Blood Pressure Targets in CKD Raymond R. Townsend With the release of the 2014 Guidelines for the Management of Hypertension in Adults, a significant amount of discussion has ensued around both the 9 major recommendations promulgated by the Panel and the nature of the evidence base used to formulate those recommendations. In this article, the author will review the data used to support the 2 recommendations made by the Panel that specifically addressed treatment goals (Recommendation 4) and desirable agents to use (Recommendation 8) in hypertensive patients with CKD. Most published recommendations are actually similar, and there is a general consensus that the blood pressure goal should be at least less than 140/90 mm Hg in CKD; some recommend a target of less than 130/80 mm Hg in patients with CKD who have significant proteinuria. This article represents the view of the author and should not be construed as Panel endorsement. Q 2015 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Blood pressure target, Chronic kidney disease, Guideline
Introduction Since 2008, a number of guidance documents have appeared in the medical literature providing recommendations for the management of high blood pressure (BP), including the most recent adult guidelines published earlier in 2014.1 These are described in Table 1. The preeminence of BP as the single most important risk factor for premature death and disability in the world2 warrants careful consideration of recommendations for target levels. Because drug therapies are not without risk, the most convincing strategy involved in the recommendation of a BP target is the demonstration of the point at which treatment benefits outweigh the risks with respect to important health outcomes. Because there are 2 numbers involved in BP measurement, and since for many years, the primary focus of BP recommendations was directed to the diastolic target value, there is less information available about systolic targets, particularly in CKD. Moreover, in patients with CKD, the presence of dipstick-detectable (11 or greater, roughly analogous to a urine protein:creatinine ratio [UPCr] of .22) urine protein excretion adds an extra level of consideration. Finally, though some evidence informing the best treatment BP target in CKD is available, not all groups looking at the same data agree on exactly what the evidence shows. In this article, the evidence base for BP targets in CKD and drug treatment and the various recommendations for BP targets are compared in the hope of providing more light than heat in this still somewhat contentious area of clinical medicine. Among the various guidelines appearing recently, the author is more familiar with the processes governing the development of recommendations 4 and 8 in the 2014 Evidence-Based Guideline for the Management of From Renal Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Raymond R. Townsend, MD, Renal Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.08.001
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Hypertension in Adults (hereafter “JAMA 2014”) published in Journal of the American Medical Association (JAMA) by the group originally empanelled as Joint National Committee (JNC) 8.1 Recommendation 4 advised a treatment goal of less than 140/90 mm Hg and did not recommend an alternate goal in the presence of proteinuria. Recommendation 8 advised the use of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB; but not both at the same time) in the management of hypertension in CKD, either as initial or as add-on therapy, regardless of race or diabetes status. What was the thinking behind these recommendations?
The JAMA 2014 Definition of “CKD” The JAMA 2014 Panel defined CKD in a person with hypertension based on the entry criteria of the studies used in the evidence base. The main component of the definition was a measured or estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 in people younger than 70 years. If a urine albuminto-creatinine ratio was greater than 30 mg to 1 g, then the definition was not restricted to an age or GFR limit.
Framing the Question of Treatment in Hypertensives With CKD For the development of the BP target in CKD in the JAMA 2014 guideline, the Panel considered the basic criteria used to answer Critical Question 2 that asked: “Among adults, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes?” To address this question, and the other questions in JAMA 2014, the Panel considered studies using PICO criteria: Population: included adults aged 18 years and older. Intervention: antihypertensive pharmacologic therapy to a specified BP goal. Comparator: comparator group has a different BP goal than the intervention group or the comparator group has no stated BP goal.
Advances in Chronic Kidney Disease, Vol 22, No 2 (March), 2015: pp 96-101
Blood Pressure Targets in CKD
Outcomes: overall mortality, cardiovascular (CV) diseaserelated mortality, CKD-related mortality, myocardial infarction, heart failure, hospitalization for heart failure, stroke, coronary revascularization (includes coronary artery bypass surgery, coronary angioplasty, and coronary stent placement), peripheral revascularization (includes carotid, kidney, and lower extremity revascularization), ESRD (ie, kidney failure resulting in dialysis or transplant), doubling of creatinine, and halving of estimated GFR.
