Extrapolation of General Population Hypertension...

Extrapolation of General

Population Hypertension

Treatment Guidelines to CKD and

ESRD Patients: Appropriate or

Inappropriate?

Csaba P Kovesdy, MD FASN

University of Tennessee, Memphis TN

Memphis VA Medical Center, Memphis TN

Objectives

Review general population guidelines for the

treatment of hypertension

Discuss rationale of using general population

guidelines for hypertension treatment in patients

with CKD and ESRD

Examine similarities and differences in CVD

and hypertension therapy between the general

population and patients with CKD and ESRD

What this talk is not meant to do…

Question the need to treat hypertension in the

general population or in patients with CKD and

ESRD

Question the validity of general population

guidelines for the treatment of hypertension

Stephen Hales (1677-1761)

Booth J. Proc Roy Soc Med. 1977;70:793-799

Ludwig’s kymograph (1847)

Booth J. Proc Roy Soc Med. 1977;70:793-799

Vierordt’s sphygmograph (1852)

Direct sphygmograph (Marey, cca 1881)

Booth J. Proc Roy Soc Med. 1977;70:793-799

Booth J. Proc Roy Soc Med. 1977;70:793-799

Von Basch's sphygmomanometer and stand (cca 1881)

History of BP measurements

Scipione Riva-Rocci: Introduction of modern

circumferential BP cuff (1896)

Friedrich von Recklinghausen: Started using

larger size cuff (1901)

Nikolai Korotkoff: Introduction

of the auscultatory technique (1905)

Nikolai Sergeyevich Korotkov

(1874-1920) Booth J. Proc Roy Soc Med. 1977;70:793-799

Messerli F. N Engl J Med 1995;332:1038-1039

Diastolic and Systolic Arterial Pressure of FDR

Messerli F. N Engl J Med 1995;332:1038-1039

Age Blood

pressure

Reduction in life

expectancy (years)

(mm Hg) Man Woman

35 years 130/90 4 -

140/95 9 -

150/100 16.5 -

45 years 130/90 3 1.5

140/95 6 5

150/100 11.5 8.5

55 years 130/90 1 0.5

140/95 4 3

150/100 6 4

METROPOLITAN LIFE INSURANCE COMPANY. "Blood pressure: insurance

experience and its implications". New York: Metropolitan Life Insurance Company; 1961.

Hypertension in Medicine: Key

Moments

Framingham Study: Kannel et al, Ann Intern

Med. 1961 Jul;55:33-50

First clinical trials of BP lowering

Hamilton M, Thompson EN: The role of blood

pressure control in preventing complications of

hypertension. Lancet 1964; 1:235-239

VA Cooperative Study Group: Effects of treatment

on morbidity of hypertension. JAMA 1967;

202:1028-1033

Relationship of BP with CV risk is “strong,

continuous, independent, predictive and

etiologically significant.”

JNC 6, Arch Intern Med. 1997;157:2413-46.

Patients with CKD are in the "highest-risk" group for CVD (Strong). Patients with CKD are at increased risk of CVD. Hypertension is a risk factor for CVD events in CKD. However, there have been few controlled trials to demonstrate the efficacy of blood pressure lowering to reduce the risk of CVD in CKD; therefore, the Work Group made recommendations for CKD based on extrapolation from evidence on the efficacy of antihypertensive therapy in the general population.

K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease

For Individuals With: BP Goal: Hypertension (no diabetes or renal disease)

Diabetes Mellitus

Renal Disease

with proteinuria >1 gram/24 hours or diabetic kidney disease

<140/90 mmHg

(JNC 7)

<130/80 mmHg

(ADA, JNC 7)

<135/85 mmHg

<125/75 mmHg

(NKF)

Chobanian AV et al. JAMA. 2003;289:2560–2571. American Diabetes Association. Diabetes Care. 2002;25:134–147. National Kidney Foundation. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.

