Objectives

Arq Bras Cardiol

abc

Arquivos Brasileiros de Cardiologia

Arq. Bras. Cardiol.

0066-782X 1678-4170

Sociedade Brasileira de Cardiologia - SBC

HhPSZ5x9GbvG5mQRht3q7Kf

S0066-782X2016004800035

10.5935/abc.20160157

Diretrizes

7^th Brazilian Guideline of Arterial Hypertension: Chapter 7 - Pharmacological Treatment

Malachias

MVB

Paulo César Veiga Jardim

PCV

Almeida

Lima

Júnior Feitosa

09 2016

107 3 Suppl 3 35 43

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives

The treatment of AH is ultimately aimed at reducing CV morbidity and mortality.1^-11 Clinical studies of outcome have provided scientific evidence of the benefits of the use of diuretics (DIUs) (GR: I; LE: A),5^,10^-15 beta-blockers (BBs) (GR: I; LE: A),10^-13^,16 calcium-channel blockers (CCBs) (GR: I; LE: A),10^,11^,15^,17^-23 angiotensin-converting-enzyme inhibitors (ACEIs) (GR: I; LE: A)10^,11^,15^,17^,18^,24^-26 and angiotensin-receptor blockers (ARBs) (GR: I; LE: A).10^,11^,27^-33 It is worth noting that most of those studies have used an association of drugs. Based on the information available, the protection observed does not depend on the type of drug used, but mainly on BP reduction.7^,9^-11^,34 Recent meta-analyses have reported that the benefits obtained from BB are smaller10^,11^,35^-37 as compared to those provided by the other drug groups, and, thus, BBs should be reserved for specific situations. Regarding alpha-blockers and direct vasodilators, there is no effective information on the outcomes of morbidity and mortality. Regarding direct renin inhibitors, only one study of outcome in diabetic patients has been early interrupted due to lack of benefits and possible harm.38 The higher the CV risk, the greater the benefits, which occur even for small BP elevations.3^-6^,8^,9^,39

General principles of the pharmacological treatment

When pharmacological treatment is indicated, the patient should be instructed about the importance of its continuity, the occasional need for dose adjustment and change or association of drugs, and the occasional appearance of adverse effects.

For one medicine to be indicated, it should preferably:

have shown the ability to reduce CV morbidity and mortality;

be effective orally;

be well tolerated;

be taken the fewest possible times per day;

be started at the smallest effective doses;

be able to be used in association;

be used for at least four weeks, before any change, except for special situations;

have quality control in its production.

Choice of the medication

All antihypertensive drugs available can be used if specific indications and contraindications are observed (Table 1). The initial preference is always for those with confirmed action in decreasing CV events, being the others reserved for special cases that require the association of multiple drugs to achieve BP targets.

Table 1 Antihypertensive drugs available

- DIUs (GR: I; LE: A)

- adrenergic inhibitors

- Central action – central alpha-2 agonists (GR: IIb; LE: C)

- BBs – beta adrenergic blockers (GR: I; LE: A)

- Alpha-blockers – alpha-1 adrenergic blockers (GR: IIb; LE: C)

- Direct vasodilators (GR: IIb; LE: C)

- CCBs (GR: I; LE: A)

- ACEIs (GR: I; LE: A)

- ARBs (GR: I; LE: A)

- Direct renin inhibitors (GR: IIb; LE: C)

General characteristics of antihypertensive drugs Diuretics

The mechanisms of antihypertensive action of DIUs are initially related to their natriuretic effects, with a decrease in the extracellular volume. After 4-6 weeks, the circulating volume normalizes and a reduction in peripheral vascular resistance (PVR) occurs. Diuretics reduce BP and CV morbidity and mortality.12^,14^,15 Their antihypertensive effect is not directly related to their doses, but the side effects are.

Thiazide or similar DIUs (chlorthalidone, hydrochlorothiazide and indapamide) at low doses should be preferred, because they are milder and have a longer time of action. Loop DIUs (furosemide and bumetanide) should be reserved for cases of renal failure (creatinine > 2.0 mg/dL or estimated GFR < 30 mL/min/1.73m²) and edema (HF or renal failure). Potassium-sparing DIUs (spironolactone and amiloride) are usually associated with a thiazide or loop DIU.

Adverse effects

Their major adverse effects are weakness, cramps, hypovolemia and erectile dysfunction. From the metabolic viewpoint, hypopotassemia is the most common, occasionally accompanied by hypomagnesemia, which can induce ventricular arrhythmias, mainly extrasystole. Diuretics can cause glucose intolerance by reducing insulin release, increasing the risk for type 2 DM. Uric acid increase is an almost universal effect of DIUs, of undocumented clinical consequences, except for triggering gout crises in predisposed individuals. The use of low doses decreases the risk for adverse effects, without hindering the antihypertensive efficacy, especially when associated with other drug classes. Spironolactone can cause hyperpotassemia, particularly in patients with impaired renal function.

Central action agents

Alpha-agonists of central action stimulate alpha-2 receptors involved in sympatho-inhibitory mechanisms.40 Not all alpha-agonists of central action are selective. Their well-defined effects are as follows: a decrease in sympathetic activity and reflex of baroreceptors, contributing to relative bradycardia and postural hypotension; mild decrease in PVR and cardiac output; a reduction in serum levels of renin; and fluid retention.

Some representatives of that group are: methyldopa, clonidine, guanabenz and inhibitors of imidazoline receptors (moxonidine and rilmenidine).41

Clonidine can be useful in hypertensive situations associated with: restless legs syndrome,42 withdrawal of opioids,43 menopausal hot flushes,44 diarrhea associated with diabetic neuropathy,45 and sympathetic hyperactivity of patients with alcoholic cirrosis.46 These drugs have no unwanted metabolic effect, because they interfere with neither peripheral resistance to insulin nor lipid profile.

Adverse effects

Methyldopa can cause autoimmune reactions, such as fever, hemolytic anemia, galactorrhea and liver dysfunction, which, in most cases, disappear with use cessation. If an adverse reaction occurs, it can be replaced by another central alpha-agonist.41 Clonidine has a higher risk for the rebound effect with discontinuation, especially when associated with a BB, and can be dangerous in the preoperative period.40 The drugs in this class have adverse reactions due to their central action, such as drowsiness, sedation, dry mouth, fatigue, postural hypotension, and erectile dysfunction.40^,41

Beta-blockers

Beta-blockers promote initial decrease in cardiac output and renin secretion, with readaptation of baroreceptors and decrease in catecholamines in nervous synapses.47^,48 In addition to such actions, third-generation drugs (carvedilol, nebivolol) have a vasodilating effect via different mechanisms: carvedilol, via concomitant blockade of alpha-1 adrenergic receptor;47^-50 and nebivolol, by increasing nitric oxide synthesis and release on the vascular endothelium.47^,48^,50 Propranolol is useful to patients with essential tremor, hyperkinetic syndromes, vascular headache and portal hypertension.47^,48

Adverse effects

They consist of bronchospasm, bradycardia, atrioventricular conduction disorders, peripheral vasoconstriction, insomnia, nightmares, psychic depression, asthenia and sexual dysfunction. First- and second-generation BBs are formally contraindicated to patients with bronchial asthma, chronic obstructive pulmonary disease (COPD) and second- and third-degree atrioventricular blocks. They can cause glucose intolerance, induce new cases of DM, and lead to hypertriglyceridemia with LDL-cholesterol elevation and HDL-cholesterol reduction. The impact on glucose metabolism is potentiated when combined with DIUs. Third-generation BBs (carvedilol and nebivolol) have neutral impact or can even improve the glucose and lipid metabolism, possibly because of the vasodilating effect with decrease in insulin resistance and improvement of glucose uptake by peripheral tissues.47^,50 Studies on nebivolol have shown less sexual dysfunction, possibly because of the effect on endothelial nitric oxide synthesis.47^,50

Alpha-blockers

Alpha-blockers act as competitive antagonists of postsynaptic alpha-1 receptors, leading to a reduction in PVR without major changes in cardiac output.41 Some representatives of this drug class are doxazosin, prazosin and terazosin. The hypotensive effect is mild in monotherapy, the combined use being preferred. They have a favorable and discrete action on the lipid and glucose metabolisms, especially improving the symptoms related to benign prostate hypertrophy.41

Adverse effects

Alpha-blockers can cause symptomatic hypotension on the first dose. The phenomenon of tolerance is frequent, requiring increasing doses. Women can have urine incontinence. There is evidence that patients treated with doxazosin are at higher risk for CHF.41

Direct acting vasodilators

Representatives of this drug class are hydralazine and minoxidil. They act directly, relaxing arterial smooth muscle, leading to a PVR reduction.40

Adverse effects

The side effects of hydralazine are headache, flushing, reflex tachycardia and lupus-like reaction (dose-dependent).41 Hydralazine should be used carefully in patients with CAD, and avoided in those with dissecting aortic aneurysm and a recent cerebral hemorrhage episode. In addition, it can cause anorexia, nausea, vomiting and diarrhea. A common side effect of minoxidil is hirsutism, in approximately 80% of the patients. A less common side effect is the general expansion of the circulating volume and reflex tachycardia.