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consequences) of treating patients with CKD to the 140/ 90 mm Hg, but not to a lower goal, is reasonable based on this study. The African American Study of Kidney Disease and Hypertension
The AASK trial tested similar MAP levels to MDRD and had the largest number of subjects enrolled among the 3 CKD studies: 1094 participants.4 Using an MAP of 102 to 107 mm Hg (about 140/90 mm Hg, the usual BP group), they compared this with an MAP of 92 mm Hg or less (about 125/75 mm Hg, the lower BP group). In the AASK The JAMA 2014 Definition of Important Health trial, the primary events were ESRD, death, halving of Outcomes GFR, and a composite of these. The AASK Investigators The JAMA 2014 guideline Panel considered 3 clinical trials as indicated that the lower BP target group did not differ evidence for Recommendation 4 that stipulated the pressignificantly from the usual BP group. With respect to CV ence of CKD and that tested 2 different goals. These 3 studies end points, the Investigators stated “The study was not and their relevant characteristics are outlined in Table 2. In powered to detect differences in the rate of myocardial reviewing and summarizing these 3 studies, it is important infarction, stroke, or death. However, we found no evidence to recall what the JAMA 2014 defined as important health 1 of differences in the rates of these events between the ranoutcomes as noted earlier in the PICO criteria. domized BP groups.” With respect to the proteinuria issue, Three studies were selected because they had Fair to the original study publication did not show a difference in Good1 quality evidence and included the Modification 3 the higher (UPCr . .22) proteinuria groups in the lower of Diet in Renal Disease (MDRD) study, African Amervs the usual BP target groups. The Investigators stated ican Study of Kidney Disease and Hypertension 4 that “. with the exception (AASK), and the Ramipril of the acute slope, the BP Efficacy in Nephropathy 2 CLINICAL SUMMARY 5 comparison for the afore(REIN-2). mentioned outcomes was not significantly different Hypertension is a critical, modifiable factor in chronic The Modification of Diet kidney disease progression. within either the lower in Kidney Disease (baseline urinary protein-to The 2014 JAMA Guidelines for Hypertension (USA) The MDRD trial tested 2 mean creatinine ratio # .22) or recommend a target blood pressure of ,140/,90 mmHg. arterial pressure (MAP) levels higher (baseline urinary Uncertainty remains about the optimal systolic BP target separated by 15 mm Hg protein-to-creatinine ratio . particularly in patients with proteinuria. (#92 mm Hg in the low and .22) proteinuria strata.” In #107 in the usual BP groups the Methods section of the for those #60 years; #98 mm primary results article, the Hg vs # 113 mm Hg for those 61 years and older,6 see AASK Investigators considered a GFR “event” to be a Table 2) and found no difference after 2.6 years in slope of reduction of GFR by 50% or a decline of 25 mL/min/ GFR in low vs usual pressure groups.3 Importantly, the 1.73m2 from the average of the 2 baseline values, and they original report did not disclose the incidence of doubling stated that “the numbers of events (rate/participant year) of serum creatinine or halving of the GFR. The MDRD Infor the main clinical composite (declining GFR events, vestigators stated that ESRD (the occurrence of which reESRD, or death) were 173 (rate, .081) and 167 (rate, .076) sulted in removal of the subject from the study) “did not in the lower and usual BP groups. After adjustment for differ significantly in the diet groups or the blood pressure the prespecified covariates, there were no significant differgroups.” Also, the Investigators stated “no significant difences between the BP groups in the risk of clinical composite ferences in the number or causes of death or stopping points outcome (risk reduction for the lower BP goal, 2%; 95% conbetween the diet and the blood-pressure groups in either fidence interval, 222% to 21%; P ¼ .85).” This author’s read study.” An important item in MDRD was that the halving of the AASK study is that it did not demonstrate, as origiof GFR was considered a “stopping point,” and it was stated nally published, significant benefit with the lower BP target that “stopping points” did not differ between BP groups. compared with a 140/90 mm Hg target.4 This article also appears to support a 140/90 mm Hg target as opposed to Neither halving of GFR, death, or ESRD were different in something lower. In the years after the original randomized the low vs the usual BP groups. The only espoused benefit trial, a follow-up publication appeared that continued surof the low BP group was a less steep slope of GFR loss that veillance of the surviving AASK cohort observing that the was not specified as an Important Health Outcome in the group with the UPCr ..22 originally randomized to the JAMA 2014 Panel criteria. This study did not demonstrate lower BP target had a lower composite end point occura benefit with respect to the JAMA 2014 criteria for the lower rence.7 Keeping in mind that the opposite is the case in BP target. Because it did not report separately on a higher the larger, less proteinuric cohort randomized to the lower than 140 mm Hg target (the 61 years and older group), BP target (ie, the lower BP target group with less proteinuria one is left to assume that the known benefit (or anticipated
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Townsend
Table 1. Comparison of Guideline Recommendations for CKD BP Targets Guideline (y)
CKD BP Target
Notes
Other Comments
1
JAMA (2014)
,140/90 mm Hg
No distinction for proteinuria; if diabetes present, no change in target BP
CHEP (2014)17
,140/90 mm Hg
Specifies nondiabetic CKD; if diabetes present target BP is ,130/80 mm Hg
ESC/ESH (2013)18
,140/90 mm Hg
KDIGO (2012)19 KDIGO (2012)19 ISHIB (2010)20
,140/90 mm Hg ,130/80 mm Hg ,130/80 mm Hg
NICE (2008) www.nice.org.uk/cg73
,140/90 mm Hg
Suggested ,130 mm Hg SBP when overt proteinuria present with eGFR monitoring In the absence of proteinuria With proteinuria Target BP shown is recommended for black patients with any target organ damage The NICE guidelines for CKD present a range of 120-139 mm Hg systolic as suggested target BP
No specific recommendations if older than 70 y. Recommendation 8 endorses using an ACEI or an ARB in the treatment Supports using ACEI (or ARB if ACEI intolerant) particularly when proteinuria present Supports using ACEI or ARB, particularly when proteinuria present — — Supports using ACEI or ARB, particularly when proteinuria present —
Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; NICE, National Institute for Clinical Excellence; SBP, systolic blood pressure.