Target Blood Pressure

Criteria for Extrapolation of General

Population Guidelines to CKD Patients

1) The mechanism and expression of CVD in CKD should be similar to those observed in the general population. Specifically, the features of CVD, the relationship of CVD outcomes to hypertension, the mechanism of blood pressure lowering, and the responsiveness of risk factors to lifestyle modifications and pharmacological therapy should be similar in patients with CKD and the general population.

2) Therapies in patients with CKD should be as safe, or nearly so, as in the general population. In particular, there should not be additional adverse effects of a specific therapy that limits its usefulness in patients with CKD, either because of altered pharmacokinetics, drug interactions, or increased risk of toxicity to the kidney.

3) The duration of therapy required to improve CVD outcomes in the general population should not exceed the life expectancy of patients with CKD. Numerous studies of CVD in the general population have shown a benefit of interventions within 2 to 5 years, with greater and earlier benefits in patients at highest risk. Thus, it is likely that patients with CKD Stages 1-4 could benefit from more effective treatment of CVD.

Levey AS et al, NKF Task Force on CVD Am J Kidney Dis 32:853-906, 1998

Rationale for Extrapolation of General

Population Guidelines to CKD Patients

1) The mechanism and expression of CVD in CKD should be similar to those observed in the general population. Specifically,

1) the features of CVD,

2) the relationship of CVD outcomes to hypertension,

3) the mechanism of blood pressure lowering, and

4) the responsiveness of risk factors to lifestyle modifications and pharmacological therapy should be similar in patients with CKD and the general population.

Levey AS et al, NKF Task Force on CVD Am J Kidney Dis 32:853-906, 1998

General population

N=310,232,863 (July 2010 est.)

Median age: 36.8 years

Ethnic composition

White 79.96%

Black 12.85%

Hispanic 15.1%

Expected remaining life time: 25.2 years

ESRD

N=368,544 (December 31, 2007)

Median age: 59.1 years

Ethnic composition

White 55.7%

Black 37.1%

Hispanic 15.6%

Expected remaining life time: 5.9 years

https://www.cia.gov/library/publications/the-world-factbook/geos/us.html

http://www.cdc.gov/NCHS/data/nvsr/nvsr58/nvsr58_19.pdf

U S Renal Data System, USRDS 2009 Annual Data Report

Platinga et al, Hypertension 2009;54;47-56

General

population

CKD p

Mean SBP (95%CI) 135.9 (135.0

to 136.9)

141.3 (139.7

to 142.9)

<0.001

Mean DBP (95%CI) 76.1 (75.4 to

76.8)

67.5 (66.1

to 68.9)

<0.001

Mean pulse pressure

(95%CI)

59.8 (58.9 to

60.7)

73.8 (71.6

to 75.9)

<0.001

On antihypertensive

medications (%,

95%CI)

37.2 (34.9 to

39.7)

66.4 (63.7 to

69.0)

<0.001

Platinga et al, Hypertension 2009;54;47-56

Platinga et al, Hypertension 2009;54;47-56

Diabetes: Major CV Risk Factor Multiplier

in Hypertension

SBP and CV mortality in the general

population

Stamler et al, Diabetes Care 1993;16:434-444

High-normal BP and CV events in the general population

Vasan et al, N Engl J Med 2001;345:1291-7

Incidence of ESRD by SBP: MRFIT

100

80

60

40

20

0

SBP, mmHg

Incid

en

ce o

f E

SR

D/

100,0

00 p

ers

on

-yrs

, %

White

African American

Klag MJ et al. JAMA. 1997;277:1293–1298.