Calcium-channel blockers

Calcium channel blockers cause a reduction in PVR, because of the decreased calcium amount inside arteriolar smooth muscle cells, due to calcium channel blockade in their membranes.51 They are classified as dihydropyridine and nondihydropyridine CCBs.

Dihydropyridine CCBs (amlodipine, nifedipine, felodipine, nitrendipine, manidipine, lercanidipine, levamlodipine, lacidipine, isradipine, nisoldipine, nimodipine) have mainly a vasodilating effect, with minimum interference in HR and systolic function, being, thus, more often used as antihypertensive agents. Nondihydropyridine CCBs, such as phenylalkylamines (verapamil) and benzothiazepines (diltiazem), have a lower vasodilating effect, can cause bradycardia and have an antiarrhythmic effect, which limit their use to specific cases. Nondihydropyridine CCBs can depress the systolic function, mainly in patients with systolic dysfunction prior to their use, and, thus, should be avoided in that condition. Long-acting CCBs should be preferred to prevent unwanted oscillations in HR and BP. They are effective antihypertensive drugs that reduce CV morbidity and mortality.52^-55 A study of outcome has reassured the efficacy, tolerability and safety of this drug class for the AH treatment of patients with CAD,56 being an alternative when BBs cannot be used, or even in association, in cases of refractory angina.

Adverse effects

Ankle swelling is usually the most common side effect, resulting from the vasodilating action (more arterial than venous), which causes capillary transudation. Throbbing headache and dizziness are not uncommon. Facial blushing is more common with fast-acting dihydropyridine CCBs. Hyperchromia of the distal third of the legs (ochre dermatitis) and gingival hypertrophy might occur. Such effects can be dose-dependent. Verapamil and diltiazem can worsen HF, bradycardia and atrioventricular block. Constipation is observed with verapamil.55

Angiotensin-converting-enzyme inhibitors

Angiotensin-converting-enzyme inhibitors are effective antihypertensive drugs whose major action is inhibition of angiotensin-converting-enzyme, hindering transformation of angiotensin I into angiotensin II, a vasoconstrictor. They are effective to treat AH, reducing CV morbidity and mortality.57 They are useful in many other CV conditions, such as HF with reduced ejection fraction, post-infarction anti-remodeling, and might have antiatherosclerotic properties. They delay renal function decline in patients with diabetic nephropathy or nephropathy of other etiologies.58

Adverse effects

Usually well-tolerated by most hypertensive patients, dry cough is their major side effect, affecting 5-20% of patients. Angioneurotic edema59 and skin rash are rare. Serum urea and creatinine elevation, usually small and reversible, is a transient phenomenon observed in the initial use of ACEIs in patients with renal failure.60 In the long run, ACEIs are effective to halt the progression of CKD. They can cause hyperpotassemia in patients with renal failure, mainly those with DM. They can reduce GFR and increase the levels of urea, creatinine and potassium in patients with bilateral stenosis of the renal arteries or renal artery stenosis in a single functioning kidney. They are contraindicated during pegnancy,61 because of the risk of fetal complicactions.62 Thus, they should be carefully used and often monitored in adolescents and childbearing-age women.

Angiotensin II AT1 receptor blockers

The ARBs antagonize the action of angiotensin II via the specific blockade of AT1 receptors, responsible for angiotensin II own actions of vasoconstriction, proliferation and stimulation of aldosterone release. In the AH treatment, especially of populations at high CV risk or with comorbidities, ARBs reduce CV and renal (diabetic nephropathy) morbidity and mortality.27^-29^,63^-66

Adverse effects

Adverse effects related to ARBs are not common, exanthema being rarely observed. Similarly to ACEIs, ARBs are contraindicated during pregnancy, and the same care should be taken for childbearing-age women.

Direct renin inhibitors

Aliskiren, the only representative of this drug class available for clinical use, causes direct renin inhibition with consequent decrease in angiotensin II production.67 Other actions might contribute to BP lowering and tissue protection, such as the reduction in renin plasma activity,67 the blockade of a renin/prorenin receptor,68 and the decrease in intracellular angiotensin II production.69 Studies of antihypertensive efficacy have confirmed its ability in monotherapy to lower BP in an intensity similar to that of other antihypertensive drugs.70 There is, however, no evidence of its benefits on morbidity and mortality.

Adverse effects

They are well tolerated. Skin rash, diarrhea [especially at high doses (> 300 mg/day)], CPK increase, and cough are the most frequent events, whose incidence is usually < 1%. Their use is contraindicated during pregnancy.

The beginning of pharmacological treatment

Pharmacological treatment is indicated for individuals with stage 1 AH and at low and intermediate CV risk, when nonpharmacological measures proved ineffective after an initial period of at least 90 days. In especial situations, in which access and/or return to medical care is difficult, the initial use of antihypertensive drugs, even for that group of patients, might be considered. For individuals with stage 1 AH and at high CV risk or with established CVD, the use of antihypertensive agents should be started immediately. Likewise, for patients with stage 2 and 3 AH, regardless of the CV risk, pharmacological treatment should be started immediately. For prehypertensive individuals, pharmacological treatment might be an option, considering the CV risk and/or presence of CVD. For 60- to 79-year-old patients with SBP ≥ 140 mm Hg and those ≥ 80 years with SBP ≥ 160 mm Hg, pharmacological therapy should begin earlier.

Therapeutic schemes

The pharmacological treatment can be performed with one or more drug classes, as required, to meet the BP targets and according to specific situations (Figure 1).

Figure 1 Flowchart for the treatment of hypertension. CVR: cardiovascular risk; NPT: non-pharmacological treatment; DIU: diuretics; ACEI: angiotensin-convertingenzyme inhibitors; CCB: calcium-channel blockers; ARB: angiotensin-receptor blockers; BB: beta-blockers.

Monotherapy

Monotherapy can be the initial antihypertensive strategy for stage 1 AH patients at low and intermediate CV risk. However, depending on the BP target to be achieved, most patients will require drug combination. The treatment should be individualized, and the initial choice of drug to be used as monotherapy should be based on the following aspects: ability to lower CV morbidity and mortality; predominant pathophysiological mechanism in the patient to be treated; individual characteristics; associated diseases; and socioeconomic conditions.

Based on those criteria, the classes of antihypertensive drugs currently preferred for BP control in the initial monotherapy are as follows (Figures 1 and 2):

Figure 2 Preferential associations of drugs according to mechanisms of action and synergy. Adapted from Journal of Hypertension 2007, 25:1751-1762.

Thiazide DIUs (preference for chlorthalidone);5^,10^-15^,39^,71^,72

ACEIs;7^-11^,15^,17^,18^,24^-26

CCBs;7^-11^,15^,17^-23

ARBs.10^,11^,27^-33^,73^-78

It is worth noting that DIUs have the greatest evidence of effectiveness regarding CV outcomes, with clear benefits for all types of events. In some situations, the indication of a certain group is reinforced, depending on the existing comorbidity. A BB can be considered the initial drug in certain situations, such as the presence of supraventricular arrhythmias, migraine, HF and CAD, and, in the last two conditions, the BB should be associated with other drugs.47^,48

The dosage should be adjusted to provide BP lowering to levels considered adequate for each case (therapeutic targets).1^,2^,8^,79 If the therapeutic objective is not achieved with the initial monotherapy, there are three possible options:

If the result is partial, but with no adverse effect, the dose of the drug used should be increased, and association with an antihypertensive drug of another group should be considered;

When the therapeutic effect expected at the maximum dose recommended is not obtained or in the presence of adverse events, the following is recommended: replace the antihypertensive agent initially used, reduce its dosage, and add another antihypertensive agent of a different class or use another association of drugs;

If the response is inappropriate, three or more drugs should be associated (Figure 1).

Combination of drugs

Most patients will need more than one drug to achieve BP targets. Therefore, patients with stage 1 AH and at high or very high CV risk or with CVD associated and those with stage 2 or 3 AH with or without other CVRF associated should be considered for drug combination (Figure 1). In addition, the association of two drugs at low doses for stage 1 hypertensive patients, even at low or intermediate CV risk, although not preferential, can be considered.