did less well in the composite outcome compared with those in the usual BP target group, but it was not statistically significant), it remains an open question in the minds of many what the optimal BP target should be in a patient with proteinuria. The Ramipril Efficacy in Nephropathy 2 REIN-2 used a BP target of a conventional diastolic BP less than 90 mm Hg (irrespective of systolic BP) and compared that with a more intensive target of less than 130/80 mm Hg (both systolic and diastolic targets). The difference in planned follow-up (36 months) and the median followup (19 months) occurred because the study was halted prematurely by the safety monitoring board for futility. Three people died in the conventional and 2 in the intensive control group (no P value stated). There was no difference in ESRD events (38 of 167 in intensive group; 34 of 168 in conventional group; HR ¼ 1.00; 95% confidence interval, .61-1.64; P ¼ .99). Halving of GFR was not specifically addressed. As to proteinuria, all subjects had proteinuria (it was an inclusion criteria), as distinguished from MDRD and AASK where the inclusion criteria were GFR based. MDRD excluded subjects with greater than 10 g daily of urine protein excretion, and AASK excluded subjects with a spot urine protein:creatinine ratio (mg) of .2.5. REIN-2 supports a 90 mm Hg diastolic BP goal as reasonable, with no additional benefit evident by a lower diastolic target. Thus, all 3 studies appear to argue for a diastolic BP target of 90 mm Hg. None of these 3 studies reported results with a systolic BP target of 140 mm Hg compared with a higher value. The JAMA 2014 Panel concluded from the studies reviewed in Table 2 that in adults younger than 70 years with CKD, the evidence was insufficient to determine if there is a benefit in Important Health Outcomes, including kidney outcomes, of treatment with antihypertensive drug therapy to any lower target BP compared with a target of
less than 140/90 mm Hg (corresponding to an MAP of 102). Said another way, the Panel could find no evidence of added benefit on important health outcomes in patients with CKD when treating to a target other than the less than 140/90 mm Hg recommendation. For CV outcomes, the AASK Investigators acknowledged in the initial publication that the trial was not powered to detect differences in the rate of myocardial infarction, stroke, or death.4 The other trials, MDRD and REIN-2, did not report CV outcomes in their efficacy reports. Furthermore, the panel also concluded that in the nondiabetic hypertensive population with proteinuria, there was an insufficient evidence to determine whether there was a benefit of treatment with antihypertensive drug therapy to a lower goal BP compared with a goal of less than 140/90 mm Hg (MAP 102) on Important Health Outcomes. In particular, in REIN-2, there were no significant differences in the ESRD outcome.5 In the AASK trial, there was a significant P value for the interaction of baseline proteinuria and BP goal (P ¼ .004), suggesting a benefit for the lower foal over the usual goal in those with higher levels of baseline proteinuria.4 In the MDRD, there was significant benefit in the slope of GFR decline when the groups were divided according to proteinuria status (,1 g/24 h, 1-3 g/24 h, .3 g/ 24 h), particularly in the group with a greater reduction in GFR at trial initiation, but slope of GFR change was not considered as an Important Health Outcome, and the incidence of death and ESRD were similar in the more aggressive, compared with the less aggressive, BP target groups.3
Use of an ACEI or an ARB in the Regimen For the development of recommendations regarding BP treatment in CKD in the JAMA 2014 guideline, the Panel considered articles that addressed Critical Question 3 that asked: “In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes?”
Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; CI, confidence interval; DBP, diastolic blood pressure; GFR, glomerular filtration rate; MAP, mean arterial pressure; MDRD, modification of diet in renal disease; n.s., not significant; REIN-2, Ramipril Efficacy in Nephropathy; SBP, systolic blood pressure.
REIN-25 SBP/DBP goal , 130/80 mm Hg 129.6/79.5 vs vs DBP goal , 90 mm Hg 133.7/82.3 mm Hg
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ESRD
38/167 ESRD events vs 34/168, P ¼ n.s.
After 3-month run-in: differences in GFR outcomes not different by BP target group but were different by agent used. Amlodipine arm stopped early. Ramipril arm was better at slowing GFR loss compared with amlodipine arm. .22 vs .24 mL/min/1.73 m2/mo, P ¼ .62 Composite* 2% risk reduction in intensive group: P ¼ .85 1094 95 vs 104 mm Hg AASK4
MDRD3
MAP , 98 vs ,113 mm Hg for age 61 y and older MAP , 92 vs 102-107 mm Hg
Less GFR slope change in The relative risk of ESRD or death was .85 (95% Only shown as graphs 840 (not broken Rate of patients with .1 g 24 h CI .60 to 1.22) in the low blood pressure target of MAP over time; down by age) change of group compared with the usual BP target no tabulated data GFR proteinuria group. There was a steeper decline in the GFR presented slope (more kidney function loss) in those randomized to the usual BP target compared with the lower BP group when urine protein excretion was .1 g/d. — — — — MDRD
3
MAP , 92 vs ,107 mm Hg if age 18-60 y
Primary Results Primary Outcome N Studied BP Achieved BP Goals Trial
Table 2. Trials of Different BP Targets in CKD
Notes on GFR Decline
Blood Pressure Targets in CKD
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Recommendation 8 in the JAMA 2014 report indicated that an ACEI or an ARB (but not both together) should be used in the management of hypertension in patients with CKD either as an initial agent or added to the regimen in the titration process. In addition, they stated that this applied to all patients with CKD (18 to 75 years) regardless of race or the presence of diabetes. This recommendation is based mostly on kidney-related outcomes because there is not much evidence supporting a CV benefit of ACEI or ARB use in CKD. ACEI Use For ACEI use, 3 CKD studies addressed this agent class vs a comparator. Table 3 presents the essential features of these studies. The AASK trial tested ramipril against both amlodipine and metoprolol in blacks with non-nephrotic, nondiabetic CKD. The amlodipine arm was discontinued early, but the results favored the ramipril group.4 Ramipril also did better than metoprolol for kidney outcomes. The Amlodipine vs Enalapril in Renal failure (AVER) trial found no significant differences between the enalapril and amlodipine treatment groups.8 The Efecto del tratan de la Insufimiento antihipertensivo Sobre la Progresio ciencia RenAL (ESPIRAL) trial observed improved outcomes in the fosinopril compared with the long-acting nifedipine.9 Attrition rates were very small in AASK but were 33% in AVER and 32% in ESPIRAL. In ESPIRAL, the fosinopril arm had up to 6 mm Hg lower systolic BP compared with the long-acting nifedipine arm. ARB Use For ARB use, there was only 1 study that met the JAMA 2014 Panel criteria, the Irbesartan Diabetic Nephropathy Trial (IDNT).10 In that trial, kidney end points were least likely to occur in the ARB group. The Reduction of End Points in Non-Insulin Dependent Diabetes Mellitus (NIDDM) With the Angiotensin II Antagonist Losartan study11 was published concurrent with IDNT but was not selected for inclusion in the JAMA 2014 database because it, unlike IDNT, did not require participants to have hypertension as an inclusion criterion. The Panel also considered the Valsartan Antihypertensive LongTerm Use Evaluation (VALUE) trial that compared an ARB to a calcium channel blocker (CCB)12 but was unable to draw conclusions specifically about CKD outcomes on an ARB vs a calcium channel antagonist because VALUE did not report kidney outcomes. Recommendation 8 in the JAMA 2014 report indicating the use of ARB treatment in CKD to benefit kidney outcomes is based solely on the 1 study of diabetics (IDNT).10 From a CV standpoint, neither AASK, IDNT, or VALUE (VALUE did report CV outcomes for the 530 subjects with a serum creatinine of 1.7 mg/dL or higher) reported significant differences on either the ACEI or the ARB vs the comparators, with the exception of heart failure events, which were significantly less in the IDNT study in the ARB arm.10 Several words of caution deserve mention at this point. ACEI or ARB treatment often increases the serum creatinine further, in the range of 25% or more, when used in
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Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; ACEI, angiotensin-converting enzyme inhibitors; Amlo, amlodipine; ARB, angiotensin receptor n de la Insuficiencia RenAL; IDNT, Irbesartan Diabetic blocker; AVER, Amlodipine vs Enalapril in Renal failure; ESPIRAL, Efecto del tratamiento antihipertensivo Sobre la Progresio Nephropathy Trial; Irb, irbesartan; n.s., not significant; Plac, placebo.
ESRD (dialysis, End point reached: Irb 189/579; transplant, or Amlo 233/567; Plac 222/569; Irb creatinine .6 mg/dL) vs Amlo P ¼ .006; Irb vs Plac or doubling of serum P ¼ .02; Amlo vs Plac; P ¼ n.s. creatinine Limited to diabetic nephropathy only 2.6
3
ESPIRAL 18-75 Fosinopril, Serum creatinine 241 (fosinopril (2001)9 129; nifedipine nifedipine-GITS 1.5-5 mg/dL (with increase of 25% or GITS 112) ..5 mg/dL in prior 2 y) ARB vs Other IDNT 30-70 Irb, Amlo, Plac Serum creatinine 1715 (2001)10 1-3 mg/dL; required (1add-on therapy) proteinuria (900 mg daily or urine protein: creatinine equivalent)
3 20-60 mL/min/1.73 m2 (Cockcroft-Gault) AVER 18-80 Amlo, enalapril (2008)8
Diabetes
At 4 y GFR (mL/min/1.73 m2) declines: Ramipril ¼ 1.81, metoprolol ¼ 2.42, Amlo ¼ 3.22 Amlo ¼ 4.92 mL/min/1.73 m2; Enalapril ¼ 3.98 mL/min/ 1.73 m2; (changes are from baseline to 3 y); P ¼ n.s. Doubling of serum Fosinopril 27/127 reached end creatinine or dialysis point; Nifedipine-GITS 40/112 reached end point; P ¼ .01 Diabetics; urine ESRD or doubling of protein:creatinine serum creatinine ratio of .2.5 (mg) Diabetes; nephrotic 51Cr-EDTA clearance range proteinuria (yearly) 3-6.4
1094 (Amlo 217; metoprolol 441; ramipril 436) 263 (Amlo 132; Enalapril 131) ACEI vs Other 18-70 Amlo, metoprolol, 20-65 mL/min/1.73 m2 AASK ramipril (2002)4
End Point Excluded Duration (y) Number GFR Criteria Comparitors Age (y) Study
Table 3. Treatment Trials Comparing an ACEI or an ARB to an Active Comparator in Patients With CKD
Results
Townsend
patients with CKD.13 Though usually tolerated well, it is important to demonstrate creatinine stability as marked increases can occur, often pointing to disorders such as bilateral kidney artery stenosis.14 The other biochemical consequence of using an ACEI or an ARB is the tendency to hyperkalemia.15 Consequently it is important to monitor periodically both the serum creatinine and the serum electrolytes when these agents are in use or when intercurrent illness may predispose the patient to acute kidney injury.16
Summary Among the guidelines that present recommendations for BP management in patients with CKD, there is far more agreement than differences as listed in Table 1. There will continue to be many in the Nephrology community who adhere to a lower treatment target of less than 130/ 80 mm Hg when proteinuria is present because it is difficult to ignore the large amount of epidemiologic evidence supporting proteinuria as an important predictor of kidney function loss. The Systolic Blood Pressure Intervention Trial (NCT01206062 at www.clinicaltrials.gov) enrolled more than 9000 subjects, about one-third of whom have nondiabetic CKD, and it is hoped that this study will provide more guidance particularly for systolic BP management in CKD and further define the role of proteinuria as a modifier of kidney outcomes with more intense systolic BP management in this vulnerable population.
References 1. James PA, Oparil S, Carter BL, 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):507-520. 2. Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med. 2013;369(5):448-457. 3. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal failure. N Engl J Med. 1994;330(13):877-884. 4. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288(19):2421-2431. 5. Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet. 2005;365(9463):939-946. 6. The Modification of Diet in Renal Disease Study: design, methods, and results from the feasibility study. Am J Kidney Dis. 1992;20(1):18-33. 7. Appel LJ, Wright JT Jr, Greene T, et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363(10):918-929. 8. Esnault VL, Brown EA, Apetrei E, et al. The effects of amlodipine and enalapril on renal function in adults with hypertension and nondiabetic nephropathies: a 3-year, randomized, multicenter, double-blind, placebo-controlled study. Clin Ther. 2008;30(3):482-498. 9. Marin R, Ruilope LM, Aljama P, Aranda P, Segura J, Diez J. A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease. J Hypertens. 2001;19(10):1871-1876. 10. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. 11. Brenner BM, Cooper ME, De Zeeuw D, et al. 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. 12. Zanchetti A, Julius S, Kjeldsen S, et al. Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan
Blood Pressure Targets in CKD
13.
14.
15.
16.
and amlodipine: an analysis of findings from the VALUE trial. J Hypertens. 2006;24(11):2163-2168. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitorassociated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160(5):685-693. Hricik DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ. Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl J Med. 1983;308(7):373-376. Johnson ES, Weinstein JR, Thorp ML, et al. Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril. Pharmacoepidemiol Drug Saf. 2010;19(3):266-272. Tomlinson LA, Abel GA, Chaudhry AN, et al. ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: a longitudinal ecological study. PLoS One. 2013;8(11):e78465.
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17. Dasgupta K, Quinn RR, Zarnke KB, et al. The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2014;30(5):485-501. 18. Mancia G, Fagard R, Narkiewicz K, et al. 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. 19. KDIGO Panel. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012;2(5):343-387. 20. Flack JM, Sica DA, Bakris G, et al. Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5): 780-800.
Introduction Since 2008, a number of guidance documents have appeared in the medical literature providing recommendations for the management of high blood pressure (BP), including the most recent adult guidelines published earlier in 2014.1 These are described in Table 1. The preeminence of BP as the single most important risk factor for premature death and disability in the world2 warrants careful consideration of recommendations for target levels. Because drug therapies are not without risk, the most convincing strategy involved in the recommendation of a BP target is the demonstration of the point at which treatment benefits outweigh the risks with respect to important health outcomes. Because there are 2 numbers involved in BP measurement, and since for many years, the primary focus of BP recommendations was directed to the diastolic target value, there is less information available about systolic targets, particularly in CKD. Moreover, in patients with CKD, the presence of dipstick-detectable (11 or greater, roughly analogous to a urine protein:creatinine ratio [UPCr] of .22) urine protein excretion adds an extra level of consideration. Finally, though some evidence informing the best treatment BP target in CKD is available, not all groups looking at the same data agree on exactly what the evidence shows. In this article, the evidence base for BP targets in CKD and drug treatment and the various recommendations for BP targets are compared in the hope of providing more light than heat in this still somewhat contentious area of clinical medicine. Among the various guidelines appearing recently, the author is more familiar with the processes governing the development of recommendations 4 and 8 in the 2014 Evidence-Based Guideline for the Management of From Renal Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Raymond R. Townsend, MD, Renal Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.08.001
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Hypertension in Adults (hereafter “JAMA 2014”) published in Journal of the American Medical Association (JAMA) by the group originally empanelled as Joint National Committee (JNC) 8.1 Recommendation 4 advised a treatment goal of less than 140/90 mm Hg and did not recommend an alternate goal in the presence of proteinuria. Recommendation 8 advised the use of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB; but not both at the same time) in the management of hypertension in CKD, either as initial or as add-on therapy, regardless of race or diabetes status. What was the thinking behind these recommendations?
The JAMA 2014 Definition of “CKD” The JAMA 2014 Panel defined CKD in a person with hypertension based on the entry criteria of the studies used in the evidence base. The main component of the definition was a measured or estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 in people younger than 70 years. If a urine albuminto-creatinine ratio was greater than 30 mg to 1 g, then the definition was not restricted to an age or GFR limit.
Framing the Question of Treatment in Hypertensives With CKD For the development of the BP target in CKD in the JAMA 2014 guideline, the Panel considered the basic criteria used to answer Critical Question 2 that asked: “Among adults, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes?” To address this question, and the other questions in JAMA 2014, the Panel considered studies using PICO criteria: Population: included adults aged 18 years and older. Intervention: antihypertensive pharmacologic therapy to a specified BP goal. Comparator: comparator group has a different BP goal than the intervention group or the comparator group has no stated BP goal.
Advances in Chronic Kidney Disease, Vol 22, No 2 (March), 2015: pp 96-101
Blood Pressure Targets in CKD
Outcomes: overall mortality, cardiovascular (CV) diseaserelated mortality, CKD-related mortality, myocardial infarction, heart failure, hospitalization for heart failure, stroke, coronary revascularization (includes coronary artery bypass surgery, coronary angioplasty, and coronary stent placement), peripheral revascularization (includes carotid, kidney, and lower extremity revascularization), ESRD (ie, kidney failure resulting in dialysis or transplant), doubling of creatinine, and halving of estimated GFR.
