AASK about Hypertension- JOURNAL CLUB

Journal Club

7-October-2010

NSLIJHS/Hofstra University

NKF: K/DOQI Hypertension is both a and a

of CKD: more than 50% to 75% of patients with CKD have blood

pressure >140/90 mm Hg but…

cause complication

NKF: K/DOQI Goals of Antihypertensive Therapy:

1. Lower Blood Pressure to:1. Reduce the Risk for CVD

2. Slow Progression of CKD

BUT, How do we KNOW what the target is???

Current Guidelines JNC 7 (2003)

Where did “130/80” Come From?

130/80

History of Blood Pressure Reverend Stephen Hales

1711: First History of Blood Pressure Measurement

Inserted a glass tube into the artery of a horse and watched as the column of blood fluctuated

The Horse Died Everytime, as the artery used was the carotid artery

History of Blood Pressure 1847-1856: First measurement in human

Faivre, measured during a limb amputation (i.e., still not exactly clinically feasible for

screening…) 1855: First Human Non-invasive

measurement Karl Vierordt used an inflatable cuff with enough

pressure to obliterate the arterial pulse Tall, bulky machine…

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1543468/pdf/procrsmed00089-0065.pdf

History of Blood Pressure 1882: Robert Ellis Dudgeon

Simplified the sphygmograph Became standard from the US Navy

1896: Riva-Rocci Developed the standard mercury

sphygmomanometer 1901: Harvey Cushing

Brought it to the US 1905: Nikoli Korotkoff

Identified diastolic blood pressure by ausculatation

(previously done only by palpation, hence the Korotkoff sounds)

BP Guidelines From 1905 to Mid-Twentieth Century…

SBP

Diastolic Blood Pressure became the “fad”…until JNC 7 came along

Current Guidelines The Urban Legend…

Is often told that “140/90” was chosen by insurance companies who noticed that people with BP lower than this lived longer than others…

JNC offers more sound clinical evidence…

JNC-7 Guidelines

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

The Lancet 360:9349, Dec 14, 2002; Pages 1903-1913

Is THE citation for JNC-7 “Blood Pressure and Cardiovascular Risk”

Age-specific relevance…

One million adults 61 prospective observational studies

During 12·7 million person-years at risk 56 000 vascular deaths

12 000 stroke 34000 IHD 10000 “other” vascular

66 000 other deaths at ages 40–89 years Meta-analyses:

Age-Specific Risk… Major Limitation?

Epidemiologic Observation Lack of Therapeutic Intervention

Early Studies Evaluating Hypertension treatment excluded patients with CKD

ACCORD:Action to Control Cardiovascular Risk in Diabetes blood pressure

4377 Patients DM 2 +

CVD, or 2 additional CV risk factors

Assigned to either: Intensive BP control Conventional BP control


Intensive BP Control Standard BP Control

SBP < 120 mmHg SBP < 140 mmHgAchieved: 119 mmHg 133 mmHg

Follow Up: No Difference: All Cause Mortality

4.7 years No Difference: Annual Rate of Nonfatal MI, stroke or death from CVD

Decreased risk of total and non-fatal stroke

Increased risk anti-hypertensive adverse effects


Intensive Control: Rx Side Effects: 3.3 vs.

1.3% Hypotension Syncope Bradycardia Arrhythmia Hyperkalemia Angioedema Renal Failure

The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of

Chronic Renal Disease

Saulo Klahr, Andrew S. Levey, Gerald J. Beck, Arlene W. Caggiula, Lawrence Hunsicker, John W. Kusek, and Gary Striker for the Modification of Diet in Renal Disease Study

GroupN Engl J Med 1994; 330:877-884

MDRD Trial

MDRD Study Hypothesis: “Lower” BP will decrease the

decline in GFR Randomized Trial

840 Patients with CKD GFR 25-55 cc/min (Study A) GFR 13-24 cc/min (Study B)

Treatment Goal: MAP < 92 mmHg (125/75) or MAP < 107 mmHg (140/90)

MDRD Design:

Comparison of 2 Groups:

“Usual” BP ControlTarget MAP <107 mmHg

Low BP ControlTarget MAP <92 mmHg

Achieved MAP 96mmHg Achieved MAP 91mmHg

130/80 125/75

GFR 25-55 cc/min (Study A) GFR 13-24 cc/min (Study B)

Results of MDRD

MDRD: Long Term Follow Up

10 years later… 32% reduction in end-stage renal-disease

(ESRD) risk for patients randomized to the low BP arm

Limitations: Lack of blood-pressure measurements for the final

seven years Higher rate of usage of ACE-I in low BP arm

REIN-2 StudyRenoprotection In Patients with Nondiabetic Chronic Renal Disease

Renoprotective Evaluated effect of BP control in nondiabetic

CKD Aim: assess the effect of “intense” versus

conventional blood-pressure control on progression to end-stage renal disease

REIN-2 Randomized Trial

338 patients receiving ramipril (2.5-5mg/day)