When choosing the drugs to be combined, antihypertensive agents sharing the same mechanism of action should be avoided, except for the association of thiazide DIUs and potassium-sparing DIUs. Loop DIUs should be reserved for individuals with GFR < 30 mL/min or severe edema. Associations with synergistic action provide better results (Figure 2).80

Particularities of the associations

Less tested associations should be reserved for cases requiring a larger number of drugs;

The association of BB and DIU should be performed carefully for patients with glucose metabolism changes, because both drugs contribute to worsen them;

The association of ACEI and ARB is not recommended, because, in addition to showing no benefit in CV outcomes, it increases the risk for adverse effects;33

Studies comparing directly the associations are scarce. A study has shown that the combination of ACEI and CCB, as compared to the association of ACEI and DIU, was more effective in lowering CV morbidity and mortality and the progression of kidney disease, for a similar reduction in BP, mainly in non-obese individuals.81^,82

Combinations can be performed freely with separate drugs or in a fixed association (same galenic formulation). If, on the one hand, free combinations allow us to choose the dose of each component, on the other hand, the use of fixed associations favors adherence to treatment, because of the smaller number of tablets.83

If BP control is not attained with two drugs, some decisions can be made:

in case of partial result and no side effect, the dose of the initial combination can be increased, or one more antihypertensive agent of another drug class can be added;

when the target is not achieved at the maximum dose recommended, or if adverse events occur, the combination should be replaced;

if, at maximum doses, BP control is not attained, other antihypertensive drugs should be associated (Figure 1).

If a DIU was not the first choice and is not being used in the association of two drugs, it should be the third drug to be added. Its use potentiates the antihypertensive action of any initial drug.

In cases of resistant AH (lack of BP control with at least three drugs at their maximum doses tolerated, one being a DIU), association of spironolactone is indicated.84^-86 Sympatholytic drugs of central action (clonidine) or BBs can be an alternative to the fourth drug to be added, direct vasodilators being reserved for special cases and in association with a DIU and a BB.

References 1

1 Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275(20):1571-6.

Kannel

Blood pressure as a cardiovascular risk factor: prevention and treatment

JAMA 1996 275 20 1571 1576

2 Padwal R, Straus SE, McAlisterFA. Evidence based management of hypertension. Cardiovascular risk factors and their impact on decision to treat hypertension: an evidence-based review. BMJ. 2001;322(7292):977-80.

Padwal

Straus

McAlister

Evidence based management of hypertension: Cardiovascular risk factors and their impact on decision to treat hypertension: an evidence-based review

BMJ 2001 322 7292 977 980

3 Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et. al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich). 2014;16(1):14-26.

Weber

Schiffrin

White

Mann

Lindholm

Kenerson

Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension

J Clin Hypertens (Greenwich) 2014 16 1 14 26

4 Daskalopoulou SS, Rabi DM, Zarnke KB, Dasgupta K, Nerenberg K, Cloutier L, et al. The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2015;31(5):549-68.

Daskalopoulou

Rabi

Zarnke

Dasgupta

Nerenberg

Cloutier

The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension

Can J Cardiol 2015 31 5 549 568

5 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-13. Erratum in: Lancet. 2003;361(9362):1060.

Lewington

Clarke

Qizilbash

Peto

Collins

Prospective Studies Collaboration

Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

nullErratum in Lancet. 2003;361(9362):1060 Lancet 2002 360 9349 1903 1913

6 Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328(13):914-21.

Materson

Reda

Cushman

Massie

Freis

Kochar

Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents

N Engl J Med 1993 328 13 914 921

7 Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 1. Overview, meta-analyses, and meta-regression analyses of randomized trials. J Hypertens. 2014;32(12):2285-95.

Thomopoulos

Parati

Zanchetti

Effects of blood pressure lowering on outcome incidence in hypertension: 1. Overview, meta-analyses, and meta-regression analyses of randomized trials

J Hypertens 2014 32 12 2285 2295

8 Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels overview and meta-analyses of randomized trials. J Hypertens. 2014;32(12):2296-304.

Thomopoulos

Parati

Zanchetti

Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels overview and meta-analyses of randomized trials

J Hypertens 2014 32 12 2296 2304

9 Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects in patients at different levels of cardiovascular risk overview and meta-analyses of randomized trials. J Hypertens. 2014;32(12):2305-14.

Thomopoulos

Parati

Zanchetti

Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects in patients at different levels of cardiovascular risk overview and meta-analyses of randomized trials

J Hypertens 2014 32 12 2305 2314

10 Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs -- overview and meta-analyses. J Hypertens. 2015;33(2):195-211.

Thomopoulos

Parati

Zanchetti

Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs -- overview and meta-analyses

J Hypertens 2015 33 2 195 211

11 Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses. J Hypertens. 2015;33(7):1321-41.

Thomopoulos

Parati

Zanchetti

Effects of blood pressure-lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses

J Hypertens 2015 33 7 1321 1341

12 Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277(9):739-45.

Psaty

Smith

Siscovick

Koepsell

Weiss

Heckbert

Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis

JAMA 1997 277 9 739 745

13 Wright JM, Lee CH, Chamber GK. Systematic review of antihypertensive therapies: does the evidence assist in choosing a first-line drug? CMAJ. 1999;161(1):25-32.

Wright

Lee

Chamber

Systematic review of antihypertensive therapies: does the evidence assist in choosing a first-line drug?

CMAJ 1999 161 1 25 32

14 Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP-Cooperative Research Group. JAMA. 1991;265(24):3255-64.

SHEP-Cooperative Research Group

Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP).

JAMA 1991 265 24 3255 3264

15 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcome in high-risk hypertensive patients to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;228(23):2981-97.

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcome in high-risk hypertensive patients to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

JAMA 2002 228 23 2981 2997

16 Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):713-20.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 39

UK Prospective Diabetes Study Group

BMJ 1998 317 7160 713 720

17 Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Trialist's Collaboration. Effects of ACE inhibitors, calcium antagonists and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Blood Pressure Lowering Trialist's Collaboration. Lancet. 2000;356(9246):1955-64.

Neal

MacMahon

Chapman

Blood Pressure Lowering Trialist's Collaboration

Effects of ACE inhibitors, calcium antagonists and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Blood Pressure Lowering Trialist's Collaboration

Lancet 2000 356 9246 1955 1964

18 Hansson L, Lindholm LH, Ekborn T, Dahlöf B, Lanke J, Scherstén B, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity. The Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354(9192):1129-33.

Hansson

Lindholm

Ekborn

Dahlöf

Lanke

Scherstén

Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity. The Swedish Trial in Old Patients with Hypertension-2 study

Lancet 1999 354 9192 1129 1133

19 Stassen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic hypertension in Europe (SYST-EUR). Lancet. 1997;350(9080):757-64.

Stassen

Fagard

Thijs

Celis

Arabidze

Birkenhäger

Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic hypertension in Europe (SYST-EUR)

Lancet 1997 350 9080 757 764

20 Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomized to double-blind treatment with long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356(9227):366-72. Erratum in: Lancet. 2000;356(9228):514.

Brown

Palmer

Castaigne

de Leeuw

Mancia

Rosenthal

Morbidity and mortality in patients randomized to double-blind treatment with long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT)

nullErratum in Lancet. 2000;356(9228):514 Lancet 2000 356 9227 366 372

21 Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomized trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazen (NORDIL) study. Lancet. 2000;356(9227):359-65.

Hansson

Hedner

Lund-Johansen

Kjeldsen

Lindholm

Syvertsen

Randomized trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazen (NORDIL) study

Lancet 2000 356 9227 359 365

22 Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Cavazzini C, et al. Health outcomes associated with calcium antagonists compared with other first line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet. 2000;356(9246):1949-54.

Pahor

Psaty

Alderman

Applegate

Williamson

Cavazzini

Health outcomes associated with calcium antagonists compared with other first line antihypertensive therapies: a meta-analysis of randomised controlled trials

Lancet 2000 356 9246 1949 1954

23 Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et. al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicenter randomised controlled trial. Lancet. 2005;366(9489):895-906.

Dahlof

Sever

Poulter

Wedel

Beevers

Caulfield

ASCOT Investigators

Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicenter randomised controlled trial

Lancet 2005 366 9489 895 906

24 Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality on hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet. 1999;353(9489):611-6.

Hansson

Lindholm

Niskanen

Lanke

Hedner

Niklason

Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality on hypertension: the Captopril Prevention Project (CAPPP) randomized trial

Lancet 1999 353 9489 611 616

25 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):145-53.

