Hypertension – old and newHypertension – old and new

Dr. Alexander WoywodtDr. Alexander Woywodt

Consultant Physician and Nephrologist

Lancashire Teaching Hospitals NHS Foundation Trust

Preston, November 2007

Consultant Physician and Nephrologist

Lancashire Teaching Hospitals NHS Foundation Trust

Preston, November 2007

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� Hypertension (and the kidney)

� How to measure blood pressure

� Tips and pitfalls

� Non-pharmacological management

� Anti-hypertensive drugs

� Hypertension (and the kidney)

� How to measure blood pressure

� Tips and pitfalls

� Non-pharmacological management

� Anti-hypertensive drugs

Blood pressure – an evolving concept in the 18th centuryBlood pressure – an evolving concept in the 18th century

In 1733 Hales inserted a glass tube into

the carotid artery of a horse – the blood

column rose to 247 cm

Stephen Hales

1671-1761

Stephen Hales

1671-1761

„Dropsy“ – a deadly disease„Dropsy“ – a deadly disease

Richard Bright F.R.S. 1789–1858

Richard Bright F.R.S. 1789–1858

"William Bonham, aet 55, a large man of

florid complexion, living as a carter in

the service of a cheesemonger […] his

legs were most enormously swollen. […]

He sunk and died on the sixth day after

his admission. […]

The heart remarkably enlarged; on the

left side it was very thick and strong

[…] The kidneys were very small, and

hard in consistence”

1827

"William Bonham, aet 55, a large man of

florid complexion, living as a carter in

the service of a cheesemonger […] his

legs were most enormously swollen. […]

He sunk and died on the sixth day after

his admission. […]

The heart remarkably enlarged; on the

left side it was very thick and strong

[…] The kidneys were very small, and

hard in consistence”

1827

„Dropsy“ in our catchment population – 180 years later„Dropsy“ in our catchment population – 180 years later

Catchment population 1.5 million

336000 patients with hypertension

£12m / year on anti-hypertensive drugs

2400 deaths per year

Catchment population 1.5 million

336000 patients with hypertension

£12m / year on anti-hypertensive drugs

2400 deaths per year

Messerli FH et al.,

Essential hypertension.

Lancet 370: 501 (2007)

Messerli FH et al.,

Essential hypertension.

Lancet 370: 501 (2007)

End-organ damage revisitedEnd-organ damage revisited

Hypertension and renal diseaseHypertension and renal disease

HypertensionHypertension

a symptom of reno-vascular diseasea symptom of reno-vascular disease

a symptom of renal

parenchymatous disease

a symptom of renal

parenchymatous disease

worsens renal disease of any causeworsens renal disease of any causea cause of end-stage renal diseasea cause of end-stage renal disease

Diabetes50%

Hypertension27%

GN13%

Other10%

<8080-84

85-8990-99

100-109≥≥≥≥110

Age

-Adj

uste

d R

ate

of E

SR

DP

er 1

00,0

00 P

erso

n-Y

ears

Age

-Adj

uste

d R

ate

of E

SR

DP

er 1

00,0

00 P

erso

n-Y

ears

≥≥≥≥180 160-179 140-159 130-139 120-129 <120

Systolic BP (mm Hg)Systolic BP (mm Hg)Diastolic BP (m

m Hg)

Diastolic BP (mm Hg)

0

50

100

150

200

250

Klag et al. N Engl J Med. 1996;334(1):13-18.Klag et al. N Engl J Med. 1996;334(1):13-18.

332,544

patients

16 years of

follow-up

332,544

patients

16 years of

follow-up

Hypertension and risk for ESRD: The MRFIT studyHypertension and risk for ESRD: The MRFIT study

1,120,295Patients

Kaiser Permanente North California

1,120,295Patients

Kaiser Permanente North California

Go et al. N Engl J Med 2004;351:1296–05Go et al. N Engl J Med 2004;351:1296–05

Renal disease and mortalityRenal disease and mortality

How to measure blood pressureHow to measure blood pressure

Karl von Vierordt1818-1884

Karl von Vierordt1818-1884

ScipioneRiva-Rocci1863-1937

ScipioneRiva-Rocci1863-1937

1896„Sfigmomanometro“

1896„Sfigmomanometro“

How to measure blood pressureHow to measure blood pressure

– After 5 minutes of rest

– Arm on level of the heart

– No coffee or smoking

– Cuff size (obese patients)

– Both arms

– White coat hypertension

– Masked hypertension

– Home monitoring

– After 5 minutes of rest

– Arm on level of the heart

– No coffee or smoking

– Cuff size (obese patients)

– Both arms

– White coat hypertension

– Masked hypertension

– Home monitoring

Home monitoringHome monitoring

“Self-measurement of BP at home is of clinical value and its prognostic significance is now demonstrated.” (2007 ESH guidelines)

“Self-measurement of BP at home is of clinical value and its prognostic significance is now demonstrated.” (2007 ESH guidelines)

“Routine use of automated ambulatory blood pressure monitoring or home monitoring devices in primary care is not currently recommended because their value has not been adequately established; appropriate use in primary care remains an issue for further research.” (NICE guidelines GC 34, 2006)

“Routine use of automated ambulatory blood pressure monitoring or home monitoring devices in primary care is not currently recommended because their value has not been adequately established; appropriate use in primary care remains an issue for further research.” (NICE guidelines GC 34, 2006)

Beware of:

The irritable few

The self-managers

Those with higher BP at home

24 hour BP24 hour BP

Confirms that BP is on target

Diagnostic for rise in BP at night

Confirms that BP is on target

Diagnostic for rise in BP at night

What blood pressure is good?What blood pressure is good?

Messerli et al., Lancet. 2007 Aug 18; 370 (9587): 591-603Messerli et al., Lancet. 2007 Aug 18; 370 (9587): 591-603

“That level of blood pressure at which

investigation and treatment do more

good than harm”

“That level of blood pressure at which

investigation and treatment do more

good than harm”

Secondary forms – common and rareSecondary forms – common and rare

Baseline diagnostics in hypertensionBaseline diagnostics in hypertension

comprehensive investigations for secondary hypertension neither

reasonable nor feasible in all patients with hypertension

• Blood pressure – both arms

• Abdominal bruit?

• Labs: Serum creatinine and eGFR, glucose, Na, K, venous blood

gases, urine dipstick

• Thyroid function tests

• Fundi?

• ECG

• Echo?

• Carotid ultrasound?

• Lipids

comprehensive investigations for secondary hypertension neither

reasonable nor feasible in all patients with hypertension

• Blood pressure – both arms

• Abdominal bruit?

• Labs: Serum creatinine and eGFR, glucose, Na, K, venous blood

gases, urine dipstick

• Thyroid function tests

• Fundi?

• ECG

• Echo?

• Carotid ultrasound?

• Lipids

Hypertension as a gateway to cardiovascular riskHypertension as a gateway to cardiovascular risk

www.escardio.orgwww.escardio.org

Hypertension as a gateway to cardiovascular riskHypertension as a gateway to cardiovascular risk

• “Low-dose aspirin should also be considered in hypertensive patients

without a history of cardiovascular disease if older that 50 years, with a

moderate increase in serum creatinine or with a high cardiovascular risk.

In all these conditions, the benefit-to-risk ratio of this intervention

(reduction in myocardial infraction greater than the risk of bleeding) has

been proven favorable”

• “Low-dose aspirin should also be considered in hypertensive patients

without a history of cardiovascular disease if older that 50 years, with a

moderate increase in serum creatinine or with a high cardiovascular risk.

In all these conditions, the benefit-to-risk ratio of this intervention

(reduction in myocardial infraction greater than the risk of bleeding) has

been proven favorable”

• “Hypertensive patients without overt cardiovascular disease but with high

cardiovascular risk ( ≥20% risk of events in 10 years) should also be

considered for statin treatment even if their baseline total and LDL serum

cholesterol levels are not elevated”

• “Hypertensive patients without overt cardiovascular disease but with high

cardiovascular risk ( ≥20% risk of events in 10 years) should also be

considered for statin treatment even if their baseline total and LDL serum

cholesterol levels are not elevated”

ESH guidelines 2007ESH guidelines 2007

Non-pharmacological management of hypertensionNon-pharmacological management of hypertension

Rubens: Bacchus, 1638Rubens: Bacchus, 1638

• Weight reduction

• Stop smoking

• Exercise

• Alcohol: moderation

• Reduce stress

• Reduce salt intake

• Weight reduction

• Stop smoking

• Exercise

• Alcohol: moderation

• Reduce stress

• Reduce salt intake

Salt and hypertensionSalt and hypertension

• Usually feasible:

reduce extra salt and

salty foods

• For those with good

compliance (& prepared

to suffer): salt-poor diet

• Usually feasible:

reduce extra salt and

salty foods

• For those with good

compliance (& prepared

to suffer): salt-poor diet

Yanomamo Indian, VenezuelaYanomamo Indian, Venezuela

Hypertension and stress: A famous case reportHypertension and stress: A famous case report

Franklin Delano RooseveltFranklin Delano Roosevelt

Messerli FH al. NEJM 332:1038-1039 (1995)Messerli FH al. NEJM 332:1038-1039 (1995)

Drug treatment of hypertensionDrug treatment of hypertension

Effects of treatment: 6 mm in systolic blood pressureEffects of treatment: 6 mm in systolic blood pressure

MacMahon S et al. Hypertension. 1989;13(suppl 5):I45-I50.MacMahon S et al. Hypertension. 1989;13(suppl 5):I45-I50.

Difficult hypertensionDifficult hypertension

“I’ve also been treating the high cholesterol and then I stopped the medicine because I got my cholesterol down low. And, I had in the past, a little [blood pressure] problem, which I treated and then I got it down…”(Former US President Clinton to Larry King Live from his hospital bed; posted Friday,Sept 3, 2004).

“I’ve also been treating the high cholesterol and then I stopped the medicine because I got my cholesterol down low. And, I had in the past, a little [blood pressure] problem, which I treated and then I got it down…”(Former US President Clinton to Larry King Live from his hospital bed; posted Friday,Sept 3, 2004).

Messerli FH et al.Lancet 370: 501 (2007)Messerli FH et al.Lancet 370: 501 (2007)

Compliance - The „other“ drug problemCompliance - The „other“ drug problem

punctualdosing

punctualdosing

all dosestaken

erratictiming

all dosestaken

erratictiming

5-20%omitted

5-20%omitted

many doses missed3-4 drug holidays

per year

many doses missed3-4 drug holidays

per year

few or no doses taken

few or no doses taken

5-20% of doses taken, monthly drug holidays

5-20% of doses taken, monthly drug holidays

Drug treatment of hypertension: Some tips and tricksDrug treatment of hypertension: Some tips and tricks

• Establish home monitoring

• Start new drugs on weekends

• Start new drugs in the evenings

• Do not start two drugs at once

• Patient must know that treatment is

permanent

• If patient or compliance and/or doctor-

patient relationship fragile: start with

low risk drugs at low dose.

• Head for early (and visible) success

• Be passionate about plans,

particulary with multiple prescribers

• Dosette for the elderly

• Establish home monitoring

• Start new drugs on weekends

• Start new drugs in the evenings

• Do not start two drugs at once

• Patient must know that treatment is

permanent

• If patient or compliance and/or doctor-

patient relationship fragile: start with

low risk drugs at low dose.