<117 117–123 124–130 131–140 >140

15.8

5.4

27.3

5.4

26.2

9.1

37.2

14.2

83.1

32.4

15-Month CV Death Risk in 40,933 HD Patients

Pre-Dialysis Systolic BP (mmHg)

<110

110-119.9

120-129.9

130-139.9

140-149.9

150-159.9

160-169.9

170-179.9

180-189.9

>=190

CV

Dea

th H

azar

d R

atio

0.5

0.6

0.7

0.80.9

2

3

4

5

1

Kalantar-Zadeh et al, Hypertension 2005

0.2

0.4

0.6

0.8

1

1.2

1.4

<133 133-154 155-170 >170

Systolic Blood Pressure (mmHg)

Ha

za

rd R

atio

Unadjusted Adjusted

Kovesdy et al, Nephrol Dial Transplant 21(5):1257-62, 2006

Unadjusted Adjusted

0

0.2

0.4

0.6

0.8

1

1.2

1.4

<65 65-75 76-86 >86

Diastolic Blood Pressure (mmHg)

Haza

rd R

atio

Kovesdy et al, Nephrol Dial Transplant 21(5):1257-62, 2006

0

0.2

0.4

0.6

0.8

1

1.2

<64 64-75 76-86 >86

DBP (mmHg)

Hazard

Rati

o

No CVD CVD

Kovesdy et al, Nephrol Dial Transplant 21(5):1257-62, 2006

Palmer BF, N Engl J Med 2002; 347(16):1256-1261

Changes in renal vasculature

Afferent arteriolar endothelial dysfunction

leading to impaired vasodilatation

Hyaline arteriosclerosis

Myointimal hyperplasia

Result is impaired autoregulatory capacity

Intraglomerular pressure begins to vary directly

with changes in systemic pressure Ditscherlein G, Hypertension 1985;7:II-29–II-32.

Bidani et al, Hypertension 1994;24:309-16.

Pelayo and Westcott, J Clin Invest 1991;88:101-5.

Hayashi et al, J Hypertens 1996;14:1387-401.

Palmer BF, Am J Med Sci 2001;321:388-400.

Abuelo JG, N

Engl J Med 2007;357:797-805.

Rationale for Extrapolation of General

Population Guidelines to CKD patients

2) Therapies in patients with CKD should be as safe, or nearly so, as in the general population. In particular, there should not be additional adverse effects of a specific therapy that limits its usefulness in patients with CKD, either because of altered pharmacokinetics, drug interactions, or increased risk of toxicity to the kidney.

Levey AS et al, NKF Task Force on CVD Am J Kidney Dis 32:853-906, 1998

Antihypertensive therapy and diastolic hypotension in CKD

Peralta et al, Hypertension. 2007;50:474-480

The role of diastolic blood pressure in ISH

Somes et al, Arch Intern Med. 1999;159:2004-2009

The role of diastolic blood pressure in ISH

Somes et al,

Arch Intern Med. 1999;159:2004-2009

Aggressive BP lowering and outcomes: The INVEST

Study

Messerli FH et al,

Ann Intern Med. 2006;144:884-893.

Messerli FH et al, Ann Intern Med. 2006;144:884-893.

Aggressive BP lowering and

outcomes: The INVEST Study

Aggressive BP lowering and outcomes: The

INVEST Study

Messerli FH et al, Ann Intern Med. 2006;144:884-893.

Stopping ACEI/ARB in advanced CKD

Ahmed AK et al, Nephrol Dial Transplant 2009 Oct 10. [Epub ahead of print]

Conclusions

The applicability of the current general

population guidelines for HTN control in

patients with CKD and ESRD is questionable.

Changes in vascular biology and subsequent

alterations in autoregulatory capacity make

patients with CKD and ESRD more susceptible

to the deleterious effects of both high and low

BP.

Conclusions

Epidemiologic studies support the possibility that low blood pressure, especially low diastolic blood pressure may be associated with adverse outcomes.

Some clinical trials in patients with characteristics similar to those found in CKD and ESRD (elderly, presence of CVD) support the idea that diastolic hypotension may be deleterious.

Conclusions

The lack of clinical trials of blood pressure

control in CKD and ESRD makes it difficult to

establish specific BP goals for this patient

population.

Management in CKD should be individualized,

taking into account patient characteristics (age,

comorbidities) and response to therapy

(Opinion).