ANTI-HYPERTENSIVE MANAGEMENT OF CHRONIC KIDNEY DISEASE DISCLOSURES Editor-in-Chief- Nephrology- UpToDate- (Wolters Klewer) Richard J. Glassock, MD, MACP Geffen School of Medicine at UCLA 1 st Annual Internal Medicine Board Review Course University of Tennessee College of Medicine Chattanooga, TN October 2, 2014 Associate Editor- NephSAP- (American Society of Nephrology) Associate Editor- American Journal of Nephrology (Karger) : KDIGO-2012 Definition/Classification (CGA) (Kidney International Supplements; January 2013) : Characteristics of the Staged Populations (James, Lancet 2010) 100% 80% 60% 40% 20% 0% 18-30 31-45 46-60 61-75 >75 Age (years) UACR >30mg/g egfr <60ml/min/1.73m2 Both 1
-NHANES Prevalence of Stage 3 by Age Group (1999-2004) egfr (MDRD) in Healthy Caucasian Males (Nijmegen Biomedical Study, 2008) Prevalence (%) 40% 35% 30% 25% 20% 15% 10% egfr (ml/min/1.73m2) 160 140 120 100 80 60 40 20 95th Percentile 50th Percentile 5th Percentile 5% 0% 20-39 40-59 60-69 70+ 0 18-25- 30-35- 40-45- 50-55- 60-65- 70-75- 80-85+ 24 29 34 39 44 49 54 59 64 69 74 79 84 Age (years) Age Group (years) egfr (MDRD) in Healthy Caucasian Females (Nijmegen Biomedical Study, 2008) egfr (ml/min/1.73m2) 160 140 120 100 80 60 40 20 0 18-25- 30-35- 40-45- 50-55- 60-65- 70-75- 80-85+ 24 29 34 39 44 49 54 59 64 69 74 79 84 Age (years) 95th Percentile 50th Percentile 5th Percentile Hypertension: Definitions JNC7 (2003)- defined and staged hypertension and pre-hypertension based on BP values (systolic/diastolic) (expert-opinion based) JNC8 (2014)- did not address definitions of hypertension or pre-hypertension on BP values but thresholds for pharmacologic treatment were defined (evidence-based recommendations) Age-Calibrated Recommendations-I In general population age 60 years initiate pharmacologic treatment to lower BP at a Systolic BP of 150mmHg or diastolic BP 90mmHg (goal <150mmHg SBP and DBP <90mmHg) (evidence Grade A) 2
Age-Calibrated Recommendations-II Categories of Hypertension according to Causal (Office), Home or Ambulatory BP Recordings In general population < age 60 years initiate pharmacologic treatment to lower BP at a Systolic BP of 140mmHg or diastolic BP 90mmHg (goal <140mmHg SBP and DBP <90mmHg) (evidence Grade A for ages 30-59; expert opinion ages 18-29 years) Casual (Office) >140/90mmHg Casual (Office) <140/90mmHg HOME or ABP >140/90mmHg Sustained Hypertension Concealed Hypertension HOME or ABP <140/90mmHg White Coat Hypertension Normotension FREQUENCY OF HYPERTENSION IN Hypertension is very common in and increases in frequency as egfr falls- but this may be in part a phenomenon of aging 3
Main Mechanisms of Hypertension in Chronic, indolent (difficult to detect) NaCl retention and expansion of ECFV Sympathetic Nervous System activation Inappropriate renin-angiotensin suppression (renal parenchymal ischemia; eg P, Diabetes) Augmented cellular actions of aldosterone Large vessel ossification (enhanced systolic wave reflection) KDIGO Recommendations for BP Management in (Kidney Int Suppl 2012; 2:337-414) Non-pharmacological (Lifestyle) Maintain a healthy body weight (BMI= 20-25kg/m2) (1D) Lower salt intake to <5.0gms/d (90mmol of Sodium)- unless contraindicated (1C) Aerobic exercise 30 minutes 5 days per week (1D) Limit alcohol intake to no more than 2 standard drinks per day in men- 1 for women (2D) (also stop smoking, avoid potassium supplementation)- (not graded) CLINICAL PRACTICE GUIDELINES- Hypertension Management in KDIGO- 2012 2014 (not specific to ) European Renal Best Practices commentary on KDIGO (2014) KDOQI commentary on KDIGO (2013) Recommendations-III In a population with (including ESRD) ages 18 years initiate pharmacologic treatment to lower BP at a SBP of 140mmHg or DBP 90mmHg (goal BP <140mmHg SBP and <90mmHg DBP)- (Expert Opinion; Grade E) Canadian Society of Nephrology commentary on KDIGO (2014) 4