Yusuf

Sleight

Pogue

Bosch

Davies

Dagenais

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators

N Engl J Med 2000 342 3 145 153

26 PROGRESS Collaborative Group. Randomized trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;354(9287):1033-41. Erratum in: Lancet. 2001;358(9292):1556. Lancet. 2002;359(9323):2120.

PROGRESS Collaborative Group

Randomized trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack

nullErratum in Lancet. 2001;358(9292):1556 Lancet 2001 354 9287 1033 1041

27 Dahlof B, Devereux R, Kjeldsen S, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the losartan intervention or endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359(9311):995-1003.

Dahlof

Devereux

Kjeldsen

Julius

Beevers

de Faire

Cardiovascular morbidity and mortality in the losartan intervention or endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol

Lancet 2002 359 9311 995 1003

28 Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al; LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359(9311):1004-10.

Lindholm

Ibsen

Dahlof

Devereux

Beevers

de Faire

LIFE Study Group

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol

Lancet 2002 359 9311 1004 1010

29 Julius S, Kejdelsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients in high cardiovascular risk treated with regimens based on valsartan and amlodipine: the VALUE radomised trial. Lancet. 2004;363(9426):2022-31.

Julius

Kejdelsen

Weber

Brunner

Ekman

Hansson

Outcomes in hypertensive patients in high cardiovascular risk treated with regimens based on valsartan and amlodipine: the VALUE radomised trial

Lancet 2004 363 9426 2022 2031

30 Julius S, Weber MA, Kjeldsen SE, McInnes GT, Zanchetti A, Brunner HR, et. al. The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy. Hypertension. 2006;48(3):385-91.

Julius

Weber

Kjeldsen

McInnes

Zanchetti

Brunner

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy

Hypertension 2006 48 3 385 391

31 Ogihara T, Nakao K, Fukui T, Fukiyama K, Ueshima K, Oba K, et al; Candesartan Antihypertensive Survival Evaluation in Japan Trial Group. Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension. 2008;51(2):393-8.

Ogihara

Nakao

Fukui

Fukiyama

Ueshima

Oba

Candesartan Antihypertensive Survival Evaluation in Japan Trial Group

Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial

Hypertension 2008 51 2 393 398

32 Suzuki H, Kanno Y; Efficacy of Candesartan on Outcome in Saitama Trial (E-COST) Group. Effects of candesartan on cardiovascular outcomes in Japanese hypertensive patients (E-COST). Hypertens Res. 2005;28(4):307-14. Erratum in: Hypertens Res. 2005;28(6):553.

Suzuki

Kanno

Efficacy of Candesartan on Outcome in Saitama Trial Group

Effects of candesartan on cardiovascular outcomes in Japanese hypertensive patients (E-COST)

nullErratum in Hypertens Res. 2005;28(6):553 Hypertens Res 2005 28 4 307 314

33 Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59.

Yusuf

Teo

Pogue

Dyal

Copland

Schumacher

ONTARGET Investigators

Telmisartan, ramipril, or both in patients at high risk for vascular events

N Engl J Med 2008 358 15 1547 1559

34 Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665

Law

Morris

Wald

Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

BMJ 2009 338 b1665 b1665

35 Calberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004;364(9446):1684-9. Erratum in: Lancet. 2005;365(9460):656.

Calberg

Samuelsson

Lindholm

Atenolol in hypertension: is it a wise choice?

nullErratum in Lancet. 2005;365(9460):656 Lancet 2004 364 9446 1684 1689

36 Lindholm LH, Calberg B, Samuelsson O. Should beta blocker remain a first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005:366(9496):1545-53.

Lindholm

Calberg

Samuelsson

Should beta blocker remain a first choice in the treatment of primary hypertension? A meta-analysis

Lancet 2005 366 9496 1545 1553

37 Bradley H, Wiysonge CS, Volmink JA, Mayosi BM, Opie LH. How strong is the evidence for the use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. J Hypertens. 2006;24(11):2131-41.

Bradley

Wiysonge

Volmink

Mayosi

Opie

How strong is the evidence for the use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis

J Hypertens 2006 24 11 2131 2141

38 Parving HH, Brenner BM, McMurray JJV, Zeeuw D, Haffner SM, Solomon SD, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-13.

Parving

Brenner

McMurray

JJV

Zeeuw

Haffner

Solomon

ALTITUDE Investigators

Cardiorenal end points in a trial of aliskiren for type 2 diabetes

N Engl J Med 2012 367 23 2204 2213

39 The hypertension optimal treatment study (the HOT study). Blood Press. 1993;2(1):62-8.

The hypertension optimal treatment study (the HOT study)

Blood Press 1993 2 1 62 68

40 Vongpatanasin W, Kario K, Atlas SA, Victor RG. Central sympatholitic drugs. J Clin Hypertens (Greenwich). 2011;13(9):658-61.

Vongpatanasin

Kario

Atlas

Victor

Central sympatholitic drugs

J Clin Hypertens (Greenwich) 2011 13 9 658 661

41 Kaplan NM, Victor RG. Clinical hypertension. 11th ed. China: Wolters Kluwer; 2015. p. 198-262.

Kaplan

Victor

Clinical hypertension 2015 11th ed

China

Wolters Kluwer

42 Wagner ML, Walters AS, Coleman RG, Hening WA, Grasing K, Chokroverty S. Randomized double-blind, placebo-controlled study of clonidine in restless legs syndrome. Sleep. 1996;19(1):52-8.

Wagner

Walters

Coleman

Hening

Grasing

Chokroverty

Randomized double-blind, placebo-controlled study of clonidine in restless legs syndrome

Sleep 1996 19 1 52 58

43 Bond WS. Psychiatric indications for clonidine. J Clin Psychopharmacol. 1986;6(2):81-7.

Bond

Psychiatric indications for clonidine

J Clin Psychopharmacol 1986 6 2 81 87

44 Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000,132(10):788-93.

Pandya

Raubertas

Flynn

Hynes

Rosenbluth

Kirshner

Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study

Ann Intern Med 2000 132 10 788 793

45 Fedorak RN, Field M, Chang EB. Treatment of diabetic diarrhea with clonidine. Ann Intern Med. 1985;102(2):197-9.

Fedorak

Field

Chang

Treatment of diabetic diarrhea with clonidine

Ann Intern Med 1985 102 2 197 199

46 Esler M, Dudley F, Jennings G, Debinski H, Lambert G, Jones P, et al. Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrohosis. Ann Intern Med. 1992;116(6):446-55.

Esler

Dudley

Jennings

Debinski

Lambert

Jones

Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrohosis

Ann Intern Med 1992 116 6 446 455

47 Helfand M, Peterson K, Dana T. Drug class review on beta adrenergic blockers: Final Report [Internet]. [Cited in 2015 Jan 10]. Available from: http://www.ohsu.edu/drugeffectiveness/reports/final.cfm

Helfand

Peterson

Dana

Drug class review on beta adrenergic blockers: Final Report Internet

2015 Jan 10

Available from: http://www.ohsu.edu/drugeffectiveness/reports/final.cfm

48 López-Sendón J, Swedberg K, McMurray J, Tamargo J, Maggioni AP, Dargie H, et al; Task Force on Beta-Blockers of the European Society of Cardiology. Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J. 2004;25(15):1341-62.

López-Sendón

Swedberg

McMurray

Tamargo

Maggioni

Dargie

Task Force on Beta-Blockers of the European Society of Cardiology

Expert consensus document on beta-adrenergic receptor blockers

Eur Heart J 2004 25 15 1341 1362

49 Dulin B, Abraham WT. Pharmacology of carvedilol. Am J Cardiol. 2004;93(9A):3B-6B.

Dulin

Abraham

Pharmacology of carvedilol

Am J Cardiol 2004 93 9A 3B 6B

50 Pedersen ME, Cockcroft JR. The vasodilatory beta-blockers. Curr Hypertens Rep. 2007;9(4):269-77.

Pedersen

Cockcroft

The vasodilatory beta-blockers

Curr Hypertens Rep 2007 9 4 269 277

51 Elliott WJ, Ram CV. Calcium channel blockers. J Clin Hypertens (Greenwich). 2011;13(9):687-9.

Elliott

Ram

Calcium channel blockers

J Clin Hypertens (Greenwich) 2011 13 9 687 689

52 Messerli FH. Calcium antagonists in hypertension: from hemodynamics to outcomes. Am J Hypertens. 2002;15(7 Pt 2):94S-97S.

Messerli

Calcium antagonists in hypertension: from hemodynamics to outcomes

Am J Hypertens 2002 15 7

Pt 2

94S 97S

53 Elliott WJ, Bandari A. The role of calcium antagonists in stroke prevention. J Clin Hypertens (Greenwich). 2005;7(4 Suppl 1):5-8.

Elliott

Bandari

The role of calcium antagonists in stroke prevention

J Clin Hypertens (Greenwich) 2005 7 4 Suppl 1 5 8

54 Nathan S, Pepine CJ, Bakris GL. Calcium antagonists: effects on cardio-renal risk in hypertensive patients. Hypertension 2005; 46(4):637-42.

Nathan

Pepine

Bakris

Calcium antagonists: effects on cardio-renal risk in hypertensive patients

Hypertension 2005 46 4 637 642

55 Oparil S, Bakir SE. [Calcium antagonists in cardiovascular disease: clinical evidence from morbidity and mortality trials]. Drugs. 2000;59 Spec No 2:25-37.

Oparil

Bakir

Calcium antagonists in cardiovascular disease: clinical evidence from morbidity and mortality trials

Drugs 2000 59 Spec 2 25 37

56 Rollins G. Calcium antagonist and beta blocker regimens found equally effective in hypertensive patients with coronary artery disease. Rep Med Guidel Outcomes Res. 2004;15(2):1, 5-6.

Rollins

Calcium antagonist and beta blocker regimens found equally effective in hypertensive patients with coronary artery disease

Rep Med Guidel Outcomes Res 2004 15 2 5 6

57 Sindone A, Erlich J, Perkovic V, Suranyi M, Newman H, Lee C, et al. ACEIs for cardiovascular risk reduction--have we taken our eye off the ball? Aust Fam Physician. 2013;42(9):634-8.

Sindone

Erlich

Perkovic

Suranyi

Newman

Lee

ACEIs for cardiovascular risk reduction--have we taken our eye off the ball

Aust Fam Physician 2013 42 9 634 638

58 Vejakama P, Thakkinstian A, Lertrattananon D, Ingsathit A, Ngarmukos C, Attia J. Reno-protective effects of renin-angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis. Diabetologia 2012;55(3):566-78.

Vejakama

Thakkinstian

Lertrattananon

Ingsathit

Ngarmukos

Attia

Reno-protective effects of renin-angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis

Diabetologia 2012 55 3 566 578

59 Baram M, Kommuri A, Sellers SA, Cohn JR. ACE inhibitor-induced angioedema. J Allergy Clin Immunol Pract. 2013;1(5):442-5.

Baram

Kommuri

Sellers

Cohn

ACE inhibitor-induced angioedema

J Allergy Clin Immunol Pract 2013 1 5 442 445

60 Ryan MJ, Tuttle KR. Elevations in serum creatinine with RAAS blockade: why isn't it a sign of kidney injury? Curr Opin Nephrol Hypertens. 2008;17(5):443-9.

Ryan

Tuttle

Elevations in serum creatinine with RAAS blockade: why isn't it a sign of kidney injury?

Curr Opin Nephrol Hypertens 2008 17 5 443 449

61 Polifka JE. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence. Birth Defects Res A Clin Mol Teratol. 2012;94(8):576-98.

Polifka

Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence

Birth Defects Res A Clin Mol Teratol 2012 94 8 576 598

62 Laube GF, Kemper MJ, Schubiger G, Neuhaus TJ. Angiotensin-converting enzyme inhibitor fetopathy: long-term outcome. Arch Dis Child Fetal Neonatal Ed. 2007;92(5):F402-3.

Laube

Kemper

Schubiger

Neuhaus

Angiotensin-converting enzyme inhibitor fetopathy: long-term outcome

Arch Dis Child Fetal Neonatal Ed 2007 92 5 F402 F403

63 Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, et al; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362(9386):759-66.

Pfeffer

Swedberg

Granger

Held

McMurray

Michelson

CHARM Investigators and Committees

Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme

Lancet 2003 362 9386 759 766

64 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-9.

Brenner

Cooper

de Zeeuw

Keane

Mitch

Parving

RENAAL Study Investigators

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy

N Engl J Med 2001 345 12 861 869

65 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al; Collaborative Study Group. Renoprotective effect of the angiotensin receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes. N Eng J Med. 2001;345(12):851-60.

Lewis

Hunsicker

Clarke

Berl

Pohl

Lewis

Collaborative Study Group

Renoprotective effect of the angiotensin receptor antagonist irbersartan in patients with nephropathy due to type 2 diabetes

N Eng J Med 2001 345 12 851 860

66 Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-8.

Parving

Lehnert

Brochner-Mortensen

Gomis

Andersen

Arner

Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group

The effect of irbersartan on the development of diabetic nephropathy in patients with type 2 diabetes

N Engl J Med 2001 345 12 870 878

67 Müller DN, Derer W, Dechend R. Aliskiren-mode of action and preclinical data. J Mol Med (Berl). 2008;86(6):659-62.

Müller

Derer

Dechend

Aliskiren-mode of action and preclinical data

J Mol Med (Berl) 2008 86 6 659 662

68 Danser AH. (Pro)renin receptors: are they biologically relevant? Curr Opin Nephrol Hypertens. 2009;18(1):74-8.

Danser

Pro)renin receptors: are they biologically relevant?

Curr Opin Nephrol Hypertens 2009 18 1 74 78

69 Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes. 2008;57(12):3297-306. Erratum in: Diabetes. 2009;58(3):770.

Singh

Khode

Baker

Kumar

Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis

nullErratum in Diabetes. 2009;58(3):770 Diabetes 2008 57 12 3297 3306

70 Musini VM, Fortin PM, Bassett K, Wright JM. Blood pressure lowering efficacy of renin inhibitors for primary hypertension. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD007066.

Musini

Fortin

Bassett

Wright

Blood pressure lowering efficacy of renin inhibitors for primary hypertension

Cochrane Database Syst Rev 2008 10 8 4 CD007066 CD007066

71 Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011;57(4):689-94.

Dorsch

Gillespie

Erickson

Bleske

Weder

Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis

Hypertension 2011 57 4 689 694

72 Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59(6):1110-7.

Roush

Holford

Guddati

Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses

Hypertension 2012 59 6 1110 1117

73 Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, Woodward M, et. al; Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5):951-8. Erratum in: J Hypertens. 2007;25(7):1524.

Turnbull

Neal

Pfeffer

Kostis

Algert

Woodward

Blood Pressure Lowering Treatment Trialists' Collaboration

Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system

nullErratum in J Hypertens. 2007;25(7):1524 J Hypertens 2007 25 5 951 958

74 Reboldi G, Angeli F, Cavallini C, Gentile G, Mancia G, Verdecchia P. Comparison between angiotensinconverting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis. J Hypertens. 2008;26(7):1282-9.

Reboldi

Angeli

Cavallini

Gentile

Mancia

Verdecchia

Comparison between angiotensinconverting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis

J Hypertens 2008 26 7 1282 1289

75 vanVark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J. 2012;33(16):2088-97.

vanVark

Bertrand

Akkerhuis

Brugts

Fox

Mourad

Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients

Eur Heart J 2012 33 16 2088 2097

76 Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, et. al; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893-906. Erratum in: N Engl J Med. 2004 Jan 8;350(2):203

Pfeffer

McMurray

Velazquez

Rouleau

Køber

Maggioni

Valsartan in Acute Myocardial Infarction Trial Investigators

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both

nullErratum in N Engl J Med. 2004/01/08;350(2):203 N Engl J Med 2003 349 20 1893 1906

77 Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547-53.

Mann

Schmieder

McQueen

Dyal

Schumacher

Pogue

ONTARGET investigators

Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial

Lancet 2008 372 9638 547 553

78 Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. Diabetes Metab. 2004;30(6):487-96.

Scheen

Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials

Diabetes Metab 2004 30 6 487 496

79 Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-16.

Wright

Jr Williamson

Whelton

Snyder

Sink

Rocco

SPRINT Research Group

A randomized trial of intensive versus standard blood-pressure control

N Engl J Med 2015 373 22 2103 2116

80 Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11 000 participants from 42 trials. Am J Med. 2009;122(3):290-300.

Wald

Law

Morris

Bestwick

Wald

Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11 000 participants from 42 trials

Am J Med 2009 122 3 290 300

81 Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28.

Jamerson

Weber

Bakris

Dahlof

Pitt

Shi

ACCOMPLISH Trial Investigators

Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients

N Engl J Med 2008 359 23 2417 2428

82 Bakris GL, Sarafi PA, Weir MR, Dahlof B, Pitt B, Jamerson K, et al; ACCOMPLISH Trial investigators. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a pre-specified secondary analysis of a randomized controlled trial. Lancet. 2010;375(9721):1173-81.

