs, which are devoid of dose-dependent side effects, the initial concept of fixed low-dose combinations has been slightly modified allowing higher doses of blockers of the RAS and calcium antagonists or diuretics. A limit of fixed-dose combinations may be a loss of flexibility, although recently, numerous combinations of doses have become available. Today, a lot of effective two- and three-drug fixed combinations have been developed and can be used for the management of hypertensive patients.

When combining drugs, long-acting drugs or preparations providing 24 h efficacy on a once-daily basis should be preferred. The advantages of such medications include improvement in adherence to therapy and minimization of BP variability, thus possibly providing greater protection against the risk of major cardiovascular events and the development of organ damage.103, 104

Particular attention should be given to adverse events, even purely subjective disturbances, because they may be an important cause of non-compliance and interruption of therapy.45 Patients should always be asked about adverse effects, and dose or drug changes made accordingly. Even within the same drug class, there may be compounds less prone to induce a specific adverse effect (e.g. among beta blockers, less fatigue or Raynaud’s phenomenon with vasodilating compounds; among calcium antagonists, no constipation with dihydropyridines, no tachycardia with verapamil and diltiazem, and a variable degree of dependent oedema with different compounds).

Choice of antihypertensive drugs

A large number of randomized trials confirm that the main benefits of antihypertensive therapy are due to lowering of BP per se, largely independently of the drugs used to lower BP.

There is also evidence, however, that specific drug classes may differ in some effect or in special groups of patients. Finally, drugs are not equal in terms of adverse disturbances, particularly in individual patients, and patients’ preference is a prerequisite for compliance and therapy success.

It can therefore be concluded that the major classes of antihypertensive agents—diuretics, beta blockers, calcium antagonists, ACE inhibitors, and ARBs—are suitable for the initiation and maintenance of antihypertensive therapy and can be combined effectively as shown in Figure 44.7.4. Emphasis on identifying the first class of drugs to be used is probably outdated by the awareness that two or more drugs in combination are necessary in the majority of patients, particularly those with higher initial BPs or subclinical organ damage or associated diseases, in order to achieve target BP. Notwithstanding, the two-drug combination that has been proven most effective in preventing clinical endpoints is a calcium antagonist plus an ACE inhibitor. In ASCOT20, the combination of amlodipine ± perindopril was superior to atenolol ± bendroflumethiazide (second drug in about 60% in both arms) in preventing most cardiovascular endpoints, renal disease and new-onset diabetes, and in ACCOMPLISH the combination of benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide.13

Figure 44.7.4 Possible combinations of major classes of antihypertensive drugs. ACE, angiotensin-converting enzyme.

Figure 44.7.4 Possible combinations of major classes of antihypertensive drugs. ACE, angiotensin-converting enzyme.

Because of the diabetogenic effects and inferiority in at least one major trial (ASCOT), the combination of a diuretic and beta blocker is no longer recommended as first-line treatment in uncomplicated hypertensives with high metabolic risk. Within the array of available agents, the choice of drugs will be influenced by many factors including the:

  • previous, favourable or unfavourable experience of the individual patient with a given class of compounds

  • effect of drugs on cardiovascular risk factors in relation to the cardiovascular risk profile of the individual patient

  • presence of subclinical organ damage, clinical cardiovascular disease, renal disease, and diabetes, which may be more favourably treated by some drugs than others

  • presence of other coexisting disorders that may either favour or limit the use of particular classes of antihypertensive drugs

  • possibility of interactions with drugs used for other conditions present

  • cost of drugs, either to the individual patient or to the health provider, although cost considerations should not predominate over efficacy and tolerability in any individual patient.

The physician should tailor the choice of drugs to the individual patient, after taking all these factors, together with patient preference, into account. Indications and contraindications of specific drug classes are listed in Tables 44.7.444.7.6, and therapeutic approaches to be preferred in special conditions are discussed in the next section.