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consequences) of treating patients with CKD to the 140/ 90 mm Hg, but not to a lower goal, is reasonable based on this study. The African American Study of Kidney Disease and Hypertension
The AASK trial tested similar MAP levels to MDRD and had the largest number of subjects enrolled among the 3 CKD studies: 1094 participants.4 Using an MAP of 102 to 107 mm Hg (about 140/90 mm Hg, the usual BP group), they compared this with an MAP of 92 mm Hg or less (about 125/75 mm Hg, the lower BP group). In the AASK The JAMA 2014 Definition of Important Health trial, the primary events were ESRD, death, halving of Outcomes GFR, and a composite of these. The AASK Investigators The JAMA 2014 guideline Panel considered 3 clinical trials as indicated that the lower BP target group did not differ evidence for Recommendation 4 that stipulated the pressignificantly from the usual BP group. With respect to CV ence of CKD and that tested 2 different goals. These 3 studies end points, the Investigators stated “The study was not and their relevant characteristics are outlined in Table 2. In powered to detect differences in the rate of myocardial reviewing and summarizing these 3 studies, it is important infarction, stroke, or death. However, we found no evidence to recall what the JAMA 2014 defined as important health 1 of differences in the rates of these events between the ranoutcomes as noted earlier in the PICO criteria. domized BP groups.” With respect to the proteinuria issue, Three studies were selected because they had Fair to the original study publication did not show a difference in Good1 quality evidence and included the Modification 3 the higher (UPCr . .22) proteinuria groups in the lower of Diet in Renal Disease (MDRD) study, African Amervs the usual BP target groups. The Investigators stated ican Study of Kidney Disease and Hypertension 4 that “. with the exception (AASK), and the Ramipril of the acute slope, the BP Efficacy in Nephropathy 2 CLINICAL SUMMARY 5 comparison for the afore(REIN-2). mentioned outcomes was not significantly different Hypertension is a critical, modifiable factor in chronic The Modification of Diet kidney disease progression. within either the lower in Kidney Disease (baseline urinary protein-to The 2014 JAMA Guidelines for Hypertension (USA) The MDRD trial tested 2 mean creatinine ratio # .22) or recommend a target blood pressure of ,140/,90 mmHg. arterial pressure (MAP) levels higher (baseline urinary Uncertainty remains about the optimal systolic BP target separated by 15 mm Hg protein-to-creatinine ratio . particularly in patients with proteinuria. (#92 mm Hg in the low and .22) proteinuria strata.” In #107 in the usual BP groups the Methods section of the for those #60 years; #98 mm primary results article, the Hg vs # 113 mm Hg for those 61 years and older,6 see AASK Investigators considered a GFR “event” to be a Table 2) and found no difference after 2.6 years in slope of reduction of GFR by 50% or a decline of 25 mL/min/ GFR in low vs usual pressure groups.3 Importantly, the 1.73m2 from the average of the 2 baseline values, and they original report did not disclose the incidence of doubling stated that “the numbers of events (rate/participant year) of serum creatinine or halving of the GFR. The MDRD Infor the main clinical composite (declining GFR events, vestigators stated that ESRD (the occurrence of which reESRD, or death) were 173 (rate, .081) and 167 (rate, .076) sulted in removal of the subject from the study) “did not in the lower and usual BP groups. After adjustment for differ significantly in the diet groups or the blood pressure the prespecified covariates, there were no significant differgroups.” Also, the Investigators stated “no significant difences between the BP groups in the risk of clinical composite ferences in the number or causes of death or stopping points outcome (risk reduction for the lower BP goal, 2%; 95% conbetween the diet and the blood-pressure groups in either fidence interval, 222% to 21%; P ¼ .85).” This author’s read study.” An important item in MDRD was that the halving of the AASK study is that it did not demonstrate, as origiof GFR was considered a “stopping point,” and it was stated nally published, significant benefit with the lower BP target that “stopping points” did not differ between BP groups. compared with a 140/90 mm Hg target.4 This article also appears to support a 140/90 mm Hg target as opposed to Neither halving of GFR, death, or ESRD were different in something lower. In the years after the original randomized the low vs the usual BP groups. The only espoused benefit trial, a follow-up publication appeared that continued surof the low BP group was a less steep slope of GFR loss that veillance of the surviving AASK cohort observing that the was not specified as an Important Health Outcome in the group with the UPCr ..22 originally randomized to the JAMA 2014 Panel criteria. This study did not demonstrate lower BP target had a lower composite end point occura benefit with respect to the JAMA 2014 criteria for the lower rence.7 Keeping in mind that the opposite is the case in BP target. Because it did not report separately on a higher the larger, less proteinuric cohort randomized to the lower than 140 mm Hg target (the 61 years and older group), BP target (ie, the lower BP target group with less proteinuria one is left to assume that the known benefit (or anticipated
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Table 1. Comparison of Guideline Recommendations for CKD BP Targets Guideline (y)
CKD BP Target
Notes
Other Comments
1
JAMA (2014)
,140/90 mm Hg
No distinction for proteinuria; if diabetes present, no change in target BP
CHEP (2014)17
,140/90 mm Hg
Specifies nondiabetic CKD; if diabetes present target BP is ,130/80 mm Hg
ESC/ESH (2013)18
,140/90 mm Hg
KDIGO (2012)19 KDIGO (2012)19 ISHIB (2010)20
,140/90 mm Hg ,130/80 mm Hg ,130/80 mm Hg
NICE (2008) www.nice.org.uk/cg73
,140/90 mm Hg
Suggested ,130 mm Hg SBP when overt proteinuria present with eGFR monitoring In the absence of proteinuria With proteinuria Target BP shown is recommended for black patients with any target organ damage The NICE guidelines for CKD present a range of 120-139 mm Hg systolic as suggested target BP
No specific recommendations if older than 70 y. Recommendation 8 endorses using an ACEI or an ARB in the treatment Supports using ACEI (or ARB if ACEI intolerant) particularly when proteinuria present Supports using ACEI or ARB, particularly when proteinuria present — — Supports using ACEI or ARB, particularly when proteinuria present —
Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; NICE, National Institute for Clinical Excellence; SBP, systolic blood pressure.
did less well in the composite outcome compared with those in the usual BP target group, but it was not statistically significant), it remains an open question in the minds of many what the optimal BP target should be in a patient with proteinuria. The Ramipril Efficacy in Nephropathy 2 REIN-2 used a BP target of a conventional diastolic BP less than 90 mm Hg (irrespective of systolic BP) and compared that with a more intensive target of less than 130/80 mm Hg (both systolic and diastolic targets). The difference in planned follow-up (36 months) and the median followup (19 months) occurred because the study was halted prematurely by the safety monitoring board for futility. Three people died in the conventional and 2 in the intensive control group (no P value stated). There was no difference in ESRD events (38 of 167 in intensive group; 34 of 168 in conventional group; HR ¼ 1.00; 95% confidence interval, .61-1.64; P ¼ .99). Halving of GFR was not specifically addressed. As to proteinuria, all subjects had proteinuria (it was an inclusion criteria), as distinguished from MDRD and AASK where the inclusion criteria were GFR based. MDRD excluded subjects with greater than 10 g daily of urine protein excretion, and AASK excluded subjects with a spot urine protein:creatinine ratio (mg) of .2.5. REIN-2 supports a 90 mm Hg diastolic BP goal as reasonable, with no additional benefit evident by a lower diastolic target. Thus, all 3 studies appear to argue for a diastolic BP target of 90 mm Hg. None of these 3 studies reported results with a systolic BP target of 140 mm Hg compared with a higher value. The JAMA 2014 Panel concluded from the studies reviewed in Table 2 that in adults younger than 70 years with CKD, the evidence was insufficient to determine if there is a benefit in Important Health Outcomes, including kidney outcomes, of treatment with antihypertensive drug therapy to any lower target BP compared with a target of
less than 140/90 mm Hg (corresponding to an MAP of 102). Said another way, the Panel could find no evidence of added benefit on important health outcomes in patients with CKD when treating to a target other than the less than 140/90 mm Hg recommendation. For CV outcomes, the AASK Investigators acknowledged in the initial publication that the trial was not powered to detect differences in the rate of myocardial infarction, stroke, or death.4 The other trials, MDRD and REIN-2, did not report CV outcomes in their efficacy reports. Furthermore, the panel also concluded that in the nondiabetic hypertensive population with proteinuria, there was an insufficient evidence to determine whether there was a benefit of treatment with antihypertensive drug therapy to a lower goal BP compared with a goal of less than 140/90 mm Hg (MAP 102) on Important Health Outcomes. In particular, in REIN-2, there were no significant differences in the ESRD outcome.5 In the AASK trial, there was a significant P value for the interaction of baseline proteinuria and BP goal (P ¼ .004), suggesting a benefit for the lower foal over the usual goal in those with higher levels of baseline proteinuria.4 In the MDRD, there was significant benefit in the slope of GFR decline when the groups were divided according to proteinuria status (,1 g/24 h, 1-3 g/24 h, .3 g/ 24 h), particularly in the group with a greater reduction in GFR at trial initiation, but slope of GFR change was not considered as an Important Health Outcome, and the incidence of death and ESRD were similar in the more aggressive, compared with the less aggressive, BP target groups.3
Use of an ACEI or an ARB in the Regimen For the development of recommendations regarding BP treatment in CKD in the JAMA 2014 guideline, the Panel considered articles that addressed Critical Question 3 that asked: “In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes?”
Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; CI, confidence interval; DBP, diastolic blood pressure; GFR, glomerular filtration rate; MAP, mean arterial pressure; MDRD, modification of diet in renal disease; n.s., not significant; REIN-2, Ramipril Efficacy in Nephropathy; SBP, systolic blood pressure.
REIN-25 SBP/DBP goal , 130/80 mm Hg 129.6/79.5 vs vs DBP goal , 90 mm Hg 133.7/82.3 mm Hg
338
ESRD
38/167 ESRD events vs 34/168, P ¼ n.s.
After 3-month run-in: differences in GFR outcomes not different by BP target group but were different by agent used. Amlodipine arm stopped early. Ramipril arm was better at slowing GFR loss compared with amlodipine arm. .22 vs .24 mL/min/1.73 m2/mo, P ¼ .62 Composite* 2% risk reduction in intensive group: P ¼ .85 1094 95 vs 104 mm Hg AASK4
MDRD3
MAP , 98 vs ,113 mm Hg for age 61 y and older MAP , 92 vs 102-107 mm Hg
Less GFR slope change in The relative risk of ESRD or death was .85 (95% Only shown as graphs 840 (not broken Rate of patients with .1 g 24 h CI .60 to 1.22) in the low blood pressure target of MAP over time; down by age) change of group compared with the usual BP target no tabulated data GFR proteinuria group. There was a steeper decline in the GFR presented slope (more kidney function loss) in those randomized to the usual BP target compared with the lower BP group when urine protein excretion was .1 g/d. — — — — MDRD
3
MAP , 92 vs ,107 mm Hg if age 18-60 y
Primary Results Primary Outcome N Studied BP Achieved BP Goals Trial
Table 2. Trials of Different BP Targets in CKD
Notes on GFR Decline
Blood Pressure Targets in CKD
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Recommendation 8 in the JAMA 2014 report indicated that an ACEI or an ARB (but not both together) should be used in the management of hypertension in patients with CKD either as an initial agent or added to the regimen in the titration process. In addition, they stated that this applied to all patients with CKD (18 to 75 years) regardless of race or the presence of diabetes. This recommendation is based mostly on kidney-related outcomes because there is not much evidence supporting a CV benefit of ACEI or ARB use in CKD. ACEI Use For ACEI use, 3 CKD studies addressed this agent class vs a comparator. Table 3 presents the essential features of these studies. The AASK trial tested ramipril against both amlodipine and metoprolol in blacks with non-nephrotic, nondiabetic CKD. The amlodipine arm was discontinued early, but the results favored the ramipril group.4 Ramipril also did better than metoprolol for kidney outcomes. The Amlodipine vs Enalapril in Renal failure (AVER) trial found no significant differences between the enalapril and amlodipine treatment groups.8 The Efecto del tratan de la Insufimiento antihipertensivo Sobre la Progresio ciencia RenAL (ESPIRAL) trial observed improved outcomes in the fosinopril compared with the long-acting nifedipine.9 Attrition rates were very small in AASK but were 33% in AVER and 32% in ESPIRAL. In ESPIRAL, the fosinopril arm had up to 6 mm Hg lower systolic BP compared with the long-acting nifedipine arm. ARB Use For ARB use, there was only 1 study that met the JAMA 2014 Panel criteria, the Irbesartan Diabetic Nephropathy Trial (IDNT).10 In that trial, kidney end points were least likely to occur in the ARB group. The Reduction of End Points in Non-Insulin Dependent Diabetes Mellitus (NIDDM) With the Angiotensin II Antagonist Losartan study11 was published concurrent with IDNT but was not selected for inclusion in the JAMA 2014 database because it, unlike IDNT, did not require participants to have hypertension as an inclusion criterion. The Panel also considered the Valsartan Antihypertensive LongTerm Use Evaluation (VALUE) trial that compared an ARB to a calcium channel blocker (CCB)12 but was unable to draw conclusions specifically about CKD outcomes on an ARB vs a calcium channel antagonist because VALUE did not report kidney outcomes. Recommendation 8 in the JAMA 2014 report indicating the use of ARB treatment in CKD to benefit kidney outcomes is based solely on the 1 study of diabetics (IDNT).10 From a CV standpoint, neither AASK, IDNT, or VALUE (VALUE did report CV outcomes for the 530 subjects with a serum creatinine of 1.7 mg/dL or higher) reported significant differences on either the ACEI or the ARB vs the comparators, with the exception of heart failure events, which were significantly less in the IDNT study in the ARB arm.10 Several words of caution deserve mention at this point. ACEI or ARB treatment often increases the serum creatinine further, in the range of 25% or more, when used in
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Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; ACEI, angiotensin-converting enzyme inhibitors; Amlo, amlodipine; ARB, angiotensin receptor n de la Insuficiencia RenAL; IDNT, Irbesartan Diabetic blocker; AVER, Amlodipine vs Enalapril in Renal failure; ESPIRAL, Efecto del tratamiento antihipertensivo Sobre la Progresio Nephropathy Trial; Irb, irbesartan; n.s., not significant; Plac, placebo.
ESRD (dialysis, End point reached: Irb 189/579; transplant, or Amlo 233/567; Plac 222/569; Irb creatinine .6 mg/dL) vs Amlo P ¼ .006; Irb vs Plac or doubling of serum P ¼ .02; Amlo vs Plac; P ¼ n.s. creatinine Limited to diabetic nephropathy only 2.6
3
ESPIRAL 18-75 Fosinopril, Serum creatinine 241 (fosinopril (2001)9 129; nifedipine nifedipine-GITS 1.5-5 mg/dL (with increase of 25% or GITS 112) ..5 mg/dL in prior 2 y) ARB vs Other IDNT 30-70 Irb, Amlo, Plac Serum creatinine 1715 (2001)10 1-3 mg/dL; required (1add-on therapy) proteinuria (900 mg daily or urine protein: creatinine equivalent)
3 20-60 mL/min/1.73 m2 (Cockcroft-Gault) AVER 18-80 Amlo, enalapril (2008)8
Diabetes
At 4 y GFR (mL/min/1.73 m2) declines: Ramipril ¼ 1.81, metoprolol ¼ 2.42, Amlo ¼ 3.22 Amlo ¼ 4.92 mL/min/1.73 m2; Enalapril ¼ 3.98 mL/min/ 1.73 m2; (changes are from baseline to 3 y); P ¼ n.s. Doubling of serum Fosinopril 27/127 reached end creatinine or dialysis point; Nifedipine-GITS 40/112 reached end point; P ¼ .01 Diabetics; urine ESRD or doubling of protein:creatinine serum creatinine ratio of .2.5 (mg) Diabetes; nephrotic 51Cr-EDTA clearance range proteinuria (yearly) 3-6.4
1094 (Amlo 217; metoprolol 441; ramipril 436) 263 (Amlo 132; Enalapril 131) ACEI vs Other 18-70 Amlo, metoprolol, 20-65 mL/min/1.73 m2 AASK ramipril (2002)4
End Point Excluded Duration (y) Number GFR Criteria Comparitors Age (y) Study
Table 3. Treatment Trials Comparing an ACEI or an ARB to an Active Comparator in Patients With CKD
Results
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patients with CKD.13 Though usually tolerated well, it is important to demonstrate creatinine stability as marked increases can occur, often pointing to disorders such as bilateral kidney artery stenosis.14 The other biochemical consequence of using an ACEI or an ARB is the tendency to hyperkalemia.15 Consequently it is important to monitor periodically both the serum creatinine and the serum electrolytes when these agents are in use or when intercurrent illness may predispose the patient to acute kidney injury.16
Summary Among the guidelines that present recommendations for BP management in patients with CKD, there is far more agreement than differences as listed in Table 1. There will continue to be many in the Nephrology community who adhere to a lower treatment target of less than 130/ 80 mm Hg when proteinuria is present because it is difficult to ignore the large amount of epidemiologic evidence supporting proteinuria as an important predictor of kidney function loss. The Systolic Blood Pressure Intervention Trial (NCT01206062 at www.clinicaltrials.gov) enrolled more than 9000 subjects, about one-third of whom have nondiabetic CKD, and it is hoped that this study will provide more guidance particularly for systolic BP management in CKD and further define the role of proteinuria as a modifier of kidney outcomes with more intense systolic BP management in this vulnerable population.
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17. Dasgupta K, Quinn RR, Zarnke KB, et al. The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2014;30(5):485-501. 18. Mancia G, Fagard R, Narkiewicz K, et al. 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. 19. KDIGO Panel. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012;2(5):343-387. 20. Flack JM, Sica DA, Bakris G, et al. Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5): 780-800.