Bakris

Sarafi

Weir

Dahlof

Pitt

Jamerson

ACCOMPLISH Trial investigators

Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a pre-specified secondary analysis of a randomized controlled trial

Lancet 2010 375 9721 1173 1181

83 Corrao G, Parodi A, Zambon A, Heiman F, Filippi A, Cricelli C, et al. Reduced discontinuation of antihypertensive treatment by two-drug combination as first step: evidence from daily life practice. J Hypertens. 2010;28(7):1584-90.

Corrao

Parodi

Zambon

Heiman

Filippi

Cricelli

Reduced discontinuation of antihypertensive treatment by two-drug combination as first step: evidence from daily life practice

J Hypertens 2010 28 7 1584 1590

84 Vaclavik J, Sediak R, Plachy M, Navratil K, Plasek J, Jarkovsky J, et. al. Addition of spirolactone in patients with resistant hypertension (ASPIRANT): a randomized double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069-75. Erratum in: Hypertension. 2015;65(2):e7.

Vaclavik

Sediak

Plachy

Navratil

Plasek

Jarkovsky

Addition of spirolactone in patients with resistant hypertension (ASPIRANT): a randomized double-blind, placebo-controlled trial

nullErratum in Hypertension. 2015;65(2):e7 Hypertension 2011 57 6 1069 1075

85 Bobrie G, Frank M, Azizi M, Peyrard S, Boutouyrie P, Chatellier G, et. al. Sequential nophron blockade vs. sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. J Hypertens. 2012;30(8):1656-64.

Bobrie

Frank

Azizi

Peyrard

Boutouyrie

Chatellier

Sequential nophron blockade vs. sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study

J Hypertens 2012 30 8 1656 1664

86 Dahal K, Kunwar S, Rijal J, Alqatahni F, Panta R, Ishak N, et al. The effects of aldosterone antagonists in patients with resistant hypertension: a meta-analysis of randomized and nonrandomized studies. Am J Hypertens. 2015;28(11):1376-85.

Dahal

Kunwar

Rijal

Alqatahni

Panta

Ishak

The effects of aldosterone antagonists in patients with resistant hypertension: a meta-analysis of randomized and nonrandomized studies

Am J Hypertens 2015 28 11 1376 1385

7ª Diretriz Brasileira de Hipertensão Arterial: Capítulo 7 - Tratamento Medicamentoso

Malachias

MVB

Paulo César Veiga Jardim

PCV

Almeida

Lima

Júnior Feitosa

Objetivos

O tratamento da HA visa, em última análise, a redução da morbimortalidade CV.1^-11 Há evidências científicas através de estudos clínicos de desfechos que mostram benefícios do tratamento realizado com o uso de diuréticos (DIU) (GR: I; NE: A),5^,10^-15 BB (GR: I; NE: A),10^-13^,16 BCC (GR: I, NE: A),10^,11^,15^,17^-23 inibidores da enzima conversora de angiotensina (IECA) (GR: I; NE: A)10^,11^,15^,17^,18^,24^-26 e bloqueadores dos receptores AT1 da angiotensina II (BRA) (GR: I; NE: A).10^,11^,27^-33 Deve ser ressaltado que a maioria desses estudos utilizou medicamentos em associação. Com base nas informações disponíveis, a proteção observada não depende do tipo de fármaco empregado, mas fundamentalmente da redução da PA.7^,9^-11^,34 Informações recentes através de meta-análises indicam que os benefícios obtidos com os BB são menores10^,11^,35^-37 quando comparados aos dos demais grupos, devendo ser reservados para situações específicas. Com relação aos alfabloqueadores e vasodilatadores diretos, não há informações efetivas sobre desfechos de morbimortalidade. Quanto aos inibidores diretos da renina, um único estudo de desfechos em pacientes diabéticos foi interrompido precocemente por ausência de benefícios e possibilidade de malefícios.38 Observa-se que os benefícios são maiores quanto maior o risco CV, mas ocorrem mesmo em pequenas elevações da PA.3^-6^,8^,9^,39

Princípios gerais no tratamento medicamentoso

Desde que exista indicação de tratamento com medicamentos, o paciente deverá ser orientado sobre a importância do uso contínuo, da eventual necessidade de ajuste de doses, da troca ou associação de medicamentos e ainda do eventual aparecimento de efeitos adversos.

Um medicamento para ser indicado deverá, preferencialmente:

Ter demonstrado a capacidade de reduzir a morbimortalidade CV;

Ser eficaz por via oral;

Ser bem tolerado;

Poder ser usado no menor número de tomadas por dia;

Ser iniciado com as menores doses efetivas;

Poder ser usado em associação;

Ser utilizado por um período mínimo de quatro semanas, antes de modificações, salvo em situações especiais;

Ter controle de qualidade em sua produção.

Escolha do medicamento

Todos os medicamentos anti-hipertensivos disponíveis podem ser utilizados desde que sejam observadas as indicações e contra-indicações específicas (Tabela 1). A preferência inicial será sempre por aqueles em que haja comprovação de diminuição de eventos CV, ficando os demais reservados a casos especiais em que haja a necessidade da associação de múltiplos medicamentos para que sejam atingidas as metas da PA.

Tabela 1 Anti-hipertensivos disponíveis

- DIU (GR: I; NE: A)

- Inibidores adrenérgicos

- Ação central – agonistas alfa-2 centrais (GR: IIb; NE: C)

- BB – bloqueadores beta-adrenérgicos (GR: I; NE: A)

- Alfabloqueadores – bloqueadores alfa-1 adrenérgicos (GR: IIb; NE: C)

- Vasodilatadores diretos (GR: IIb; NE: C)

- BCC (GR: I; NE: A)

- IECA (GR: I; NE: A)

- BRA (GR: I; NE: A)

- Inibidor direto da renina (GR: IIb; NE: C)

Características gerais dos anti-hipertensivos Diuréticos

Os mecanismos de ação anti-hipertensiva dos DIU relacionam-se inicialmente aos seus efeitos natriuréticos, com diminuição do volume extracelular. Após quatro a seis semanas, o volume circulante praticamente se normaliza e ocorre redução da resistência vascular periférica (RVP). Os DIU reduzem a PA e diminuem a morbimortalidade CV.12^,14^,15 O efeito anti-hipertensivo não está diretamente relacionado às doses utilizadas, porém, os efeitos colaterais estão.

Deve-se dar preferência aos DIU tiazídicos ou similares (clortalidona, hidroclorotiazida e indapamida) em doses baixas, pois são mais suaves e com maior tempo de ação, reservando-se os DIU de alça (furosemida e bumetanida) aos casos de insuficiência renal (creatinina > 2,0 mg/dl ou RFG calculado < 30 ml/min/1,73m²) e situações de edema (IC ou insuficiência renal). Os poupadores de potássio (espironolactona e amilorida) são habitualmente utilizados em associação com os tiazídicos ou DIU de alça.

Efeitos adversos

Seus principais efeitos adversos são fraqueza, câimbras, hipovolemia e disfunção erétil. Do ponto de vista metabólico, o mais comum é a hipopotassemia, eventualmente acompanhada de hipomagnesemia, que podem induzir arritmias ventriculares, sobretudo extrassistolia. Podem provocar intolerância à glicose por reduzir a liberação de insulina, aumentando o risco do desenvolvimento de DM tipo 2. O aumento do ácido úrico é um efeito quase universal dos DIU, mas de consequências clínicas não documentadas, exceto pela precipitação de crises de gota nos indivíduos com predisposição. O uso de doses baixas diminui o risco dos efeitos adversos, sem prejuízo da eficácia anti-hipertensiva, especialmente quando em associação com outras classes de medicamentos. A espironolactona pode causar hiperpotassemia, em particular em pacientes com déficit de função renal.

Agentes de ação central

Os agentes alfa-agonistas de ação central agem através do estímulo dos receptores α₂ que estão envolvidos nos mecanismos simpatoinibitórios.40 Nem todos são seletivos. Os efeitos bem definidos dessa classe são: diminuição da atividade simpática e do reflexo dos barorreceptores, contribuindo para bradicardia relativa e a hipotensão notada em ortostatismo; discreta diminuição na RVP e no débito cardíaco; redução nos níveis plasmáticos de renina e retenção de fluidos.

São representantes desse grupo: metildopa, clonidina, guanabenzo e os inibidores dos receptores imidazolínicos (moxonidina e rilmenidina).41

O uso da clonidina pode ser favorável em situações de hipertensão associada a: síndrome das pernas inquietas,42 retirada de opioides,43 "flushes" da menopausa,44 diarréia associada a neuropatia diabética45 e hiperatividade simpática em pacientes com cirrose alcoólica.46 Não apresentam efeito metabólico indesejado por não interferirem na resistência periférica à insulina nem no perfil lipídico.

Efeitos adversos

A metildopa pode provocar reações auto-imunes, como febre, anemia hemolítica, galactorreia e disfunção hepática, que na maioria dos casos desaparecem com a cessação do uso. No desenvolvimento de uma reação adversa, esse pode ser substituído por outro alfa-agonista central.41 A clonidina apresenta um risco maior do efeito rebote com a descontinuação, especialmente quando associada a um BB e pode ser perigosa em situações pré-operatórias.40 Os medicamentos dessa classe, apresentam reações adversas decorrentes da ação central, como sonolência, sedação, boca seca, fadiga, hipotensão postural e disfunção erétil.40^,41

Betabloqueadores

Promovem diminuição inicial do débito cardíaco e da secreção de renina, havendo readaptação dos barorreceptores e diminuição das catecolaminas nas sinapses nervosas.47^,48 Os fármacos de terceira geração (carvedilol, nebivolol) além das ações anteriores, têm efeito vasodilatador por mecanismos diferentes: o carvedilol, pelo seu efeito de bloqueio concomitante do receptor alfa-1 adrenérgico;47^-50 e o nebivolol, por aumentar a síntese e liberação de óxido nítrico no endotélio vascular.47^,48^,50 O propranolol mostra-se também útil em pacientes com tremor essencial, síndromes hipercinéticas, cefaleia de origem vascular e hipertensão portal.47^,48

Efeitos adversos

Broncoespasmo, bradicardia, distúrbios da condução atrioventricular, vasoconstrição periférica, insônia, pesadelos, depressão psíquica, astenia e disfunção sexual. Os BB de primeira e segunda geração são formalmente contraindicados a pacientes com asma brônquica, doença pulmonar obstrutiva crônica (DPOC) e bloqueio atrioventricular de segundo e terceiro graus, podem acarretar intolerância à glicose, induzir ao aparecimento de novos casos de DM, hipertrigliceridemia com elevação do LDL-colesterol e redução da fração HDL-colesterol. O impacto sobre o metabolismo da glicose é potencializado quando são utilizados em combinação com DIU. Os BB de terceira geração (carvedilol e o nebivolol) têm impacto neutro ou até podem melhorar o metabolismo da glicose e lipídico, possivelmente em decorrência do efeito de vasodilatação com diminuição da resistência à insulina e melhora da captação de glicose pelos tecidos periféricos.47^,50 Estudos com o nebivolol também têm apontado para uma menor disfunção sexual, possivelmente em decorrência do efeito sobre a síntese de óxido nítrico endotelial.47^,50

Alfabloqueadores

Os medicamentos dessa classe agem como antagonistas competitivos dos α₁-receptores pós-sinápticos, levando a redução da RVP sem maiores mudanças no débito cardíaco.41 São representantes dessa classe a doxazosina, prazosina e terazosina. O efeito hipotensor é discreto como monoterapia, sendo a preferência pelo uso associado. Apresentam contribuição favorável e discreta no metabolismo lipídico e glicídico, e em especial na melhora da sintomatologia relacionada à hipertrofia prostática benigna.41

Efeitos adversos

Podem provocar hipotensão sintomática na primeira dose. O fenômeno de tolerância é frequente, necessitando aumento da dose, ao longo do uso. Incontinência urinária em mulheres pode ser causada pelo uso de alfabloqueadores. Há evidência de que os pacientes tratados com doxazosina têm maior risco de incidência de ICC.41

Vasodilatadores diretos

Os medicamentos que representam essa classe são hidralazina e minoxidil. Atuam diretamente, relaxando a musculatura lisa arterial, levando a redução da RVP.40

Efeitos adversos

Os efeitos colaterais da hidralazina são cefaleia, flushing, taquicardia reflexa e reação lupus-like (dose-dependente).41 O uso dessa medicação deve ser cuidadoso em pacientes com DAC e deve ser evitado naqueles com aneurisma dissecante da aorta e episódio recente de hemorragia cerebral. Seu uso pode também acarretar anorexia, náusea, vômito e diarreia. Um efeito colateral comum do minoxidil é o hirsutismo, que ocorre em aproximadamente 80% dos pacientes. Um efeito menos comum é a expansão generalizada de volume circulante e taquicardia reflexa.

Bloqueadores dos canais de cálcio

Os BCC agem primordialmente proporcionando redução da RVP como consequência da diminuição da quantidade de cálcio no interior das células musculares lisas das arteríolas, decorrente do bloqueio dos canais de cálcio na membrana dessas células.51 São classificados em 2 tipos básicos: os di-idropiridínicos e os não di-idropiridínicos.

Os BCC di-idropiridínicos (amlodipino, nifedipino, felodipino, nitrendipino, manidipino, lercanidipino, levanlodipino, lacidipino, isradipino, nisoldipino, nimodipino) exercem um efeito vasodilatador predominante, com mínima interferência na frequência e na função sistólica, sendo, por isso, mais frequentemente usados como anti-hipertensivos. Os não di-idropiridínicos, como as fenilalquilaminas (verapamil) e as benzotiazepinas (diltiazem), têm menor efeito vasodilatador, e podem ser bradicadizantes e antiarrítmicos, o que restringe seu uso a alguns casos específicos. Os BCC não di-idropiridínicos podem deprimir a função sistólica cardíaca, principalmente em pacientes que já apresentavam tal disfunção antes do início do seu uso, devendo ser evitados nessa condição. Deve-se dar preferência aos BCC de ação prolongada para que se evitem oscilações indesejáveis na FC e na PA. São anti-hipertensivos eficazes e reduzem a morbimortalidade CV.52^-55 Estudo de desfecho reafirmou a eficácia, a tolerabilidade e a segurança do uso dessa classe de medicamentos no tratamento da HA de pacientes com DAC,56 constituindo-se uma alternativa aos BBs quando esses não puderem ser utilizados, ou mesmo, em associação, quando em angina refratária.

Efeitos adversos

Edema maleolar costuma ser o efeito colateral mais registrado, e resulta da própria ação vasodilatadora (mais arterial que venosa), promovendo a transudação capilar. Cefaleia latejante e tonturas não são incomuns. O rubor facial é mais comum com os BCC di-idropiridínicos de ação rápida. Hipercromia do terço distal das pernas (dermatite ocre) e a hipertrofia gengival podem ocorrer ocasionalmente. Tais efeitos podem ser dose-dependentes. Verapamil e diltiazem podem agravar a IC, além de bradicardia e bloqueio atrioventricular. Obstipação intestinal é observada com verapamil.55

Inibidores da enzima conversora da angiotensina

São anti-hipertensivos eficazes que têm como ação principal a inibição da enzima conversora de angiotensina I, impedindo a transformação de angiotensina I em angiotensina II, de ação vasoconstritora. São eficazes no tratamento da HA, reduzindo a morbimortalidade CV.57 São medicações comprovadamente úteis em muitas outras afecções CV, como em IC com fração de ejeção reduzida, anti-remodelamento cardíaco pós-infarto, além de possíveis propriedades antiateroscleróticas. Também retardam o declínio da função renal em pacientes com nefropatia diabética ou de outras etiologias.58

Efeitos adversos

Habitualmente bem tolerados pela maioria dos pacientes hipertensos, a tosse seca é seu principal efeito colateral, acometendo 5 a 20% dos pacientes. Edema angioneurótico59 e erupção cutânea ocorrem mais raramente. Um fenômeno passageiro observado quando do seu uso inicial em pacientes com insuficiência renal é a elevação de ureia e creatinina séricas, habitualmente de pequena monta e reversível.60 A longo prazo, revelam-se eficazes em reduzir a progressão da DRC. Podem provocar hiperpotassemia em pacientes com insuficiência renal, particularmente diabéticos. Podem promover redução do RFG e aumento em graus variáveis de ureia, creatina e potássio em pacientes com estenose bilateral das artérias renais ou com estenose de artéria renal em rim único funcionante. Seu uso é contraindicado na gravidez,61 pelo risco de complicações fetais.62 Por isso, seu emprego deve ser cauteloso e frequentemente monitorado em adolescentes e mulheres em idade fértil.

Bloqueadores dos receptores AT <sub>1</sub> da angiotensina II

Os BRA antagonizam a ação da angiotensina II por meio do bloqueio específico dos receptores AT₁, responsáveis pelas ações vasoconstritoras, proliferativas e estimuladoras da liberação de aldosterona, próprias da angiotensina II. No tratamento da HA, especialmente em populações de alto risco CV ou com comorbidades, proporcionam redução da morbimortalidade CV e renal (nefropatia diabética).27^-29^,63^-66

Efeitos adversos

São incomuns os efeitos adversos relacionados aos BRA, sendo o exantema raramente observado. Pelas mesmas razões dos IECA, são contraindicados na gravidez, devendo os mesmos cuidados ser tomados em mulheres em idade fértil.