Table 44.7.4 Preferred drugs in some indications

Subclinical organ damage

Left ventricular hypertrophy

ACE inhibitors, calcium antagonists, ARBs

Asymptomatic atherosclerosis

Calcium antagonists, ACE inhibitors

Microalbuminuria

ACE inhibitors, ARBs

Renal dysfunction

ACE inhibitors, ARBs

Clinical event

Previous stroke

Any BP-lowering agent

Previous MI

Beta blockers, ACE inhibitors, ARBs

Angina pectoris

Beta blockers, calcium antagonists

Heart failure

Atrial fibrillation:

    Recurrent

    Continuous

Renal failure/proteinuria

Peripheral artery disease

Diuretics, beta blockers, ACE inhibitors, ARBs, antialdosterone agents

ACE inhibitors, ARBs

Beta blockers, non-dihydropyridine calcium antagonists ACE inhibitors, ARBs, loop diuretics

Calcium antagonists

Condition

Isolated systolic hypertension (elderly)

Diuretics, calcium antagonists

Metabolic syndrome

ACE inhibitors, ARBs, calcium antagonists

Diabetes mellitus

ACE inhibitors, ARBs

Pregnancy

Calcium antagonists, methyldopa, beta blockers

Black patients

Diuretics, calcium antagonists

Resistant hypertension

ACE inhibitors, ARBs, calcium antagonists, diuretics, antialdosterone agents

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure.

Table 44.7.5 Conditions favoring use of some antihypertensive drugs

Thiazide diuretics

Beta blockers

Calcium antagonists (dihydropyridines)

Calcium antagonists (verapamil/diltiazem)

Isolated systolic hypertension (elderly)

Heart failure

Hypertension in black patients

Resistant hypertension

Angina pectoris

Post-myocardial infarction

Heart failure

Tachyarrhythmias

Glaucoma

Pregnancy

Isolated systolic hypertension (elderly)

Angina pectoris

LV hypertrophy

Carotid/ coronary atherosclerosis

Pregnancy

Hypertension in black patients

Angina pectoris

Carotid atherosclerosis

Supraventricular tachycardia

Proteinuria

ACE inhibitors

Angiotensin receptor antagonists

Diuretics (antialdosterone)

Loop diuretics

Heart failure

LV dysfunction

Post-myocardial infarction

Diabetic nephropathy

Non-diabetic nephropathy

LV hypertrophy

Carotid atherosclerosis

Proteinuria/ microalbuminuria

Atrial fibrillation

Metabolic syndrome

Heart failure

Post-myocardial infarction

Diabetic nephropathy

Proteinuria/ microalbuminuria

LV hypertrophy

Atrial fibrillation

Metabolic syndrome

ACEI-induced cough

Heart failure

Post-myocardial infarction

Resistant hypertension

End stage renal disease

Heart failure

ACEI, angiotensin-converting enzyme inhibitor; LV, left ventricular.

Table 44.7.6 Compelling and possible contraindications to use of antihypertensive drugs

Drug classes

Compelling

Possible

Thiazide diuretics

Gout

Glucose intolerance

Pregnancy

Beta blockers

Asthma

Peripheral artery disease

Atrioventricular block (grade 2 or 3)

Glucose intolerance

Athletes and physically active patients

Chronic obstructive pulmonary disease

Calcium antagonists (dihydropyridines)

Tachyarrhythmias

Calcium antagonists (verapamil, diltiazem)

Atrioventricular block (grade 2 or 3)

Heart failure

ACE inhibitors

Pregnancy

Angioneurotic oedema

Hyperkalaemia

Bilateral renal artery stenosis

Angiotensin receptor antagonists

Pregnancy

Hyperkalaemia

Bilateral renal artery stenosis

Diuretics (antialdosterone)

Renal failure

Hyperkalaemia

Treatment strategy in resistant hypertension

Hypertension may be termed resistant or refractory to treatment, when a therapeutic plan that has included attention to lifestyle measures and the prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower systolic and diastolic BP below 140/90 mmHg. This definition has evolved in recent years including patients with a well-controlled BP but with prescription of four drugs or more. The prevalence of resistant hypertension is highly variable depending on the definition but also on the seriousness of the medical work-up to exclude pseudo-resistance, which is actually more common than true resistant hypertension.

Before modifying therapy, several causes of apparent resistance to treatment should be excluded as illustrated in Table 44.7.7 and Figure 44.7.5. Thus, one should first ascertain that the patient is receiving the appropriate drug doses and that any prescribed drug combination is adequate and effective. In this respect, the place of diuretics is particularly important. Up to 40% of patients with apparent resistant hypertension have a suboptimal medical treatment. Drug interactions, which blunt the efficacy of antihypertensive drugs, should also be carefully investigated. Substances that increase sodium retention such as non-steroidal anti-inflammatory drugs should be withdrawn in case of resistant hypertension.

Table 44.7.7 Potential factors causing apparent or true resistant hypertension

Apparent resistance to treatment

Poor adherence to therapeutic plan

Failure to modify lifestyle modifications (high sodium intake, alcohol, etc.)

