Treatment of Hypertension in Patients on Hemodialysis

Treatment of Hypertension in Patients on Hemodialysis
Hermann Haller Department of Nephrology Hannover Medical School

Blood pressure treatment - “conventional“ wisdom in ESRD patients
Salt ??? Changes over time ??? volume-dependent Salt/water Heart failure Blood pressure regulation Arterial compliance calcification vasoconstriction RAS, sympathetic activity, lack of NO, medullipin etc. What is the “real” RR ??? Since 1998, first-year mortality rates have fallen nearly 30% for pts on PD, and 16% for those with Tx. Mortality in the HD population, in contrast, has decreased ONLY by 5%. Every year between 20 and 30% of all patients on dialysis die. Around 45% of these deaths are attributed to cardiovascular events. Even higher rates are observed in older people. HD HD HD Acute changes ??? HD HD HD

Definition of Hypertension
K/DOQI 2005 guidelines on cardiovascular disease in dialysis patients Predialysis and postdialysis blood pressure goals should be <140/90mmHg and <130/80mmHg respectively (C) K/DOQI 2006 update of hemodialysis adequacy guidelines Focus on volume control, dietary sodium restriction and avoidance of high dialysate sodium DO NOT recommend specific blood pressure targets in hemodialysis patients K/DOQI 2007 clinical practice guidelines for diabetes and CKD Target blood pressure in diabetes and CKD stages 1-4 should be <130/80mmHg (B) Targets for patients on dialysis are not recommended. Most large scale clinical trials exclude patients with ESRD, and thus guidelines targeting these patients are opinion-based and extrapolated from other populations. CV benefits of lowering bp in the general population and patients with early CKD have been proved. However, the efficacy and safety of lowering blood pressure in HD pts is uncertain. In contrast to the general population, no adequately powered randomized clinical trials examining hard outcomes have been conducted among hemodialysis patients to determine hard outcomes. Grade C strength of recommendation, which means that the recommendation is based on either weak evidence or on the opinions of the Work Group.

Home blood pressure monitoring is of greater prognostic value than hemodialysis units recordings
Design, setting, participants, & measurements: A prospective cohort study was conducted in 150 patients who were onchronic hemodialysis dialyzing at four university-affiliated units. BP was self-measured at home for 1 wk, for an interdialytic interval by ambulatory recording, and by “routine” and standardized methods in the dialysis unit for 2 wk. Patients were followed for a median of 24 mo to assess the end points of all-cause and cardiovascular mortality. Hazard ratios for mortality for quartiles of systolic BP. Both home bp and ABPM had prognostic information. Conversely dialysis unit BP readings did not achieve statistic significance in terms of prognostic value. In this cohort, self measured SBP of 125 to 145 mmHg and 115 to 125 by ABPM was associated with the best prognosis in HD patients. Alborzi et al. CJASN 2007;2:

Prevalence of hypertension in chronic HD pts (N=65393, mean age 61 yr, mean duration on HD 8 yr)
Prevalence of hypertension by the duration of HD and sex in the Japanese Society of Dialysis Therapy 2000 database. Hypertension was defined as either systolic bp> 140 or diastolic bp>90mmHg. 77.5% had hypertension and 61% were prescribed antihypertensive drugs. Nevertheless, bp control was unsatisfactory. Those who survived longer on HD were less likely to have hypertension. Iseki et al. Ther Apher Dial 2007;11:

Patients achieving pre- and post-dialysis UK RA blood pressure targets (<140/90 or <130/80 mm Hg) BP targets in UK : predialysis <140/90, postdialysis <130/80mmHg 1-week observational study 36% achieved predialysis BP targets, 42% achieved postdialysis BP targets and only 26% met both standards. Blood pressure control was achieved at the cost of increased intradialytic hypotension Use of antihypertensive medications was not associated with intradialytic hypotension Davenport et al. Kidney International 2008; 73:

Blood pressure control rates in a cohort of hemodialysis patients (N=2360)
BP targets in UK : predialysis <140/90, postdialysis <130/80mmHg 1-week observational study 36% achieved predialysis BP targets, 42% achieved postdialysis BP targets and only 26% met both standards. Blood pressure control was achieved at the cost of increased intradialytic hypotension Use of antihypertensive medications was not associated with intradialytic hypotension Davenport et al. Kidney International 2008; 73:

Patients achieving post-dialysis UK RA blood pressure targets and intradialytic hypotension