Inibidores diretos da renina

Alisquireno, único representante da classe disponível para uso clínico, promove a inibição direta da ação da renina com consequente diminuição da formação de angiotensina II.67 Outras ações podem contribuir para a redução da PA e a proteção tissular, tais como redução da atividade plasmática de renina,67 bloqueio de um receptor celular próprio de renina/pró-renina68 e diminuição da síntese intracelular de angiotensina II.69 Estudos de eficácia anti-hipertensiva comprovam sua capacidade, em monoterapia, de redução da PA de intensidade semelhante aos demais anti-hipertensivos.70 Não existem, contudo, evidências de seus benefícios sobre morbimortalidade.

Efeitos adversos

Apresentam boa tolerabilidade. "Rash" cutâneo, diarreia (especialmente com doses elevadas, acima de 300 mg/dia), aumento de CPK e tosse são os eventos mais frequentes, porém, em geral, com incidência inferior a 1%. Seu uso é contraindicado na gravidez.

O início do tratamento medicamentoso

O tratamento com medicamentos está indicado para os indivíduos com PA estágio 1 e risco CV baixo e moderado, quando as medidas não farmacológicas não surtirem efeito após um período inicial de pelo menos 90 dias. Em situações especiais, onde o acesso e/ou retorno a assistência médica seja difícil, poderá ser considerado o emprego inicial de medicação anti-hipertensiva, mesmo para esse grupo de pacientes. Para aqueles em estágio 1 e alto risco CV ou DCV estabelecida, o uso de medicamentos deverá ser iniciado de imediato. Da mesma maneira, nos casos de HA estágio 2 e 3, independentemente do risco CV, o tratamento medicamentoso deverá ser iniciado de imediato. Para os indivíduos com pré-hipertensão, a utilização de medicamentos poderá ser uma opção, levando-se em consideração o risco CV e/ou a presença de DCV. Em pacientes de 60 a 79 anos, com PAS ≥ 140 mmHg e naqueles com ≥ 80 anos com PAS ≥ 160 mmHg, o início da terapia medicamentosa deverá ser mais precoce.

Esquemas terapêuticos

O tratamento com medicamentos poderá ser realizado com uma ou mais classes de fármacos, de acordo com a necessidade, para que sejam obtidas as metas para a PA e de acordo com situações específicas (Figura 1).

Figura 1 Fluxograma para o tratamento da hipertensão. RCV: risco cardiovascular; TNM: tratamento não medicamentoso; DIU: diuréticos; IECA: inibidores da enzima de conversão da angiotensina; BCC: bloqueador dos canais de cálcio; BRA: bloqueador do receptor de angiotensina; BB: betabloqueadores.

Figura 2 Esquema preferencial de associações de medicamentos, de acordo com mecanismos de ação e sinergia. Adaptado de Journal of Hypertension 2007, 25:1751-1762

Monoterapia

A monoterapia pode ser a estratégia anti-hipertensiva inicial para pacientes com HA estágio 1, com risco CV baixo e moderado. Entretanto, deve-se observar que, de acordo com a meta a ser atingida, a maioria dos pacientes irá necessitar da associação de medicamentos. O tratamento deve ser individualizado e a escolha inicial do medicamento a ser utilizado como monoterapia deve basear-se nos seguintes aspectos: capacidade de o agente escolhido reduzir a morbimortalidade CV; mecanismo fisiopatogênico predominante no paciente a ser tratado; características individuais; doenças associadas; condições socioeconômicas.

Com base nesses critérios, as classes de anti-hipertensivos atualmente consideradas preferenciais para o controle da PA em monoterapia inicial são (Figuras 1 e 2):

DIU tiazídicos (preferência para clortalidona);5^,10^-15^,39^,71^,72

IECA;7^-11^,15^,17^,18^,24^-26

BCC;7^-11^,15^,17^-23

BRA.10^,11^,27^-33^,73^-78

Deve ser observado que os DIU são os fármacos que apresentam mais evidências de efetividade com relação aos desfechos CV, com claros benefícios para todos os tipos de eventos. Há situações em que a indicação de um ou outro grupo ganha destaque, de acordo com a comorbidade presente. O BB poderá ser considerado como fármaco inicial em situações específicas, como a associação de arritmias supraventriculares, enxaqueca, IC e coronariopatia, sendo que, nas duas últimas condições, deverá estar associado a outros fármacos.47^,48

A posologia deve ser ajustada para que se consiga redução da PA até valores considerados adequados para cada caso (metas terapêuticas).1^,2^,8^,79 Se o objetivo terapêutico não for conseguido com a monoterapia inicial, três condutas são possíveis:

se o resultado for parcial, mas sem efeitos adversos, recomenda-se aumentar a dose do medicamento em uso, podendo também ser considerada a associação com anti-hipertensivo de outro grupo terapêutico;

quando não houver efeito terapêutico esperado na dose máxima preconizada ou se surgirem eventos adversos, recomenda-se substituir o anti-hipertensivo inicialmente utilizado, reduzir a dosagem e associar outro anti-hipertensivo de classe diferente ou instituir uma outra associação de fármacos;

se, ainda assim, a resposta for inadequada, devem-se associar três ou mais medicamentos (Figura 1).

Combinação de medicamentos

A maioria dos pacientes vai necessitar do uso de mais de um medicamento para que sejam atingidas as metas. Por esse motivo, os pacientes com HA estágio 1 e com risco CV alto ou muito alto ou com DCV associada e aqueles com estágio 2 ou 3 com ou sem outros FRCV associados devem ser considerados para o uso de combinação de fármacos (Figura 1). A utilização de associações de dois medicamentos em baixas dosagens em hipertensos estágio 1, mesmo com baixo ou moderado risco CV, embora não preferencial, também poderá ser considerada em casos individuais.

Para a escolha dos medicamentos em associação, deve ser evitado o uso de anti-hipertensivos com mesmo mecanismo de ação. Fazem exceção a essa regra a associação de DIU tiazídicos com poupadores de potássio. O uso de DIU de alça deve ser reservado para aqueles com RFG abaixo de 30ml/min ou com edema grave. As associações que tenham atuação sinérgica sempre propiciarão resultados melhores (Figura 2).80

Particularidades das associações:

As associações menos testadas devem ser reservadas para os casos em que haja necessidade de maior número de medicamentos;

O uso de BB associado a DIU deve ser feito com cautela em pacientes que apresentem alterações do metabolismo dos glicídeos, pois ambos os fármacos favorecem seu agravamento;

A associação de IECA com BRA não é recomendada, pois, além de não mostrar benefício em desfechos CV, acrescentou risco de efeitos adversos;33

São praticamente inexistentes estudos comparando diretamente uma associação com outra. Um estudo demonstrou que a combinação de IECA a BCC, comparada à associação de IECA com DIU, foi mais efetiva na redução de morbimortalidade CV e progressão de doença renal, para uma redução da PA semelhante, sobretudo em indivíduos não obesos.81^,82

As combinações podem ser feitas com fármacos em separado ou em associação fixa (na mesma formulação galênica). Se, por um lado, o uso de combinações livres permite-nos a escolha da dose de cada um dos componentes, por outro, verificou-se que o uso de associações fixas favorece a adesão à terapêutica, pelo uso de menor número de comprimidos.83

Caso não sejam alcançadas as metas de controle da PA com dois fármacos, podem ser tomadas algumas decisões:

em caso de resultado parcial e sem efeitos colaterais, pode-se optar por aumentar a dose da combinação inicial ou acrescentar mais um anti-hipertensivo de outra classe;

quando a meta não tiver sido atingida na dose máxima preconizada, ou se surgirem eventos adversos, recomenda-se a substituição da combinação;

se, nas doses máximas possíveis, não se obtiver controle da PA, devem-se associar outros anti-hipertensivos (Figura 1).

Caso o DIU não tenha sido a primeira escolha e não esteja sendo utilizado na associação de dois fármacos, deve ser o terceiro a ser acrescentado. Seu uso potencializa a ação anti-hipertensiva de qualquer dos medicamentos iniciais.

Nos casos em que se configure a HA resistente (falta de controle da PA com o uso de pelo menos três medicamentos em dosagens máximas toleradas, sendo um deles um DIU), está indicada a associação de espironolactona.84^-86 Os simpaticolíticos de ação central (clonidina) ou BB podem ser uma alternativa ao quarto fármaco, ficando o uso de vasodilatadores diretos reservado para casos especiais e em associação com DIU e BB.