Continued intake of drugs or products increasing BP (non-steroidal anti-inflammatory drugs, liquorice, cocaine, glucocorticoids, etc.)

Inadequate treatment: inadequate diuretic therapy, failure to increase drug doses

Inadequate measurement of BP (failure to use the adequate cuff etc.)

Office hypertension (white coat hypertension)

True resistant hypertension

Secondary forms of hypertension:

Hyperaldosteronism

Chronic kidney disease

Obstructive sleep apnoea

Renovascular hypertension

Spurious causes of true resistant hypertension

Figure 44.7.5 Management of resistant hypertension. ABPM, ambulatory blood pressure monitoring; BP, blood pressure; NSAIDs, non-steroidal anti-inflammatory drugs.

Figure 44.7.5 Management of resistant hypertension. ABPM, ambulatory blood pressure monitoring; BP, blood pressure; NSAIDs, non-steroidal anti-inflammatory drugs.

A crucial determinant of an insufficient response to therapy is poor adherence to therapy.105 Recent studies have assessed the role of drug adherence in resistant hypertension measuring drug levels in blood or urine.106,107 Interestingly, up to two-thirds of patients with resistant hypertension did not take their prescribed medication adequately. In this clinical situation, physicians should work on understanding the barriers to adherence and on the approaches to improve adherence rather than adding new drugs to control BP. When these people with poor adherence to medication have been characterized, there still remain a small percentage of patients with true treatment resistant hypertension or refractory hypertension.

In patients with resistant hypertension, volume overload due to salt and water retention belongs to the most common pathophysiological mechanisms leading to the rise in BP despite medical therapy. Reduction of salt intake has been reported to be an effective way to lower BP in resistant hypertension.108 Similarly, the combination of diuretics has also been shown to be effective in controlling BP in resistant hypertension. The concept of sequential nephron blockade has been evaluated in patients with resistant hypertension and was found to be more effective than combining blockers of the RAS.109,110 Recently, several studies have focused on the potential benefits of inhibiting mineralocorticoid receptors with aldosterone antagonists.11,111,112,113 All of them suggest that adding a mineralocorticoid antagonist on top of a triple therapy combining a RAS blocker, a calcium antagonist, and a diuretic, is effective in reducing BP and achieving BP targets in resistant hypertension.114 The PATHWAY-2 study which compared the BP effect of adding either spironolactone, or doxazosin or bisoprolol or placebo in patients with resistant hypertension, has actually confirmed that spironolactone is the most effective add-on drug for the treatment of resistant hypertension11 (Figure 44.7.1).

If BP cannot be improved with these measures, patients should be referred to a specialist because resistant hypertension may be due to secondary hypertension and is often associated with subclinical organ damage and a high added cardiovascular risk. In true resistant hypertension with a very high cardiovascular risk, interventional treatments may be considered as discussed in Chapter 44.8.

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Further reading

Agabiti-Rosei E, Mancia G, O’Rourke MF, Roman MJ, Safar ME, Smulyan H, Wang JG, Wilkinson IB, Williams B, Vlachopoulos C. Central blood pressure measurements and antihypertensive therapy: a consensus document. Hypertension 2007;50:154–60.Find this resource:

Burnier M, Wuerzner G. Ambulatory blood pressure and adherence monitoring: diagnosing pseudoresistant hypertension. Semin Nephrol 2014;34:498–505.Find this resource:

Chapman N, Chen CY, Fujita T, Hobbs FD, Kim SJ, Staessen JA, Tanomsup S, Wang JG, Williams B. Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension? J Hypertens 2010;28:1796–803.Find this resource:

Gupta P, Patel P, Horne R, Buchanan H, Williams B, Tomaszewski M. How to screen for non-adherence to antihypertensive therapy. Curr Hypertens Rep 2016;18:89.Find this resource:

Hirakawa Y, Arima H, Webster R, Zoungas S, Li Q, Harrap S, Lisheng L, Hamet P, Mancia G, Poulter N, Neal B, Williams B, Rogers A, Woodward M, Chalmers J. Risks associated with permanent discontinuation of blood pressure-lowering medications in patients with type 2 diabetes. J Hypertens 2016;34:781–7.Find this resource:

Kjeldsen S, Feldman RD, Lisheng L, Mourad JJ, Chiang CE, Zhang W, Wu Z, Li W, Williams B. Updated national and international hypertension guidelines: a review of current recommendations. Drugs 2014;74:2033–51.Find this resource: