Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC x5BZ3tQwsNJsCdd8nCbjJGN S0066-782X2016004800044 10.5935/abc.20160158 Diretrizes 7th Brazilian Guideline of Arterial Hypertension: Chapter 8 - Hypertension and Associated Clinical Conditions Malachias MVB Amodeo C Paula RB Cordeiro AC Júnior Magalhães LBNC Bodanese LC 09 2016 107 3 Suppl 3 44 48 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. Diabetes mellitus

The association of AH and DM doubles the CV risk and has increased the AH prevalence, which is related to the elevation in overweight and obesity rates, as well as the increase in the elderly population.1 The incidence of AH in type 1 diabetic patients increases from 5%, at the age of 10 years, to 33%, at the age of 20 years, and to 70%, at the age of 40 years.2 There is a strict relationship between the development of AH and the presence of albuminuria in that population.3 That increase in the AH incidence can reach 75-80% in patients with diabetic kidney disease.4 Approximately 40% of patients with a recent diagnosis of DM have AH.5 In approximately 50% of type 2 diabetic patients, AH occurs before the development of albuminuria. All diabetic hypertensives are at high CV risk. In addition to all complementary tests recommended for hypertensives, diabetic patients require the search for urine albumin excretion, fundoscopic eye exam and assessment of probable postural hypotension, which can characterize the presence of autonomic nervous system dysfunction.6

The BP targets to be achieved are still controversial. However, there is recent consensus on a BP target < 130/80 mm Hg. (GR: IIb; LE: B). For the NPT of AH in diabetic individuals, all recommendations expressed in Chapter 6 apply. The therapeutic choice should be based on drug efficacy and tolerability. Considering that all diabetic patients are at high CV risk, the initial treatment includes the association of at least two drugs of different classes.7 In diabetic hypertensives without nephropathy, all antihypertensive drugs can be used. In the presence of diabetic nephropathy, however, RAAS inhibitors are preferred.8 (GR: I; LE: A). Simultaneous use of ACEI and ARB should be avoided because of the risk of complications.9,10 Although worsening insulin resistance, BB are useful for BP control in diabetic patients, especially when used in combinations to treat hypertensives with CAD or HF.11

Metabolic syndrome

Metabolic syndrome (MS) is characterized by the coexistence of CVRFs (low HDL-C, high triglycerides, AH and dysglycemia) either associated or not with central obesity (identified by the AC measure). The definitions of MS differ according to different entities. In 2009, those entities convened a task force to conciliate the different definitions of MS.12 The criteria are described in Chapter 4 about CV risk stratification. The presence of AH in MS increases global CV risk. The initial treatment is based on lifestyle changes in association or not with the use of drugs. Because nonpharmacological measures isolated do not control BP, pharmacological treatment is required whenever BP ≥ 140/90 mm Hg.13 There is no evidence of benefit in the use of antihypertensive agents for MS with normal BP levels. When dysglycemia is present, the preferred drugs to begin AH treatment in MS are RAAS blockers and CCB.13-19

Coronary artery disease

The treatment of AH associated with CAD, which includes patients after myocardial infarction, with chest angina and myocardial revascularization, should preferably comprise BBs, ACEIs and ARBs, in addition to statins and acetylsalicylic acid. Beta-blockers have proven highly beneficial after AMI, especially within 2 years from the acute event.20 Similarly, ACEIs tested on that condition have also proven beneficial.21,22 In patients with chronic CAD and multiple RFs, such as AH, ACEIs have shown a favorable effect to reduce relevant clinical outcomes.23 (GR: I; LE: A). Regarding BP target, it is worth considering the likelihood of the J curve effect, demonstrated in different studies,24-27 in which the excessive BP reduction, mainly in DBP, can precipitate CV events in patients with obstructive CAD. Additional drugs to meet target BP (BP < 130/80 mm Hg) are CCBs and thiazide DIUs.28 (GR: IIa; LE: B).

 Stroke

Stroke is the most common manifestation of the vascular damage caused by AH. In transient ischemic attack (TIA), the neurologic deficit is solved in 24 hours, with no clinically detectable sequelae.

Pharmacological treatment of AH in the patient with previous stroke

Chronically, the effective antihypertensive therapy, maintaining BP < 130/80 mm Hg, has played a decisive role in the secondary prevention of all types of stroke and TIA.29-35 (GR: IIa; LE: B). As long as BP is reduced, any antihypertensive drug can be used.20,36,37 There is no clinical evidence allowing a definitive conclusion about the preferential use of ARBs as compared to other antihypertensive drugs for the secondary prevention of stroke.34,35 There is currently no evidence showing the effectiveness of beginning antihypertensive therapy for SBP < 140 mm Hg for patients with a previous stroke. (GR: III; LE: B).

 Chronic kidney disease

For patients with that disease, BP reduction is the most effective measure to reduce CV risk and to slow kidney damage progression, regardless of the antihypertensive drug used.38,39 (GR: I; LE: A). Special attention should be paid to patients with high albuminuria, which determines the unfavorable course of kidney disease40 and increases CV risk.41 (GR: IIa; LE: A). Elderly patients with renovascular disease, CAD and risk for postural hypotension often require customization of the antihypertensive treatment.40 (GR: IIa; LE: C). Usually, BP levels < 130/80 mm Hg are recommended, especially for those with albuminuria > 30 mg/g of creatinine and diabetic patients.42,43 In such patients, maintaining BP < 130/80 mm Hg reduces albuminuria and the risk for stroke, but there is no evidence that it decreases CV events and mortality.44,45 (GR: IIa; LE: A). However, it is controversial whether BP reduction to those levels is associated with better CKD course and with a reduction in mortality.7,46,47 (GE: IIb; LE: B). The present guideline suggests the adoption of BP targets shown in Chart 1.

Blood pressure targets for patients on conservative treatment, according to kidney disease etiology and albuminuria
ALBUMINURIA < 30 mg/24 hours ALBUMINURIA > 30 mg/24 hours
Non-diabetic CKD < 140/90 mm Hg < 130/80 mm Hg
Preferential drug Any ACEI or ARB
Diabetic CKD <130/80 mm Hg <130/80 mm Hg
Preferential drug Any ACEI or ARB

CKD: chronic kidney disease; ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin receptor blocker.

 Choice of antihypertensive drug: stage 1 to 5 chronic kidney disease on conservative treatment

Thiazide DIUs are recommended, because they are effective in stages 1, 2 and 3 CKD, while loop DIUs are recommended for stages 4 and 5 CKD. That drug class reduces CV morbidity and mortality,48,49 being considered the choice for association in CKD.38,49,50 (GR: I; NE: A). The ACEIs and ARBs are widely used for CKD, being effective for AH control and albuminuria reduction.51-55 (GR: I; LE: A). Regarding direct renin inhibitors and mineralocorticoid receptor antagonists, both with an antiproteinuric action, there is no evidence for their use in clinical practice.56-58 The risk of hyperpotassemia should be considered, especially with the latter. The double RAAS block is controversial. The combination of ACEI with ARB59,60 or of a renin inhibitor with ACEI or ARB10 has resulted in more acute kidney damage and hyperpotassemia, leading to a ban on that strategy from nephrological practice. (GR: I; LE: A). However, in a recent study on adult polycystic kidney disease61 and a meta-analysis on diabetic patients with CKD,62 the association of IECA and ARB has delayed the course of nephropathy without causing severe hyperpotassemia and acute kidney damage. (GR: IIb; LE: B). However, the double RAAS block remains contraindicated. (GR: I; LE: A). The CCBs are effective, especially for combined use with ACEI or ARB, being associated with a reduction in CV events.63,64 Other options include BBs, adrenergic inhibitors of central action, and, occasionally, direct acting vasodilators, such as minoxidil and hydralazine.

 Approach to stage 5 chronic kidney disease on kidney replacement therapy

Most studies on AH in patients with CKD undergoing dialysis is based on measuring pre-dialysis BP levels. However, BP obtained in that way is known to have large variability, in addition to being usually overestimated, as it is underestimated when obtained after dialysis.65,66 In those patients, BP should be preferably measured outside the dialysis centers, in the interdialytic intervals.67 (GR: IIa; LE: B). Home BP measures are more reproducible than those obtained before and after dialysis, have a fair association with both 44-hour ABPM and CV prognosis in patients undergoing dialysis.68-70 (GR: IIa; LE: B). In addition, a randomized study has shown that therapeutic decisions based on HBPM associate with better interdialytic BP control assessed with 24-hour ABPM as compared to pre-dialysis BP measurement.71 Regarding ABPM, it is worth noting that, although the 44-hour long exam is considered gold-standard for assessment of hemodialysis patients, its technical difficulties favor the use of 24-hour ABPM and home BP measurements.

The association between BP and mortality in patients with CKD undergoing dialysis has a "U" distribution for SBP and DBP, thus, both elevated and reduced levels relate to bad prognosis.70 (GR: IIa; LE: B). There are not enough studies to support with satisfactory level of evidence the diagnosis of AH in patients undergoing dialysis; however, the most accepted pre- and post-hemodialysis BP levels for that purpose are ≥ 140/90 mm Hg and ≥ 130/80 mm Hg, respectively.70,71 (GR: IIa; LE: C). A study with 326 hemodialysis patients has associated better prognosis with mean SBP levels between 120 and 130 mm Hg, in HBPM, and between 110 and 120 mm Hg, in ABPM.68 (GR: IIb; LE: B).

Because, in that population, hypervolemia plays a major role in AH etiology, the therapeutic management should consider that variable, focusing the treatment on gradual control of "dry weight", via salt and water restriction, in addition to promoting adequate ultrafiltration during hemodialysis sessions.71-75 (GR: IIa, LE: B). The choice of antihypertensive drugs should be individualized and based on characteristics, such as comorbidities, and drug's cardioprotective effect, intra- and interdialytic pharmacokinetic characteristics, and side effects.71,72 (GR: IIa; LE: C).

In kidney-transplanted patients, CCBs are a good option for AH treatment, because they are effective antihypertensive agents that antagonize arteriolar vasoconstriction caused by cyclosporine.76 The RAAS blockers can improve the transplant outcome in patients with increased urine albumin excretion. Diuretics, BBs, central action sympatholytic drugs and vasodilators can be used based on clinical judgement.77,78

References 1 Grossman E, Messerli FH, Goldbourt U. High blood pressure and diabetes mellitus: are all antihypertensive drugs created equal. Arch Intern Med. 2000;160(16):2447-52. Grossman E Messerli FH Goldbourt U High blood pressure and diabetes mellitus: are all antihypertensive drugs created equal Arch Intern Med 2000 160 16 2447 2452 2 Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension. 1992;19(5):403-18. Epstein M Sowers JR Diabetes mellitus and hypertension Hypertension 1992 19 5 403 418 3 Kidney Disease Improving Global Outcomes. Definition and classification of CKD. Kidney Int Suppl. 2013;3(1):19-62. Kidney Disease Improving Global Outcomes Definition and classification of CKD Kidney Int Suppl 2013 3 1 19 62 4 Mogensen CE, Hansen KW, Pedersen MM, Christensen CK. Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM. Diabetes Care. 1991;14 Suppl 4:13-26. Mogensen CE Hansen KW Pedersen MM Christensen CK Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM Diabetes Care 1991 14 4 13 26 5 Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens. 1993;11(3):309-17. Hypertension in Diabetes Study (HDS): I Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications J Hypertens 1993 11 3 309 317 6 James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20. Erratum in: JAMA. 2014;311(17):1809. James PA Oparil S Carter BL Cushman WC Dennison-Himmelfarb C Handler J 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) nullErratum in JAMA. 2014;311(17):1809 JAMA 2014 311 5 507 520 7 Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus. ACCORD Study Group. N Engl J Med. 2010;362(17):1575-85. Cushman WC Evans GW Byington RP Goff DC Jr Grimm RH Jr Cutler JA Effects of intensive blood pressure control in type 2 diabetes mellitus. ACCORD Study Group N Engl J Med 2010 362 17 1575 1585 8 Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al; Blood Pressure Lowering Tratment Trialists´collaboration. Effects of different blood pressure lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively-designed overviews of randomized trials. Arch Intern Med. 2005;165(12):1410-9. Turnbull F Neal B Algert C Chalmers J Chapman N Cutler J Blood Pressure Lowering Tratment Trialists´collaboration Effects of different blood pressure lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively-designed overviews of randomized trials Arch Intern Med 2005 165 12 1410 1419 9 Mancia G, Schumacher H, Redon J, Verdecchia P, Schmiever R, Jennings G, et al. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET). Circulation. 2011;124(16):1727-36. Mancia G Schumacher H Redon J Verdecchia P Schmiever R Jennings G Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET) Circulation 2011 124 16 1727 1736 10 Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al; ALTITUDE Investigators. Cardiorenal endpoints in a trial of aliskiren for type 2 diabetes, New Engl J Med. 2012;367(23):2204-13. Parving HH Brenner BM McMurray JJ de Zeeuw D Haffner SM Solomon SD ALTITUDE Investigators Cardiorenal endpoints in a trial of aliskiren for type 2 diabetes New Engl J Med 2012 367 23 2204 2213 11 Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357. Mancia G Fagard R Narkiewicz K Redon J Zanchetti A Bohm M Task Force Members 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) J Hypertens 2013 31 7 1281 1357 12 Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-5. Alberti KG Eckel RH Grundy SM Zimmet PZ Cleeman JI Donato KA Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity Circulation 2009 120 16 1640 1645 13 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-52. Erratum in: Circulation. 2005;112(17):e298. Grundy SM Cleeman JI Daniels SR Donato KA Eckel RH Franklin BA American Heart AssociationNational Heart.Lung.and Blood Institute Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement nullErratum in Circulation. 2005;112(17):e298 Circulation 2005 112 17 2735 2752 14 Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. National Institutes of Health. Obes Res. 1998;6 Suppl 2:51S-209S. Erratum in: Obes Res. 1998;6(6):464. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report National Institutes of Health nullErratum in Obes Res. 1998;6(6):464 Obes Res 1998 6 2 51S 209S 15 World Health Organization. (WHO). Obesity: preventing and managing the global epidemic: report on a WHO consultation. (Technical Report Series 894). Geneva, Switzerland: World Health Organization; 2000. World Health Organization Obesity: preventing and managing the global epidemic: report on a WHO consultation (Technical Report Series 894) 2000 Geneva, Switzerland World Health Organization 16 Canadian guidelines for body weight classification in adults. Ottawa (Canada): Health Canada Publications Centre; 2003. (Publication ID No. 4645). Canadian guidelines for body weight classification in adults 2003 Ottawa(Canada) Health Canada Publications Centre (Publication ID No. 4645) 17 Khan NA, McAlister FA, Rabkin SW, Padwal R, Feldman RD, Campbell NR, et al. Canadian Hypertension Education Program. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension, part II: therapy. Can J Cardiol. 2006;22(7):583-93. Khan NA McAlister FA Rabkin SW Padwal R Feldman RD Campbell NR Canadian Hypertension Education Program. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension, part II: therapy Can J Cardiol 2006 22 7 583 593 18 Hara K, MatsushitaY, Horikoshi M, Yoshiike N, Yokoyama T, Tanaka H, et al. A proposal for the cutoff point of waist circumference for the diagnosis of metabolic syndrome in the Japanese population. Diabetes Care. 2006;29(5):1123-4. Hara K Matsushita Y Horikoshi M Yoshiike N Yokoyama T Tanaka H A proposal for the cutoff point of waist circumference for the diagnosis of metabolic syndrome in the Japanese population Diabetes Care 2006 29 5 1123 1124 19 Brandão AP, Brandão AA, Nogueira AR, Suplicy H, Guimarães JI, Oliveira JE. Sociedade Brasileira de Cardiologia. I Diretriz brasileira de diagnóstico e tratamento da síndrome metabólica. Arq Bras Cardiol. 2005;84(supl 1):1-28. Brandão AP Brandão AA Nogueira AR Suplicy H Guimarães JI Oliveira JE Sociedade Brasileira de Cardiologia. I Diretriz brasileira de diagnóstico e tratamento da síndrome metabólica Arq Bras Cardiol 2005 84 Suppl 1 1 28 20 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 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 b1665 21 Borghi C, Bacchelli S, Degli Esposti D, Bignamini A, Magnani B, Ambrosioni E. Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation. Am J Hypertens. 1999;12(7):665-72. Borghi C Bacchelli S Degli Esposti D Bignamini A Magnani B Ambrosioni E Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation Am J Hypertens 1999 12 7 665 672 22 Gustafsson F, Kober L, Torp-Pedersen C, Hildebrandt P, Ottesen MM, Sonne B, et al. Long-term prognosis after acute myocardial infarction in patients with a history of arterial hypertension. TRACE study group. Eur Heart J. 1998;19(4):588-94. Gustafsson F Kober L Torp-Pedersen C Hildebrandt P Ottesen MM Sonne B Long-term prognosis after acute myocardial infarction in patients with a history of arterial hypertension. TRACE study group Eur Heart J 1998 19 4 588 594 23 Arnold JM, Yusuf S, Young J. Prevention of heart failure in patients in the heart outcomes prevention evaluation (HOPE) study. Circulation. 2003;107(9):1284-90. Arnold JM Yusuf S Young J Prevention of heart failure in patients in the heart outcomes prevention evaluation (HOPE) study Circulation 2003 107 9 1284 1290 24 Messerli FH, Mancia G, Conti CR, Hewkin AC, Kupfer S, Champion A, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144(12):884-93. Messerli FH Mancia G Conti CR Hewkin AC Kupfer S Champion A Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006 144 12 884 893 25 Sleight P, Redon J, Verdecchia P, Mancia G, Gao P, Fagard R, et al; ONTARGET investigators. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens. 2009;27(7):1360-9. Sleight P Redon J Verdecchia P Mancia G Gao P Fagard R ONTARGET investigators Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study J Hypertens 2009 27 7 1360 1369 26 Zanchetti A, Mancia G. Longing for clinical excellence: a critical outlook into the NICE recommendations on hypertension management--is nice always good? J Hypertens. 2012;30(4):660-8. Zanchetti A Mancia G Longing for clinical excellence: a critical outlook into the NICE recommendations on hypertension management--is nice always good? J Hypertens 2012 30 4 660 668 27 Mancia G, Parati G, Bilo G, Gao P, Fagard R, Redon J, et al. Ambulatory blood pressure values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Hypertension. 2012;60(6):1400-6. Mancia G Parati G Bilo G Gao P Fagard R Redon J Ambulatory blood pressure values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) Hypertension 2012 60 6 1400 1406 28 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 Hypertens. 2014;32(1):3-15. Weber MA Schiffrin EL White WB Mann S Lindholm LH Kenerson JG 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 Hypertens 2014 32 1 3 15 29 Rashid P. Leornardi-Bee J. Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke. 2003;34(11):2741-8. Rashid P Leornardi-Bee J Bath P Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review Stroke 2003 34 11 2741 2748 30 PATS Collaborating Group. Poststroke antihypertensive treatment study: a preliminary result. Chin Med J (Engl). 1995;108(9):710-7. PATS Collaborating Group Poststroke antihypertensive treatment study: a preliminary result Chin Med J (Engl) 1995 108 9 710 717 31 Gueyffier F, Boissel JP, Boutitie F, Pocock S, Coope J, Cutler J, et al. Effect of antihypertensive treatment in patients having already suffered from stroke. Gathering the evidence. The INDANA (IN-dividual Data Analysis of Antihypertensive intervention trials) Project Collaborators. Stroke. 1997;28(12):2557-62. Gueyffier F Boissel JP Boutitie F Pocock S Coope J Cutler J Effect of antihypertensive treatment in patients having already suffered from stroke. Gathering the evidence. The INDANA (IN-dividual Data Analysis of Antihypertensive intervention trials) Project Collaborators Stroke 1997 28 12 2557 2562 32 PROGRESS Collaborative Group. Randomised trial of a perindopril based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033-41. Erratum in: Lancet. 2001;358(9292):1556; Lancet. 2002;359(9323):2120. PROGRESS Collaborative Group Randomised trial of a perindopril based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack nullErratum in Lancet. 2001;358(9292):1556 Lancet 2001 358 9287 1033 1041 33 Liu L, Wang Z, Gong L, Zhang Y, Thijs L, Staessen JA, et al. Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature. Hypertens Res. 2009;32(11):1032-40. Liu L Wang Z Gong L Zhang Y Thijs L Staessen JA Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature Hypertens Res 2009 32 11 1032 1040 34 Schrader J. Luders S. Kulschewski A, Hammersen F, Plate K, Berger J, et al; MOSES Study Group. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36(6):1218-26. Schrader J Luders S Kulschewski A Hammersen F Plate K Berger J MOSES Study Group. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES) Stroke 2005 36 6 1218 1226 35 Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al; ProFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225-37. Yusuf S Diener HC Sacco RL Cotton D Ounpuu S Lawton WA ProFESS Study Group Telmisartan to prevent recurrent stroke and cardiovascular events N Engl J Med 2008 359 12 1225 1237 36 White CL, Pergola PE, Szychowski JM, Talbert R, Cervantes-Arriaga A, Clark HD, et al; SPS3 Investigators. Blood pressure after recent stroke: baseline findings from the secondary prevention of small subcortical strokes trial. Am J Hypertens. 2013;26(9):1114-22. White CL Pergola PE Szychowski JM Talbert R Cervantes-Arriaga A Clark HD SPS3 Investigators Blood pressure after recent stroke: baseline findings from the secondary prevention of small subcortical strokes trial Am J Hypertens 2013 26 9 1114 1122 37 Paul SL, Thrift AG. Control of hypertension 5 years after stroke in the North East Melbourne Stroke Incidence Study. Hypertension. 2006;48(2):260-5. Paul SL Thrift AG Control of hypertension 5 years after stroke in the North East Melbourne Stroke Incidence Study Hypertension 2006 48 2 260 265 38 Kidney Disease: Improving Global Outcomes (KDIGO) Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements. 2013;3(1):1-150. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease Kidney International Supplements 2013 3 1 1 150 39 Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smith L, D'Hingorani AD, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366(9502):2026-33. Casas JP Chua W Loukogeorgakis S Vallance P Smith L D'Hingorani AD Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis Lancet 2005 366 9502 2026 2033 40 Ruggenenti P, Perna A, Mosconi L, Matalone M, Pisoni R, Gaspari F, et al. Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN). Kidney Int Suppl. 1997;63:S54-7. Ruggenenti P Perna A Mosconi L Matalone M Pisoni R Gaspari F Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN) Kidney Int Suppl 1997 63 S54 S57 41 Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al; Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073-81. Matsushita K van der Velde M Astor BC Woodward M Levey AS de Jong PE Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis Lancet 2010 375 9731 2073 2081 42 Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease study. Ann Intern Med. 2005;142(5):342-51. Sarnak MJ Greene T Wang X Beck G Kusek JW Collins AJ The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease study Ann Intern Med 2005 142 5 342 351 43 Appel LJ, Wright JT Jr, Greene T, Agodoa LY, Astor BC, Bakris GL, Cleveland WH, et al; AASK Collaborative Research Group. Intensive blood pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363(10):918-29. Appel LJ Wright JT Jr Greene T Agodoa LY Astor BC Bakris GL Cleveland WH AASK Collaborative Research Group Intensive blood pressure control in hypertensive chronic kidney disease N Engl J Med 2010 363 10 918 929 44 Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123(24):2799-810. Bangalore S Kumar S Lobach I Messerli FH Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials Circulation 2011 123 24 2799 2810 45 Reboldi G, Gentile G, Angeli F, Ambrosio G, Mancia G, Verdecchia P. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients. J Hypertens. 2011;29(7):1253-69. Reboldi G Gentile G Angeli F Ambrosio G Mancia G Verdecchia P Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients J Hypertens 2011 29 7 1253 1269 46 Upadhyay A, Earley A, ShaHaynes SM, Uhlig K. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med. 2011;154(8):541-8. Upadhyay A Earley A ShaHaynes SM Uhlig K Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier Ann Intern Med 2011 154 8 541 548 47 McBrien K, Rabi DM, Campbell N, Barnieh L, Clement F, Hemmelgarn BR, et al. Intensive and standard blood pressure targets in patients with type 2 diabetes mellitus systematic review and meta-analysis. Arch Intern Med. 2012;172(17):1296-303. McBrien K Rabi DM Campbell N Barnieh L Clement F Hemmelgarn BR Intensive and standard blood pressure targets in patients with type 2 diabetes mellitus systematic review and meta-analysis Arch Intern Med 2012 172 17 1296 1303 48 Verbeke F, Lindley E, Van Bortel L, Vanholder R, London G, Cochat P, et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Non-dialysis-dependent Chronic Kidney Disease. Nephrol Dial Transplant. 2014;29(3):490-6. Verbeke F Lindley E Van Bortel L Vanholder R London G Cochat P A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Non-dialysis-dependent Chronic Kidney Disease Nephrol Dial Transplant 2014 29 3 490 496 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 2008 (ALLHAT). JAMA. 2002;288(23):2981-97. Erratum in: JAMA. 2004;291(18):2196. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 2008 (ALLHAT) JAMA 2002 288 23 2981 2997 Erratum in: JAMA. 2004;291(18):2196 50 Rahman M, Ford CE, Cutler JA, Davis BR, Piller LB, Whelton PK, et al; ALLHAT Collaborative Research Group. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol. 2012;7(6):989-1002. Rahman M Ford CE Cutler JA Davis BR Piller LB Whelton PK ALLHAT Collaborative Research Group Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR Clin J Am Soc Nephrol 2012 7 6 989 1002 51 Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-40. Patel A MacMahon S Chalmers J Neal B Woodward M Billot L ADVANCE Collaborative Group Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial Lancet 2007 370 9590 829 840 52 Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355(9200):253-9. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy Heart Outcomes Prevention Evaluation Study Investigators Lancet 2000 355 9200 253 259 53 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 BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving HH RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropath N Engl J Med 2001 345 12 861 869 54 Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-8. Parving HH Lehnert H Brochner-Mortensen J Gomis R Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes N Engl J Med 2001 345 12 870 878 55 Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-63. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia) Lancet 1997 349 9069 1857 1863 56 Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358(23):2433-46. Parving HH Persson F Lewis JB Lewis EJ Hollenberg NK AVOID Study Investigators Aliskiren combined with losartan in type 2 diabetes and nephropathy N Engl J Med 2008 358 23 2433 2446 57 Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 2006;70(12):2116-23. Bianchi S Bigazzi R Campese VM Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease Kidney Int 2006 70 12 2116 2123 58 Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis. 2008;51(2):199- 211. Bomback AS Kshirsagar AV Amamoo MA Klemmer PJ Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review Am J Kidney Dis 2008 51 2 199 211 59 Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. 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 JF Schmieder RE McQueen M Dyal L Schumacher H Pogue J 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 60 Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckortt W, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013; 369(20):1892-903. Erratum in: N Engl J Med. 2014;158:A7255. Fried LF Emanuele N Zhang JH Brophy M Conner TA Duckortt W VA NEPHRON-D Investigators Combined angiotensin inhibition for the treatment of diabetic nephropathy nullErratum in N Engl J Med. 2014;158:A7255 N Engl J Med 2013 369 20 1892 1903 61 Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al; HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371(24):2255-66. Schrier RW Abebe KZ Perrone RD Torres VE Braun WE Steinman TI HALT-PKD Trial Investigators Blood pressure in early autosomal dominant polycystic kidney disease N Engl J Med 2014 371 24 2255 2266 62 Palmer SC, Mavridis D, Navarese E, Craig JC, Tonelli M, Salanti G, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015;385(9982):2047-56. Palmer SC Mavridis D Navarese E Craig JC Tonelli M Salanti G Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis Lancet 2015 385 9982 2047 2056 63 Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caufield M, et al. 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 multicentre randomised controlled trial. Lancet. 2005;366(9489):895-906. Dahlof B Sever PS Poulter NR Wedel H Beevers DG Caufield M 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 multicentre randomised controlled trial Lancet 2005 366 9489 895 906 64 Bakris GL, Sarafidis 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 prespecified secondary analysis of a randomized controlled trial. Lancet. 2010;375(9721):1173-81. Bakris GL Sarafidis PA Weir MR Dahlof B Pitt B Jamerson K ACCOMPLISH Trial Investigators Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomized controlled trial Lancet 2010 375 9721 1173 1181 65 Agarwal R, Peixoto AJ, Santos SF, Zoccali C. Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure. Clin J Am Soc Nephrol. 2006;1(3):389-98. Agarwal R Peixoto AJ Santos SF Zoccali C Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure Clin J Am Soc Nephrol 2006 1 3 389 398 66 Rohrscheib MR, Myers OB, Servilla KS, Adams CD, Miskulin D, Bedrick EJ, et al; DCI Medical Directors. Age-related blood pressure patterns and blood pressure variability among hemodialysis patients. Clin J Am Soc Nephrol. 2008;3(5):1407-14. Rohrscheib MR Myers OB Servilla KS Adams CD Miskulin D Bedrick EJ DCI Medical Directors Age-related blood pressure patterns and blood pressure variability among hemodialysis patients Clin J Am Soc Nephrol 2008 3 5 1407 1414 67 Agarwal R, Andersen MJ, Bishu K, Saha C. Home blood pressure monitoring improves the diagnosis of hypertension in hemodialysis patients. Kidney Int. 2006;69(5):900-6. Agarwal R Andersen MJ Bishu K Saha C Home blood pressure monitoring improves the diagnosis of hypertension in hemodialysis patients Kidney Int 2006 69 5 900 906 68 Bansal N, McCulloch CE, Rahman M, Kusek JW, Anderson AH, Xie D, et al; CRIC Study Investigators. Blood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the chronic renal insufficiency cohort study. Hypertension. 2015;65(1):93-100. Bansal N McCulloch CE Rahman M Kusek JW Anderson AH Xie D CRIC Study Investigators Blood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the chronic renal insufficiency cohort study Hypertension 2015 65 1 93 100 69 Agarwal R, Satyan S, Alborzi P, Light RP, Tegegne GG, Mazengia HS, et al. Home blood pressure measurements for managing hypertension in hemodialysis patients. Am J Nephrol 2009;30(2):126-34. Agarwal R Satyan S Alborzi P Light RP Tegegne GG Mazengia HS Home blood pressure measurements for managing hypertension in hemodialysis patients Am J Nephrol 2009 30 2 126 134 70 Agarwal R. Blood pressure and mortality among hemodialysis patients. Hypertension. 2010;55(3):762-8. Agarwal R Blood pressure and mortality among hemodialysis patients Hypertension 2010 55 3 762 768 71 da Silva GV, de Barros S, Abensur H, Ortega KC, Mion D Jr; Cochrane Renal Group Prospective Trial Register: CRG060800146. Home blood pressure monitoring in blood pressure control among haemodialysis patients: an open randomized clinical trial. Nephrol Dial Transplant. 2009;24(12):3805-11. da Silva GV de Barros S Abensur H Ortega KC Mion D Jr Cochrane Renal Group Prospective Trial Register: CRG060800146 Home blood pressure monitoring in blood pressure control among haemodialysis patients: an open randomized clinical trial Nephrol Dial Transplant 2009 24 12 3805 3811 72 Levin NW, Kotanko P, Eckardt KU, Kasiske BL, Chazot C, Cheung AK, et al. Blood pressure in chronic kidney disease stage 5D - report from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2010;77(4):273-84. Levin NW Kotanko P Eckardt KU Kasiske BL Chazot C Cheung AK Blood pressure in chronic kidney disease stage 5D - report from a Kidney Disease: Improving Global Outcomes controversies conference Kidney Int 2010 77 4 273 284 73 K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005;45(4 Suppl 3):S1-S153. K/DOQI Workgroup K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients Am J Kidney Dis 2005 45 4 Suppl 3 S1 S153 74 Horl MP, Horl WH. Dialysis: normovolemia is a therapeutic target for hypertension. Nat Rev Nephrol. 2009;5(8):438-9. Horl MP Horl WH Dialysis: normovolemia is a therapeutic target for hypertension Nat Rev Nephrol 2009 5 8 438 439 75 Agarwal R, Alborzi P, Satyan S, Light RP. Dry-weight reduction in hypertensive hemodialysis patients (DRIP): a randomized, controlled trial. Hypertension. 2009;53(3):500-7. Agarwal R Alborzi P Satyan S Light RP Dry-weight reduction in hypertensive hemodialysis patients (DRIP): a randomized, controlled trial Hypertension 2009 53 3 500 507 76 Grzesk G, Wicinski M, Malinowski B, Grzesk E, Manyslak S, Odrawaz-Sypniewska G, et al: Calcium blockers inhibit cyclosporine A-induced hyperreactivity of vascular smooth muscle cells. Mol Med Rep. 2012;5(6):1469-74. Grzesk G Wicinski M Malinowski B Grzesk E Manyslak S Odrawaz-Sypniewska G Calcium blockers inhibit cyclosporine A-induced hyperreactivity of vascular smooth muscle cells Mol Med Rep 2012 5 6 1469 1474 77 Cross NB, Webster AC, Masson P, O'connell PJ, Craig JC. Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled trials. Transplantation. 2009;88(1):7-18. Cross NB Webster AC Masson P O'connell PJ Craig JC Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled trials Transplantation 2009 88 1 7 18 78 Weir MR, Burgess ED, Cooper JE, Fenves AZ, Goldsmith D, McKay D, et al. Assessment and Management of Hypertension in Transplant Patients. J Am Soc Nephrol. 2015;26(6):1248-60. Weir MR Burgess ED Cooper JE Fenves AZ Goldsmith D McKay D Assessment and Management of Hypertension in Transplant Patients J Am Soc Nephrol 2015 26 6 1248 1260 7ª Diretriz Brasileira de Hipertensão Arterial: Capítulo 8 - Hipertensão e Condições Clínicas Associadas Malachias MVB Amodeo C Paula RB Cordeiro AC Júnior Magalhães LBNC Bodanese LC Diabetes melito

A associação de HA e DM dobra o risco CV e tem aumentado a prevalência de HA, fato ligado à elevação nas taxas de sobrepeso e obesidade, bem como ao aumento da população de idosos em nosso meio.1 A incidência de HA em pacientes diabéticos tipo 1 aumenta de 5%, aos 10 anos de idade, para 33%, aos 20 anos, e para 70%, aos 40 anos.2 Há uma estreita relação entre o desenvolvimento de HA e a presença de albuminúria nessa população.3 Esse aumento na incidência de HA pode atingir 75-80% nos pacientes com doença renal diabética.4 Cerca de 40% dos pacientes com diagnóstico recente de DM tipo 2 têm HA.5 Em aproximadamente 50% dos diabéticos tipo 2, a HA ocorre antes do desenvolvimento de albuminúria. Todo hipertenso diabético é considerado de alto risco CV. Além de todos os exames complementares recomendados para os hipertensos, especificamente nos diabéticos é necessária a pesquisa da excreção urinária de albumina, o exame de fundo de olho e a avaliação de provável hipotensão postural, que pode caracterizar a presença de disfunção do sistema nervoso autônomo.6

Quanto às metas de PA a serem atingidas, há muitas controvérsias. Tem havido, contudo, recente consenso para o alcance de valores de PA < 130/80 mmHg. (GR: IIb; NE: B). Para o TNM da HA no diabético, valem todas as recomendações expressas no capítulo desta diretriz que trata especificamente desse assunto. A escolha terapêutica deve ser baseada na eficácia do medicamento e na tolerabilidade ao mesmo. Considerando-se que todo diabético apresenta alto risco CV, o tratamento inicial inclui a associação de dois ou mais fármacos de classes diferentes.7 Nos hipertensos diabéticos sem nefropatia, todos os anti-hipertensivos podem ser utilizados. Entretanto, na presença de nefropatia diabética, o uso de medicamentos inibidores do SRAA é preferencial.8 (GR: I; NE: A). A utilização simultânea de IECA e BRA deve ser evitada devido ao risco de complicações.9,10 Apesar de agravarem a resistência à insulina, os BB são úteis no controle pressórico dos diabéticos, em especial quando usados em combinação no tratamento de hipertensos com DAC ou IC.11

Síndrome metabólica

A síndrome metabólica (SM) é caracterizada pela coexistência de FRCV (HDL baixo, triglicérides elevados, HA e disglicemia) associada ou não à presença de obesidade central (identificada pela medida da CA). Várias são as definições de SM emitidas por diversas entidades. Em 2009, essas entidades realizaram uma força-tarefa, na tentativa de harmonizar as diversas definições de SM.12 Os critérios estão descritos no capítulo de estratificação de risco CV. A presença de HA na SM aumenta o risco CV global. O tratamento inicial baseia-se em MEV associada ou não ao uso de medicamentos. Uma vez que as medidas não farmacológicas isoladamente não controlam a PA, o tratamento medicamentoso se impõe toda vez que a PA estiver igual ou superior a 140/90 mmHg.13 Não existem evidências de benefícios do uso de medicamentos anti-hipertensivos na SM com PA normal. Na presença de disglicemia, os medicamentos preferenciais para início de tratamento da HA na SM são os bloqueadores do SRAA e os BCC.13-19

Doença coronária

O tratamento da HA associada com DAC, que inclui pacientes pós-infarto do miocárdio, com angina de peito e revascularização miocárdica, deve contemplar preferencialmente os BB, IECA ou BRA, além de estatinas e aspirina. Os BB demonstraram grande benefício após IAM, especialmente no período de dois anos após o evento agudo.20 Do mesmo modo, os IECA testados nessa condição também demonstraram efeito benéfico.21,22 Em pacientes com DAC crônica e múltiplos FR, como HA, o IECA demonstrou efeito favorável na redução de desfechos clínicos relevantes.23 (NE: I; GR: A). Em relação ao nível pressórico a ser atingido, deve-se considerar a possibilidade de efeito da curva J, demonstrado em diferentes estudos,24-27 em que a redução sobretudo diastólica excessiva pode precipitar eventos CV em pacientes com DAC obstrutiva. Medicamentos adicionais para atingir a meta (PA < 130/80 mmHg) são BCC e DIU tiazídicos.28 (GR: IIa; NE: B).

 Acidente vascular encefálico

O AVE é a manifestação mais comum da lesão vascular causada pela HA. No ataque isquêmico transitório (AIT), o déficit neurológico é restabelecido dentro de 24 horas, sem sequelas clinicamente detectáveis.

Tratamento medicamentoso da hipertensão no paciente com AVE prévio

Cronicamente, a terapia anti-hipertensiva eficaz, mantendo PA menor que 130/80 mmHg, tem tido um papel decisivo na prevenção secundária de todos os tipos de AVE e AIT.29-35 (GR: IIa; NE: B). Desde que se obtenha a redução da PA, qualquer medicamento anti-hipertensivo poderá ser utilizado.20,36,37 Evidências clínicas não permitem uma conclusão definitiva para o uso preferencial de BRA quando comparados aos outros anti-hipertensivos na prevenção secundária de AVE.34,35 No momento, não há evidências que iniciar a terapêutica anti-hipertensiva seja efetiva com PAS menor que 140 mmHg em pacientes com passado de AVE. (GR: III; NE: B).

Doença renal crônica

Nessa população, a redução pressórica constitui a medida mais eficaz para a redução do risco CV e atenuação da progressão do dano renal, independentemente do anti-hipertensivo utilizado.38,39 (GR: I; NE: A). Atenção especial deve ser dispensada a pacientes com albuminúria elevada, pois essa é determinante de evolução desfavorável da doença renal,40 bem como de aumento do risco CV.41 (GR: IIa; NE: A). Pacientes idosos com doença renovascular, DAC e com risco de hipotensão postural frequentemente requerem a individualização do tratamento anti-hipertensivo.40 (GR: IIa; NE: C). De modo geral, recomendam-se valores pressóricos inferiores a 130/80 mmHg, especialmente naqueles com albuminúria acima de 30 mg/g de creatinina e em diabéticos.42,43 Nesses, a manutenção de PA inferior a 130/80 mmHg reduz a albuminúria e o risco de AVE, porém sem evidência de diminuição de evento CV e mortalidade.44,45 (GR: IIa; NE: A). Permanece, contudo, incerto se a redução pressórica para esses valores se associa à melhor evolução da DRC e à redução de mortalidade.7,46,47 (GE: IIb; NE: B). A presente diretriz sugere a adoção das metas pressóricas do Quadro 1.

Metas pressóricas para pacientes em tratamento conservador, de acordo com a etiologia da doença renal e com a excreção urinária de albumina
ALBUMINÚRIA <30mg/24 horas ALBUMINÚRIA >30 mg/24horas
DRC não diabética <140/90 mmHg <130/80 mmHg
Fármaco preferencial Qualquer IECA ou BRA
DRC diabética <130/80 mmHg <130/80 mmHg
Fármaco preferencial Qualquer IECA ou BRA

DRC: doença renal crônica; IECA: inibidor da enzima conversora da angiotensina; BRA: bloqueador dos receptores da angiotensina II.

 Escolha do anti-hipertensivo: doença renal crônica estágios 1 a 5 em tratamento conservador

Os DIU tiazídicos continuam recomendados, por serem eficazes nos estágios 1, 2 e 3 da DRC, enquanto os DIU de alça são preconizados para os estágios 4 e 5. Essa classe de fármacos reduz a morbimortalidade CV,48,49 sendo considerada de escolha para associação em DRC.38,49,50 (GR: I; NE: A). Os IECA ou BRA são fármacos largamente utilizados em DRC, sendo eficazes para o controle da HA bem como para a redução da albuminúria.51-55 (GR: I; NE: A). Em relação aos inibidores diretos da renina e aos antagonistas dos receptores mineralocorticoides, ambos com ação anti-proteinúrica, não existem evidências para sua aplicação na prática clínica.56-58 O risco de hiperpotassemia deve ser considerado especialmente com os últimos. Um aspecto polêmico refere-se ao bloqueio duplo do SRAA. A combinação de IECA com BRA59,60 ou de um inibidor de renina com IECA ou BRA10 resultou em maior ocorrência de lesão renal aguda e de hiperpotassemia, levando a proscrição dessa estratégia da prática nefrológica. (GR: I; NE: A). Por outro lado, em estudo recém-publicado na doença renal policística do adulto61 bem como em metanálise realizada em diabéticos com DRC,62 a associação de IECA com BRA retardou a evolução da nefropatia sem causar hiperpotassemia grave e lesão renal aguda. (NE: IIb, GR: B). No entanto, à luz das evidências atuais, o bloqueio duplo do SRAA permanece contraindicado. (GR: I; NE: A). Os BCC são eficazes, em especial para uso combinado com IECA ou BRA, associando-se a redução de eventos CV.63,64 Outras opções incluem BB, inibidores adrenérgicos de ação central e, eventualmente, vasodilatadores de ação direta, como minoxidil e hidralazina.

 Abordagem da doença renal crônica estágio 5 em terapia renal substitutiva

A maior parte dos estudos sobre HA nos pacientes com DRC em terapia dialítica baseia-se na mensuração dos níveis pressóricos pré-diálise; sabe-se, contudo, que a PA obtida dessa forma, além de apresentar grande variabilidade, está geralmente superestimada, assim como é subestimada quando obtida após a diálise.65,66 Nesse sentido, a medição da PA desses pacientes deve ser feita preferencialmente fora das unidades de diálise, nos intervalos interdialíticos.67 (GR: IIa; NE: B). As medidas de PA residencial são mais reprodutíveis que as obtidas no pré- e pós-diálise, apresentam boa associação com a MAPA de 44 horas, bem como com o prognóstico CV em pacientes dialíticos.68-70 (GR: IIa; NE: B). Além disso, um estudo randomizado, mostrou que decisões terapêuticas baseadas na medição de PA residencial associam-se a melhor controle pressórico interdialítico avaliado pela MAPA de 24h em comparação à medição de PA pré-diálise.71 Com relação à MAPA, deve-se ressaltar que, apesar do exame com 44 horas de duração ser considerado o padrão ouro em estudos para avaliação nos pacientes hemodialíticos, as dificuldades técnicas para sua realização, favorecem o uso da MAPA de 24 horas e das medidas residenciais da PA.

A associação entre PA e mortalidade em pacientes com DRC em terapia dialítica tem distribuição em "U" para a PAS e a PAD, de tal forma que tanto os níveis elevados, quanto os reduzidos, relacionam-se com mau prognóstico.70 (GR: IIa; NE: B). Não existem estudos suficientes para embasar com grau de evidência satisfatório o diagnóstico de HA nos pacientes em terapia dialítica; contudo, os valores mais aceitos para esse propósito são para as pressões arteriais pré- e pós-hemodiálise ≥ 140/90 mmHg e ≥ 130/80 mmHg, respectivamente.70,71 (GR: IIa; NE: C). Médias de PAS na medição domiciliar entre 120 e 130 mmHg e na MAPA entre 110 e 120 mmHg associaram-se com melhor prognóstico em um estudo que envolveu 326 pacientes em hemodiálise.68 (GR: IIb; NE: B).

Como nessa população, a hipervolemia tem papel principal na etiologia da HA, o manejo terapêutico deve considerar essa variável, focando-se o tratamento no controle gradual do "peso-seco", via restrição hídrica e salina, além de se promover ultrafiltração adequada nas seções de hemodiálise.71-75 (GR: IIa, NE: B). A escolha dos anti-hipertensivos deve ser individualizada e baseada em características como comorbidades, efeito cardioprotetor do fármaco, características farmacocinéticas intra- e interdialítica e efeitos colaterais.71,72 (GR: IIa; NE: C).

Em pacientes transplantados renais, os BCC constituem boa opção para o tratamento da HA, pois são anti-hipertensivos eficazes e possuem a propriedade de antagonizar a vasoconstrição arteriolar causada pela ciclosporina.76 Medicamentos que bloqueiam o SRAA podem melhorar os resultados do transplante em pacientes com excreção urinária de albumina aumentada. Os DIU, BB, simpaticolíticos de ação central e vasodilatadores podem ser utilizados de acordo com o julgamento clinico.77,78