Primary Endpoint Time to ESRD over 36 months of follow up

Conventional GroupGoal: DBP<90 mmHg

Achieved: 134/82

Intensive GroupGoal: <130/80

Achieved: 130/80Add-On Therapy:

Felodipine 5-10mg/day

REIN-2 Reported no decrease in ESRD events

Concluded: No additional benefit from further blood-pressure reduction by felodipine added to therapy with ACE-I

Terminated at 19months for “futility”

AASK:African-American Study of Kidney Disease and Hypertension

Hypothesis: Intensive Blood Pressure Control may retard the

progression of Chronic Kidney Disease


Objective: To compare the effects of 2 levels of BP control

and 3 antihypertensive drug classes of GFR decline in hypertension

AASK: Study Design Patient Population:

Ages 18-70 years Black Hypertensive Kidney Disease

DBP >95 mmHg GFR 20-65 mL/min by labeled iothalamate

clearance

Exclusion Criteria Diabetes

Fasting glucose >140 mg/dL Random Glucose >200 mg/dL Drug therapy for diabetes

Urinary Tp:Cr > 2.5 Malignant Hypertension

Defined by each center “Serious Systemic Disease” Heart Failure Specific Indication for, or contraindication to a study drug

Outcomes Primary: Progression of CKD

Doubling of sCr Diagnosis of ESRD

Initiation of RRT Transplant

Death

Study Design:Two Phases

Initial Trial Phase 1995-1998 3 x 2 Design

Cohort Phase April 2002 Included Surviving

patients without ESRD All Switched to Ramipril Conventional Control

140/90 until 130/80 in 2004


Effect of Blood Pressure Lowering and Antihypertensive Drug Class on Progression

of Hypertensive Kidney Disease Results From the AASK Trial

Jackson T. Wright, Jr, MD, PhD; George Bakris, MD; Tom Greene, PhD; Larry Y. Agodoa, MD; Lawrence J. Appel, MD, MPH; Jeanne Charleston, RN; DeAnna

Cheek, MD; Janice G. Douglas-Baltimore, MD; Jennifer Gassman, PhD; Richard Glassock, MD; Lee Hebert, MD; Kenneth Jamerson, MD; Julia Lewis, MD; Robert A. Phillips, MD, PhD; Robert D. Toto, MD; John P. Middleton, MD; Stephen G. Rostand, MD; for the African American Study of Kidney Disease and Hypertension Study

Group

JAMA. 2002;288:2421-2431.

Copyright restrictions may apply.

Wright, J. T. et al. JAMA 2002;288:2421-2431.

Participant Recruitment and Follow-up Flow Diagram

2:2:1 Ratio used for CCB

Initial PhaseFeb 1995 – Sept 1998

N = 1094

Intensive Group

MAP: 92 mmHg

Standard Control Group

MAP: 102 - 107 mmHg

Ramipril

AmlodipineMetoprolol

Ramipril

Metoprolol Amlodipine

Furosemide

Doxazosin

Clonidine

Hydralazine

Minoxidil


Measurements Blood Pressure

3 Consecutive seated BP measurements Mean of second two BP recorded

GFR estimation I125 iothalamate

Twice at baseline Once at 3, 6, and Q6 months thereafter

Proteinuria Urinary Tp:Cr Q6months


Outcome: Slope of decline of GFR

Secondary Composite Outcome: Reduction in GFR by 50% Proteinuria ESRD Death


Interruptions: September 2000:

Termination of Amlodipine arm of trial Data censored after 3 years



Mean Change in Glomerular Filtration Rate by Randomized Group



Mean Change in Glomerular Filtration Rate by Randomized Group for Proteinuria Subgroups



Percentage Changes in Proteinuria by Randomized Group

Trial Phase


Cohort Phase Published NEJM 2010 Follow up of Trial Phase Followed patients from

Transition Phase Cohort Phase

Cohort Phase Initiated April 2002

Patients who had not progressed to ESRD invited to participate

All Patients received Ramipril Common target BP:

<140/90 from 2002-2004 <130/80 from 2004 to completion

Cohort Phase Outcomes

Progression of CKD Doubling of creatinine ESRD Death

Monitoring sCr measured Q6months

Conclusions of AASK:Trial Phase In the comparison of target BP:

MAP of 102-107 versus <92 mmHg:

In the comparison of class of antihypertensive:

NO Difference in rate of decline of GFR

ACE-I may be more effective than B-blockers in slowing GFR decline

However… Average rate of decline of GFR in both BP

treatment groups was 2mL/min/year

Similar to previous trial of Hypertensive CKD

Cohort Phase Conclusions: After follow up of 8.8-12.2 years:

“Intensive” BP control had no effect on CKD progression

There MAY be differential effects on patients with more severe proteinuria

Other Endpoints… ???Effect in patients with significant

proteinuria

Final Thought… Lower BP goals may be protective in

patients with significant proteinuria

Lower BP targets did not increase adverse effects such as ischemic heart disease or ischemic stroke.

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