Recommendations-IV In a population with Diabetes ages 18 years initiate pharmacologic treatment to lower BP at a SBP of 140mmHg or DBP 90mmHg (goal BP <140mmHg SBP and <90mmHg DBP)- (Evidence- Grade B) Recommendations-V In general non-black population (without ) initial treatment should include a thiazide-type diuretic (TTD), a calcium channel blocker (CCB), and angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin-receptor blocker (ARB) (Evidence- Grade B) In general black population (without ; with or without diabetes) initial treatment should include a TTD or CCB (Evidence- Grade B-C) Recommendations-VI In population with (irrespective of race or diabetes status) age 18 years initial (or add on) treatment should include an ACEi or an ARB ( but not both simultaneously) (Evidence- Grade B) Recommendations-VII If goal not reached with 1 month, increase dose of initial drug or add a second drug in a different class. If goal not attained in another month add a third drug (but do not use ACEi and ARB together) If goal not attained (3 or more drugs required and not at goal) then refer to a hypertension specialist DIABETIC UACR >30mg/gm KDIGO- (2012) Recommendations UACR >300mg/gm INITIATE AT GOAL NO NO NO 140/90 < 140/90 1B NO YES NO 130/80 < 130/80 2D (RAS- 2D) NO YES YES 130/80 <130/80 2D (RAS- 2D) YES NO NO 140/90 <140/90 1B YES YES NO 130/80 (RAS- 2D) YES YES YES 130/80 (RAS- 1B) <130/80 2D <130/80 1B EVIDENCE LEVEL Special Considerations in with Hypertension Thiazide-type diuretics work poorly (if at all) when egfr is <30ml/min (Stage 4-5 ) Loop-acting diuretic (Furosemide; Bumetanide) may have salutary effects down to an egfr of 8-10ml/min; but high doses may be required NaCl restriction (and possibly PO4 restriction) needed when RAS inhibition used to obtain optimal effects Aldosterone receptor blockers (Spironolactone, Eplerenone) may had additive effects on BP control but hyperkalemia is a risk (especially with concomitant RAS inhibition) 5
Cornerstones of Management of Hypertension in Adequate control of ECFV near euvolemia (NaCl restriction; diuretics) Suppression of RAS (ACEi or ARB) Treatment of patients over 65-70 years with must be individualized; elderly patients not tolerate RAS inhibition A NEW TWIST Blood pressure lowering treatment based on CVD risk (The Blood Pressure <Lowering Treatment Trialist Collaboration. Lancet 2014; 384: 591-598) Using an individuals predicted absolute risk of CVD events (mortal or not) to inform treatment decisions for avoidance of CV has been recognized for decades and formalized in recent AHA/ACC guidelines for lipid management. Such recommendations are based on multiple validated risk factor rather than LDL concentrations No similar approach is currently used for BP control A NEW TWIST Blood pressure lowering treatment based on CVD risk (The Blood Pressure <Lowering Treatment Trialist Collaboration. Lancet 2014; 384: 591-598) A meta-analysis of 11 RCT (67,475 individuals) was carried out to determine the impact of application of risk equations (5 year risk of a major CV event) in trials of hypertension treatment. The % of subjects with were not quantitated. Four risk groups were identified (6%, 12%. 18% and 27% 5 year risk of CV events The number needed to treat (NNT) with antihypertensive drugs to avoid one CV event according to baseline CV risk was determined A NEW TWIST Blood pressure lowering treatment based on CVD risk (The Blood Pressure <Lowering Treatment Trialist Collaboration. Lancet 2014; 384: 591-598 RISK GROUP 6% 71 12% 51 18% 41 NNT (for five years to avoid one major CV event) 27% 26 Blood Pressure Lowering and Major CV Events with and without (Blood Pressure Lowering Treatment Trialist Collaboration- Metaanalysis of RCT-BMJ. 2013; 347) A systematic review and meta-analysis of 26 RCT- (152,290 participants) Outcomes- Major CV events (Stroke, AMI, CHF, CV death) egfr > or <60ml/min/1.73m2. (30,295 with egfr <60ml/min/1.73m2) 6
Hazard Ratio of Major CV events for more vs less intensive BP lowering egfr 60ml/min/1.73m2= 0.87 (CI= 0.73-1.03) egfr <60ml/min/1.73m2= 1.24 (CI= 0.62-2.48) Overall- 0.93 (CI= 0.80-1.07) NO EVIDENCE OF BENEFIT FOR INTENSIVE BP LOWERING - <120/130mmHg) HR for Major CV events according to drug class and status (BMJ. 2013; 347) ACEi v BB/Diuretic- egfr 60-1.03 (CI=0.97-1.01) egfr <60-1.00 (CI= 0.97-1.08) CCB v BB/Diuretic- egfr 60-1.04 (CI=0.98-1.11) egfr <60-1.05 (CI= 0.93-1.16) ACEi v CCB- egfr 60-0.97 (CI=0.90-1.05) egfr <60-0.95(CI=0.85-1.06) Effects of ACEi or ARB on All-cause mortality, CV death and CV events in patients with Diabetes (Cheng J, et al JAMA 2014) Meta-analysis of 35 trials, many participants had (n=56,444 participants) Cause specific CV outcomes