The effects of different drug classes on intradialytic hypotension

Blood pressure and coronary artery disease
Prospective Studies Collaboration, Lancet 2002;360:1903 Mehr als 1 Mill. Patienten

Association between BP and 15-month CV death in 40 933 MHD patients
(95% confidence interval bars are depicted) We studied a 15-month cohort of hemodialysis patients in the United States whose predialysis and postdialysis blood pressure valueswere recorded routinely during each hemodialysis treatment. Patients were years old; 54% were women and 46% diabetics. Predialysis systolic hypertension remained a significant predictor of highest all-cause and cardiovascular survival rate. Although these associations may not be causal, they call into question whether treatment goals for the general population can be applied to dialysis patients or other similar populations. Unadjusted, case-mix and dialysis dose–adjusted, and additional malnutrition-inflammation–adjusted hazard ratios of all-cause and cardiovascular death showed progressivelyincreasing all-cause and cardiovascular death risk for decreasing blood pressure values. The lowest mortality was associated with predialysis systolic pressure of 160 to 189 mm Hg, whereas normal to low predialysis pressure values were associated with significantly increased mortality. Adjustment for the malnutrition-inflammation mitigated only a small portion of paradoxical associations between the low blood pressure and mortality. Kalantar-Zadeh et al. Hypertension 2005;45:

Unadjusted survival by baseline predialysis systolic BP
Incident HD patients who were treated at Dialysis Clinic Inc. facilities between 1993 and 2003 were studied. Primary end points were atherosclerotic cardiovascular disease and all-cause mortality. The relationship between BP and mortality was analyzed in two sets of Cox proportional hazards models. SBP. Kaplan-Meier survival curves of patients who were stratified by baseline predialysis SBP demonstrated that sur-vival was lower among patients with baseline SBP<130 mmHg. Stidley et al. J Am Soc Nephrol 2006;17:

Relationship between blood pressure and mortality in dialysis patients.
Large observational studies describe a U shaped mortality curve with regard to BP in dialysis patients. Not do they fail to demonstrate a correlation between worse outcome and significant hypertension, but they demonstrate increased mortality at lower BP. Is the hemodialysis population truly unique in that hypertension somehow provides protection against dialysis related adverse effects ? Several large trials in HD patients failed to show any mortality benefit for rational treatment goals such as raising Hb levles, increasing the dose of dialysis and prescribing statins or antioxidants. If BP target is absent from the guidelines, then hypertension may receive inadequate medical attention. If BP targets are set too low, then nephrologists may expose their patients to an increase risk of indtradialytic hypotension or other adverse events in an attempt to appease oversigth committees or to attain pay-for performance rewards. WE NEED ADEQUATELY POWERED CLINICAL TRIALS TO DETERMINE THE RISKS AND BENEFITS OF BP CONTROL. THE ASSOCIATION OF BETTER OUTCOMES WITH HIGHER BP, THE SO CALLED REVERSE EPIDEMOLOGY SHOULD NOT BE TAKEN AS CAUSAL Luther JM Kidn Int 2008;73:

Hazard ratios (HR) for all-cause (AC) mortality by baseline predialysis SBP
Model-B explored the relationship between baseline BP and mortality in sequential time periods. Predialysis baseline SBP 120 mmHg was associated with increased AC mortality in the first 2 y. The magnitude of the HR associated with predialysis SBP above the referent category (140 to 149 mmHg) tended to increase over the successive follow-up periods. Among participants with 3 yr of follow-up, baseline predialysis SBP 150 mmHg was associated with mortality Observational studies in patients on dialysis have suggested a time dependent association between bp levels and cardiovascular outcomes, with low bp being associated with higher mortality rates in the short term, but lower mortality rates in the long run. Low bp in dialysis pts is frequently a sign of heart failure. Stidley et al. J Am Soc Nephrol 2006;17:

Hazard ratios (HR) for all-cause (AC) mortality by baseline predialysis DBP

Hazard ratios (HR) for all-cause (AC) mortality by baseline postdialysis SBP

Hazard ratios (HR) for all-cause (AC) mortality by baseline pulse pressure

Blood pressure and mortality risk in peritoneal dialysis Time-Stratified Cox Proportional Hazards Model for Components of BP Setting & Participants: 2,770 patients on PD therapy at 180 days from start of renal replacement therapy in England and Wales between 1997 and 2004. Predictors: Systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) measured in the first 6 months of renal replacement therapy and other baseline demographic and laboratory variables. Outcomes: All-cause mortality was studied using time-stratified Cox regression models (to account for nonproportionality) dividing follow-up time into 4 intervals: year 1 (days 180 to 365), years 2 to 3, years 4 to 5, and years 6. Interactions between BP components and transplant waitlist and diabetes status were explored. Abbreviations: BP= blood pressure; CI= confidence interval; RH= relative hazard; RRT= renal replacement therapy; TWL=deceased-donor transplant waiting list. *Covariates adjusted: age; sex; cause of end-stage renal disease; ethnicity; baseline hemoglobin, calcium, and phosphate levels; time to registration on TWL after starting RRT; and change in RRT modality as time-dependent variable. †RH quoted per 10-mm Hg increase. ‡P from likelihood ratio tests comparing models with and without interaction term. In the fully adjusted models for day 180 to 1 year, greater baseline SBP, DBP, MAP, and PP were all associated with lower mortality. In years 2, 3, 4, and 5, there was no evidence of an association between any BP component and mortality. In year 6 and beyond, greater baseline SBP and PP (but not DBP or MAP) were associated with greater mortality. Udayaraj et al. AJKD 2009;53:70-78

Blood Pressure and mortality risk in PD Patients
(A, B) Relative hazards (RHs) for blood pressure (BP) components comparing patients placed on the transplant wait list (TWL) in the first 6 months (TWL 6 months), beyond 6 months (TWL 6 months), and those not placed on the TWL in the time-stratified Cox models for (A) year 1 (days 180 to 365) and (B) years 4 to 5. RHs quoted per 10-mm Hg increase and adjusted for age; sex; cause of end-stage renal disease; ethnicity; baseline hemoglobin, calcium, and phosphate levels; and change in renal replacement therapy modality as a time-dependent variable. Abbreviations: DBP, diastolic BP; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic BP. Greater SBP, DBP, MAP, and PP were associated with decreased early mortality, ie, in the period 6 to 12 months after the start of RRT, but not subsequently. PD pts who were waitlisted for kidney Tx within 6 months of initiating dialysis exhibited a relationship between mortality and BP that was similar to that of the general population. The adverse effects of high SBP and PP were apparent only beyond 5 years in survivors. Udayaraj et al. AJKD 2009;53:70-78

Blood Pressure and mortality risk in transplanted patients
(A, B) Relative hazards (RHs) for blood pressure (BP) components comparing patients placed on the transplant wait list (TWL) in the first 6 months (TWL 6 months), beyond 6 months (TWL 6 months), and those not placed on the TWL in the time-stratified Cox models for (A) year 1 (days 180 to 365) and (B) years 4 to 5. RHs quoted per 10-mm Hg increase and adjusted for age; sex; cause of end-stage renal disease; ethnicity; baseline hemoglobin, calcium, and phosphate levels; and change in renal replacement therapy modality as a time-dependent variable. Abbreviations: DBP, diastolic BP; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic BP. Greater SBP, DBP, MAP, and PP were associated with decreased early mortality, ie, in the period 6 to 12 months after the start of RRT, but not subsequently. PD pts who were waitlisted for kidney Tx within 6 months of initiating dialysis exhibited a relationship between mortality and BP that was similar to that of the general population. The adverse effects of high SBP and PP were apparent only beyond 5 years in survivors. Opelz et al. Am J Transplant 2005; 5: 2725

Beta blockers in the management of chronic kidney disease
Increased sympathetic activity in patients with moderate renal failure as well as in ESRD. Level of sympathetic activity is an independent predictor of total and cardiovascular mortality in patients with ESRD. Coronary heart disease and heart failure (HF) are the most common causes of death in these patients. The sympathetic nervous system modulates renal function through its receptors namely b1 (cardiac output and renin release), a1 (systemic and renovascular constriction), and b2 renovascular dilation. Sympathetic overactivity is commonlyseen in chronic kidney disease (CKD) and is an important contributor to increasing the risk of cardiovascular events as well as increasing renal disease progression. Recent evaluations of drug use in people with CKD shows a remarkably low percentage of patients receiving b-blockers,especially in more advanced stage CKD when cardiovascular risk is higher. This is in large part due to tolerability of these agents. Moreover, water-soluble b-blockers such as atenolol and metoprolol are dialyzable and require supplementation to avoid exacerbation of arrhythmias following dialysis. Newer vasodilating b-blockers have better tolerability and different effects on renal hemodynamics as well as metabolic variables. These effects are related to the relative a1-blocking effect of agents such as carvedilol and labetolol, with carvedilol having relatively greater a-blocking effects. Few studies evaluate b-blockers on cardiovascular risk in CKD patients. Studies with carvedilol demonstrate attenuated increases in albuminuria as well as reduction in cardiovascular events in CKD patients with hypertension. This paper reviews the animal and clinical trial data that evaluate b-blockers in CKD highlighting the vasodilating b-blockers. It is apparent that greater use of this drug class for blood pressure control would further enhance reduction of risk of heart failure, the most common cause of death in the first year of starting dialysis.

Observational studies of beta blockers (Analyses of the Dialysis Morbidity and Mortality Studies DMMS conducted by the US Renal Data System ) 2550 pts observed 60 days after dialysis In patients WITHOUT a history of HF, use of beta blockers was associated with lower subsequent risk of de novo HF, combined HF and cardiac death and all cause death. Beta-blockers were used by only 20% of patients in this cohort regardless of the presence of previous HF. 2250 Patients observed 60 days after the start of dialysis. Kaplan-Meier plot of unadjusted time to Medicare institutional claims for de novo heart failure (HF) (International Classification of Diseases, Ninth Revision, code 428.x) by use or nonuse of -blockers 60 days or more after the start of dialysis in patients with Medicare as the primary payer at day 60, United States Renal Data System Morbidity and Mortality Study Wave 2 cohort, excluding patients with a known diagnosis of HF. Time to de novo chronic heart failure was significantly longer for use of -blockers, P=.007 by the log rank test. No such associations were seen for dialysis patients with a previous history of HF Abbott et al. Arch Intern Med 2004;164:

Observational studies of beta blockers beta blockers and mortality -USRDS Waves 3 and 4 Study
Unadjusted HR Adjusted HR patients were followed up for a maximum of nearly 7 years. Only the effect of beta blockers was preserved after mulitvariate analysis. Thus lending support to the argument that beta blockers per se are beneficial ie beta blocker use shows a robust association with survival ONLY 8.5% of dialysis patients were treated with beta blockers ! Foley et al. Kidney International 2002;62:

Observational studies of beta blockers Predictors of survival after cardiac arrest in outpatient hemodialysis clinics (after 24hours and after 6 months) 729 patients who sustained in-clinic cardiac arrest. 310 patients (42.5%) survived 24 hours and 80 (11%) survived 6 months Prescription of beta blocker at the time of event was the only predictive variable of survival at 24 hours. After adjustement, only use of betablockers ACEI and ARBs remained significantly associated with survival after 6 months Pun et al. CJASN 2007;2:

Observational studies of beta blockers ESRD Database + Cooperative Cardiovascular Project Database Association of medication classes with 30-day mortality after Myocardial infarction in pts with ESRD The most convincing evidence for a short term benefit conferred by -blockers in post-MI patients comes from the Cooperative Cardiovascular Project (CCP). By linking CCP and US Renal Data System data, the association of medication classes with 30-day mortality post-MI was examined in 1,025 patients with ESRD and compared with 145,000 individuals without ESRD. Figure: Aspirin, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors were less likely to be provided to patients with end-stage renal disease (ESRD) than those without ESRD. In an analysis of patients considered ideal for the individual therapies, the overall administration rates were higher, but patients with ESRD still remained less likely to receive the therapy than those without ESRD. The p value for each comparison between ESRD and non-ESRD patients was Berger et al. JACC 2003;42:

Poor short-term survival and low use of cardiovascular medications in elderly dialysis patients after acute myocardial infarction, We identified 902 dialysis patients who were hospitalized with MI. Of these, 39.5% died within 90 days and 63.6% died within 1 year after MI. Of 494 patients who were discharged within 21 days or less and survived longer than 90 days, 31.0% were administered an ACE inhibitor and/or ARB; 19.4%, a statin; and 34.2%, a -blocker after discharge. Fig 1. Use of cardiovascular medications by year of admission. Use of -blockers, ACE inhibitors and/or ARBs, and statins after discharge between 1995 and Use of statins (P < 0.01) and ACE inhibitors and/or ARBs (P 0.01) increased during the study period, whereas use of -blockers did not (P 0.29).Percent and upper 95% confidence limit shown. Winkelmeyer et al AJKD 2005;47:

Carvedilol increases two year survival in dialysis patients with dilated cardiomyopathy
Only a single randomized control trial has investigated the effects of beta blockers on survival in hemodialysis patients Investigators randomly assigned 114 individuals with NYHA class II or III congestive heart failure to standard therapy with ACEI or ARBs plus digitalis or standard tdherapy plus carvedilol. All patients were receiving digitalis; 128 patients (96.9%) were also receiving angiotensin-converting enzyme (ACE) inhibitors; The echocardiographic data and clinical status assessment revealed that structural and functional benefits obtained by one-year carvedilol therapy were maintained also at year 2 Cice et al. JACC 2003; 41:

Carvedilol in patients on hemodialysis Impact on all cause mortality
1.0 .8 .6 Survival Carvedilol .4 Placebo .2 Carvedilol use was associated with decreased rates of all cause mortality ( 51.7% vs 73.2%, cardiovascular deaths ( 29.3 vs 67.9%) and all cause hospitalizations (34.5 vs 58.9%) at 2 years. Limitations : the trial consisted of only 114 individuals, participants were unblinded at 1 year and mortality benefits did not accrue until the second year Strenths: rigorus inclusion criteria, uniformity of treatment regimen ( with 100% receiving ACEI/ARBs and improvement in both echocardiographic findings and clinical end points. p<0.005 0.0 10 15 20 25 Time After Inclusion (months) Cice et al. JACC 2003; 41:

CARDIOVASCULAR MORTALITY
Carvedilol in patients on hemodialysis Cardiovascular mortality and all cause hospitalization CARDIOVASCULAR MORTALITY EVENT-FREE SURVIVAL 1,0 1.0 Carvedilol Carvedilol ,9 ,8 .8 ,7 ,6 ,6. Event free survival Survival ,5 Placebo Placebo ,4 .4 ,3 ,2 p< .2 p<0.005 ,1 0,0 0.0 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Time After Inclusion (months) Time After Inclusion (months) Cice et al. JACC 2003; 41:

RAS Inhibitors in patients on HD Studies focusing on end-organ damage
A 12-month treatment with ramipril did not cause significant regression of left ventricular hypertrophy in 46 normotensive hemodialysis patients (Wen-Chung Yu et al. AJKD 2006;47: ) Valsartan ( in combination with amlodipine) reduced markers of oxidative stress in 30 pts on HD (Aslam et al. Kidney International 2006;70: ) Losartan and tandolapril improved arterial stiffness in 64 pts on HD (Ichihara et al. AJKD 2005;45: ) Enalapril and Losartan lead to regression of LVH in 33 incident hemodialysis patients ( Suzuki et al. Ther Apheresis and Dialysis 2004;4: ) The use of ACE inhibitors in the dialysis population is theoretically attractive. Only three studies with contradictory results and small patient numbers.

ACE inhibitors after cardiac events in patients on HD ESRD Database + Cooperative Cardiovascular Project Database Association of medication classes with 30-day mortality after Myocardial infarction in pts with ESRD The most convincing evidence for a short term benefit conferred by -blockers in post-MI patients comes from the Cooperative Cardiovascular Project (CCP). By linking CCP and US Renal Data System data, the association of medication classes with 30-day mortality post-MI was examined in 1,025 patients with ESRD and compared with 145,000 individuals without ESRD. Figure: beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors were less likely to be provided to patients with end-stage renal disease (ESRD) than those without ESRD. In an analysis of patients considered ideal for the individual therapies, the overall administration rates were higher, but patients with ESRD still remained less likely to receive the therapy than those without ESRD. The p value for each comparison between ESRD and non-ESRD patients was ACEI USE WAS ASSOCIATED WITH 43%RR REDUCTION OF DEATH AT 30 DAYS. THESE EFFECTS WERE EVEN MORE PRONOUNCED FOR THE NON ESRD POPULATION. Berger et al. JACC 2003;42:

ACE Inhibitors after cardiac events in patients on Hemodialysis
Congestive heart failure was present in 80% of the study cohort ACE inhibitors were used in only 30% of the patients 1 year mortality rate was very high (63%) Use of ACE I or ARB was associated with a 30% reduction in 1year mortality We identified 902 dialysis patients who were hospitalized with MI. Of these, 39.5% died within 90 days and 63.6% died within 1 year after MI. Of 494 patients who were discharged within 21 days or less and survived longer than 90 days, 31.0% were administered an ACE inhibitor and/or ARB; 19.4%, a statin; and 34.2%, a -blocker after discharge. Fig 1. Use of cardiovascular medications by year of admission. Use of -blockers, ACE inhibitors and/or ARBs, and statins after discharge between 1995 and Use of statins (P < 0.01) and ACE inhibitors and/or ARBs (P 0.01) increased during the study period, whereas use of -blockers did not (P 0.29).Percent and upper 95% confidence limit shown. Winkelmeyer et al AJKD 2005;47:

Fosinopril in Dialysis (FOSIDIAL)Study
The composite cardiovascular event rate was 32.7% during the 2yr follow up period In the intention to treat analysis there was no significant difference in the primary end point between the two groups (RR=0.93; 95%CI 0.68 to 1.26; P=0.35) The only placebo controlled RCT of ACE I was the Fosinopril in Dialysis Study. 400 pts were included and followed up for two years. The study assessed the efficacy and safety of fosinopril in preventing fatal and nonfatal cv events in prevalent HD pts with left ventricle hypertrophy. The composite cardiovascular event rate was 32.7% during the 2 year follow up. In the intention to treat analysis there was no significant difference in the primary end point between the two groups. Some baseline characteristics between the two groups differed significantly. Participants in the fosinopril group had greater LVH, had been on dialysis longer and had lower BMI. Zannad et al. Kidney International 2006;70:

Fosinopril in Dialysis (FOSIDIAL)Study (change in SBP and DBP)
Normotensive pts had no change in BP, whereas hypertensive pts had an 11.7/4.9 mmHg reduction in SBP and DBP respectively with fosinopril and a 5.4/2.1 with placebo. In the hypertensive group, 19% of pts in the placebo group and 35% in the fosinopril group had BP< 140/90mmHg. LOWERING OF BLOOD PRESSURE DID NOT LEAD TO AN INCREASE IN MORTALITY AS WOULD BE EXPECTED FROM THE REVERSE EPIDEMIOLOGY THEORIES OF HT IN HD. Zannad et al. Kidney International 2006;70:

Fosinopril in Dialysis (FOSIDIAL)Study
The only placebo controlled RCT of ACE I was the Fosinopril in Dialysis Study. 400 pts were included and followed up for two years. The study assessed the efficacy and safety of fosinopril in preventing fatal and nonfatal cv events in prevalent HD pts with left ventricle hypertrophy. The composite cardiovascular event rate was 32.7% during the 2 year follow up. In the intention to treat analysis there was no significant difference in the primary end point between the two groups. Some baseline characteristics between the two groups differed significantly. Participants in the fosinopril group had greater LVH, had been on dialysis longer and had lower BMI. Zannad et al. Kidney International 2006;70:

Angiotensin Receptor Blockers on Cardiovascular Events in Patients undergoing Hemodialysis
SBP and diastolic blood pressure did not differ significantly between the 2 groups at 12, 24, and 36 months. Finally, mean weekly dose of erythropoietin was 7, units in the control group and 7, units in the ARB group, and hemoglobin levels remainedrelatively constant during the course of the trial THE FINDINGS SUGGEST A BENEFICIAL EFFECT OF ARB BEYOND BP SMALL SAMPLE SIZE THE LARGE EFFECT SIZE MAY BE SPURIOUS (TYPE I ERROR) OPEN LABEL DESIGN, 3 DIFFERENT AGENTS. Low mortality rates observed. Suzuki et al. AJKD 2008;52:

Angiotensin Receptor Blockers on Cardiovascular Events in Patients undergoing Hemodialysis
RCT. 360 prevalent (1 to 5 years ) HD pts. Treatment with ARB ( valsartan up to 160mg/d, candesartan up to 12mg/d, or losartan up to 100mg/d ) versus without ARBs. Follow up 3 yr. Predialysis SBP > 160mmHg or >150 mmHg if receiving antihypertensive agents. ARBs reduced the rate of cv events by 50% and of total mortality by 36% Suzuki et al. AJKD 2008;52:

Six of the trials were published in peer-reviewed journals and two were presented at scientific meetings and have not been published yet. 3 studies assessed the effects of ARBs , two an ACI and two a b blocker. 1 studie was with amlodipine. Study follow up period ranged from 12 M two 36 M. Lancet Published Online February 26, 2009

The weighted mean difference in blood pressure during follow up between active and control treatment across all trials was -4.5 mmHg for systolic -2.3 mmHg for diastolic blood pressure. Overall treatment with bp lowering drugs was associated with a lower risk of cardiovascular events compared with control regimens ( RR=0.71). Exclusion of the two unpublished studies did not alter the findings (RR=0.64). The results did not show any differences in cardiovascular events caused by different drug classes The benefit of blood pressure was lowering drugs was similar in trials that did and did not select participants on the basis of raised baseline blood pressure levels. DATA ON THE MANAGEMENT OF OF VOLUME CONTROL WERE NOT PROVIDED IN THE VARIOUS STUDIES.This variable was not assessed. Thus, treatment with bp lowering agents should routinely be considered for patients undergoing dialysis to prevent cardiovascular events and mortality. They CALCULATED THAT BP LOWERING TREATMENT COULD PREVENT TWO OF THE TEN DEATHS EXPECTED TO OCCUR IN EVERY 100 PATIENTS PER YEAR. This absolute benefit will be greater for individuals at higher absolute risk and is much greater than reported for many other interventions in routine use.

Risk of cardiovascular events for blood pressure lowering treatment vs control regimens
The weighted mean difference in blood pressure during follow up between active and control treatment across all trials was -4.5 mmHg for systolic -2.3 mmHg for diastolic blood pressure. Overall treatment with bp lowering drugs was associated with a lower risk of cardiovascular events compared with control regimens ( RR=0.71). Exclusion of the two unpublished studies did not alter the findings (RR=0.64). The results did not show any differences in cardiovascular events caused by different drug classes The benefit of blood pressure was lowering drugs was similar in trials that did and did not select participants on the basis of raised baseline blood pressure levels. DATA ON THE MANAGEMENT OF OF VOLUME CONTROL WERE NOT PROVIDED IN THE VARIOUS STUDIES.This variable was not assessed. Thus, treatment with bp lowering agents should routinely be considered for patients undergoing dialysis to prevent cardiovascular events and mortality. They CALCULATED THAT BP LOWERING TREATMENT COULD PREVENT TWO OF THE TEN DEATHS EXPECTED TO OCCUR IN EVERY 100 PATIENTS PER YEAR. This absolute benefit will be greater for individuals at higher absolute risk and is much greater than reported for many other interventions in routine use. Lancet Published Online February 26, 2009 DOI: /S (09)

Subgroup analyses for the effects of treatment on cardiovascular events
The weighted mean difference in blood pressure during follow up between active and control treatment across all trials was -4.5 mmHg for systolic -2.3 mmHg for diastolic blood pressure. Overall treatment with bp lowering drugs was associated with a lower risk of cardiovascular events compared with control regimens ( RR=0.71). Exclusion of the two unpublished studies did not alter the findings (RR=0.64). The results did not show any differences in cardiovascular events caused by different drug classes The benefit of blood pressure was lowering drugs was similar in trials that did and did not select participants on the basis of raised baseline blood pressure levels. DATA ON THE MANAGEMENT OF OF VOLUME CONTROL WERE NOT PROVIDED IN THE VARIOUS STUDIES.This variable was not assessed. Thus, treatment with bp lowering agents should routinely be considered for patients undergoing dialysis to prevent cardiovascular events and mortality. They CALCULATED THAT BP LOWERING TREATMENT COULD PREVENT TWO OF THE TEN DEATHS EXPECTED TO OCCUR IN EVERY 100 PATIENTS PER YEAR. This absolute benefit will be greater for individuals at higher absolute risk and is much greater than reported for many other interventions in routine use. Lancet Published Online February 26, 2009

Risk of cardiovascular mortality for blood pressure lowering treatment vs control regimens

Risk of all-cause mortality for blood pressure lowering treatment vs control regimens

Study treatment discontinuation rates
Drugs that lower bp might increase the risk of intradialytic hypotension. However, bp lowering was well tolerated with no consistent evidence of higher drop out rates in the active treatmetn groups than in the control groups of the studies. Increase mortality with antihypertensive medications was not observed. Lancet Published Online February 26, 2009 DOI: /S (09)

The effect of dry weight reduction on interdialytic ambulatory systolic and diastolic BP in hypertensive hemodialysis pts. Figure : The effect of dry weight reduction on interdialytic ambulatory systolic and diastolic BP in hypertensive hemodialysis pts. To determine whether additional volume reduction will result in improvement in blood pressure (BP) among hypertensive patients on hemodialysis and to evaluate the time course of this response, we randomly assigned long-term hypertensive hemodialysis patients to ultrafiltration or control groups. The additional ultrafiltration group (n=100) had the dry weight probed without increasing time or duration of dialysis, whereas the control group (n=50) only had physician visits. The primary outcome was change in systolic interdialytic ambulatory BP. Postdialysis weight was reduced by 0.9 kg at 4 weeks and resulted in 6.9 mm Hg (95% CI: 12.4 to 1.3 mm Hg; P0.016) change in systolic BP and 3.1 mm Hg (95% CI: 6.2 to 0.02 mm Hg; P0.048) change in diastolic BP. At 8 weeks, dry weight was reduced 1 kg, systolic BP changed 6.6 mm Hg (95% CI: 12.2 to 1.0 mm Hg; P0.021), and diastolic BP changed 3.3 mm Hg (95%CI: 6.4 to 0.2 mm Hg; P0.037) from baseline. METHODS Patients found to have well controlled hypertension had antihypertensive medications withdrawn until they became hypertensive. Conclusions : 1) reduction in dry weight as defined by clinical sings and symptoms results in reduction in ambulatory BP. This improvement can be achieved without increasing the time or frequency of dialysis treatments. 2) More than half of the patients in the intervention group had reduction in systolic BP by >10mmHg, suggesting that dry weight reduction results in improved systolic BP equivlent to or greater than a single antihypertensive drug. 3) The reduction in systolic BP was nearly twice as much as diastolic BP, which results in attenuation of pulse pressure. Agarwal et al. Hypertension 2009; 53:

Major problems before randomized prospective trials
What is (are) the blood pressure measurement(s) a diagnosis of hypertension is based upon ? Do we have to subclassify according to heart failure (or other) ? How to account for „time on dialysis“ ? Role of dialysis regime ?

Pharmacologic properties of β-blockers in chronic dialysis patients
T1/2(h) normal ESRD Initial dose in HD Maintenance dose in HD Removal during HD Acebutolol 3.5 200 q24h q24h yes Atenolol 6-9 <120 25 q48h 25-50 q48h Yes Carvedilol 4-7 5 q24h no Metoprolol 3-4 50 b.i.d. b.i.d. high Propranolol 2-4 40 b.i.d. 40-80 b.i.d. The pharmacologic properties and cardiac indications of a selected number of beta blockers. There have been no randomized trials using any type of beta blocker in the general dialysis population who do not have the usual, absolute indications for these agents defined in the nondialysis population. Protein binding : ATENOLOL <5%, ACEBOUTOL 30%, CARVEDILOL 95%, METOPROLOL 12%, PROPRANOLOL 90% Metabolism : ATENOLOL: kidney, ACEBUTOLOL,CARVEDILOL,METOPROLOL,PROPRANOLOL: liver Henrich W. Principles and Practice of Dialysis

Observational studies of beta blockers ESRD Database + Cooperative Cardiovascular Project Database Association of medication classes with 30-day mortality after Myocardial infarction in pts with ESRD After covariate adjustment, -blockers were associated with improved survival (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99). This outcome was not significantly different from that in individuals without ESRD (RR, 0.70), indicating that concerns over dialysis patients not receiving benefit comparable to nondialysis patients may be unfounded. THE FACT THAT THESE PATIENTS ACHIEVED THE SAME BENEFIT AS THOSE NOT RECEIVING DIALYSIS PROVIDES A STRONG JUSTIFICATION FOR THE ADMINISTRATION OF THESE MEDICATIONS. Berger et al. JACC 2003;42:

Pharmacokinetic properties of ACE Inhibitors in ESRD
T1/2(h) normal ESRD Initial dose in HD Maintenance dose in HD Removal during HD Captopril 2-3 20-30 12.5 q24h 25-50 q24h Yes Enalapril 11 prolonged 2.5 q24h or q48h q24h or q48h Fosinopril 12 10 q24h 10-20 q24h Lisinopril 13 54 Ramipril 2.5-5q24h q24h yes Henrich W. Principles and Practice of Dialysis

Pharmacokinetic properties of ARB’s in ESRD
T1/2(h) normal ESRD Initial dose in HD Maintenance dose in HD Removal during HD Candesartan 9 ? 4 q24h 8-32 q24h No Irbesartan 11-15 q24h q24h Losartan 2 4 50 q24h q24h Telmisartan 24 40 q24h 20-80 q24h Valsartan 6 80 q24h q24h Henrich W. Principles and Practice of Dialysis

Treatment of Hypertension in Patients on Hemodialysis

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Treatment of Hypertension in Patients on Hemodialysis

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Presentation on theme: "Treatment of Hypertension in Patients on Hemodialysis"— Presentation transcript:

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