assessed Acute MI Specific CV Outcomes: Risk Ratio ACEi v non RAS Control- 0.79 (CI=0.65-0.95) ARB v non RAS Control- 0.89 CI= 0.74-1.07) CHF ACEi v non-ras Control- 0.81 (CI= 0.71-0.93) ARB v non-ras Control- 0.70 (0.59-0.82) Stroke ACEi v non-ras Control- 0.95 (CI= 0.86-1.04) ARB v non-ras Control- 1.00 (CI=0.89-1.12) CONCLUSIONS on CVD and - Treatment of Hypertension More intensive lowering of BP <120-130mmHg is not more effective for avoiding CV events in (and might be harmful in those with pre-existing coronary artery lesions) No clear reason for a preference of antihypertensive agents for avoidance of CV event in general ACEi may be preferred in DM for avoidance of CV events and mortality Hypertension Control in CVD for avoiding ESRD Several large RCT have shown that control of BP to <140/90mmHg slows rate of progression of in Diabetic subjects with overt proteinuria (UACR>300mg/gm creatinine) and the effect is closely related to the degree of reduction of albuminuria (or proteinuria). This effect is mainly seen with RAS inhibition Data showing a similar effect in non-diabetic is also available but threshold for benefit is seen at a higher level of proteinuria (UACR>3000mg/gm) 7
Hypertension Control in CVD for avoiding ESRD Evidence favoring a beneficial effect on BP control in avoiding ESRD is weak in subjects with (diabetic/non-diabetic) and absent or moderate proteinuria (UACR<300mg/gm) This is largely due to the slow rate of progression (typically <3ml/min/year) seen in such subjects and the need for very long-duration trials to be adequately powered to show effects CONCLUSIONS- I is currently defined and categorized (N=16) on the basis of a matrix of two bio-markers- egfr and UACR. The thresholds for diagnosis of are not agecalibrated- this is controversial and may lead to over-diagnosis of. CONCLUSIONS- II Hypertension is currently defined on a basis of levels of BP (systolic and diastolic) needing for pharmacologic therapy in an ageand disease- calibrated fashion. Pre-hypertension is no longer recognized as a sub-category of hypertension. CONCLUSIONS- III Hypertension is common, but not universal, in and its frequency increases as egfr declines. Hypertension in promotes its progression to ESRD (especially in the presence of concomitant proteinuria, and increases the likelihood of CV, as modified by baseline CV disease. CONCLUSIONS- IV Chronic indolent NaCl retention is a major factor in hypertension associated with, but other factors may also play a role (SNS, renin activation, aldosterone activation, vascular ossification). 8
CONCLUSIONS- V Treatment of hypertension with pharmacologic agents to a goal of 140/90mmHg, but probably not to <120-130/70-80mmHg, is indicated in to reduce rate of progression to ESRD; especially in diabetes with severe proteinuria. CONCLUSIONS- VI The effect of BP lowering on progression is less certain in those with no or moderate proteinuria. Lowering of urine protein excretion has an effect on progression independent of BP control CONCLUSIONS- VII CONCLUSIONS- VIII Angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), but not both simultaneously, either alone or combined with a CCB (or a diuretic) are preferred for treatment of hypertension in associated with moderate-severe proteinuria, especially in Diabetics, in order to slow progression to ESRD Angiotensin converting enzyme inhibitors (ACEi) may be preferred for treatment of hypertension in associated with diabetes in order to lower the risk of cardiac events CONCLUSIONS- IX In non-diabetics with evidence that any one class of drugs is more effective than another in avoiding CVD is weak Avoidance of stroke is more dependent on the extent of lowering BP rather than how it is achieved Older Adults with and Hypertension (Kaiser EA, et al Clin Issues in Aging; 20125:9) Use Home BP or ABPM when possible The J curve is real- too low BP (<120/70mmHg) can be harmful Recognize the Osler phenomenon; rigid non-compressible brachial artery Initiate Rx when BP >150/90mmHg is sustained Start low, go slow Monitor for postural hypotension Avoid BB, unless prior MI. Do not use RAS inhibitors unless CHF Single pill combinations may be best Individualize care!! Avoid medication-related adverse events Wait for SPRINT or ESH-CHL-SHOT large RCT in Elderly 9