• Head for early (and visible) success

• Be passionate about plans,

particulary with multiple prescribers

• Dosette for the elderly

Drug treatment of hypertensionDrug treatment of hypertension

Beta blockers

Central alphaagonists

ACE inhibitors

AngiotensinReceptorblockers

Calciumantagonists Minoxidil

Reninblocker

Thiazidediuretics

Loop diuretics

Hypertension causes few symptoms – unlike its treatmentHypertension causes few symptoms – unlike its treatment

Impotence, depression

, creatinine!

, creatinine!

What the guidelines say (2,160,000 hits in Google)What the guidelines say (2,160,000 hits in Google)

NICE (2006)

NICE (2006)

calcium antagonists, ACE inhibitors, angiotensin receptor antagonists and β-blockers – are suitable for the initiation and maintenance of antihypertensive treatment, alone or in combination.

β-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes

calcium antagonists, ACE inhibitors, angiotensin receptor antagonists and β-blockers – are suitable for the initiation and maintenance of antihypertensive treatment, alone or in combination.

β-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes

ESH(2007)

ESH(2007)

JNC VII (2003)

JNC VII (2003)

0

4

8

12

16

20

ALLHAT Primary OutcomeALLHAT Primary Outcome

by Treatment Groupby Treatment Group

Cumulative Fatal CHD and

Nonfatal MI event rate (%)

Time to event, yrs0 1 2 3 4 5 6

1525590489054

7

No. at Risk

ChlorthalidoneAmlodipineLisinopril

1447785768535

1382082188123

1310278437711

1136268246662

634038703832

295618781770

209215195

Chlorthalidone

Amlodipine

Lisinopril

www.hypertensiononline.orgALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright ©2002, American Medical Association.

Diuretics, Beta blockers and the risk of DiabetesDiuretics, Beta blockers and the risk of Diabetes

Absolute risk of diabetes 3.5% higher with chlorthalidoneAbsolute risk of diabetes 3.5% higher with chlorthalidone

Absolute risk of diabetes 2.5% higher with atenololAbsolute risk of diabetes 2.5% higher with atenolol

Equalling to 250000 extra cases of diabetes per year in USA(in USA 20 million patients are on thiazides and 20 million on diuretics)

Equalling to 250000 extra cases of diabetes per year in USA(in USA 20 million patients are on thiazides and 20 million on diuretics)

Congestive heart failure

Congestive heart failure

Post MIPost MI

High risk /atherosclerosis

High risk /atherosclerosis

DiabetesDiabetes

Chronic renalfailure

Chronic renalfailure

StrokeStroke

Diure

tics

Beta

blo

cker

s

ACE

inhi

bito

rs

ARBs

CCBs

Differential treatment after ALLHATDifferential treatment after ALLHAT

MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, CHARM

ACC/AHA guidelines, BHAT, SAVE, CAPRICORN, VALIANT, OPTIMAAL

NKF + ADA guidelines, UKPDS, ALLHAT, VALUE,INVEST, ASCOT, LIFE

NKF + ADA guidelines, Captopril trial, RENAAL, IDNT, REIN, AASK

PROGRESS, SCOPE, ACCESS, LIFE, SYSTEUR, MRC Trial

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA,INVEST

?

? ?

Differential treatment after ALLHATDifferential treatment after ALLHAT

Blood pressure treatment has to follow guidelines.

Blood pressure treatment has to follow guidelines.

Most importantly, the bloodPressure has to come down.

Individual patient characteristics?

Most importantly, the bloodPressure has to come down.

Individual patient characteristics?

vs.vs.

ACE-IARB

CCB

Loop diuretics

Beta-Blocker

MoxonidinDoxazosin

Minoxidil

Alpha-MD

Low potentialfor trouble

If compliant +renovascularUnlikelyBeware of spironolactone

If edemaand thiazidesnot enough

Excellent add-on e.g. evening

Only add-ondizziness

If pregnant

If compliantwith diureticsand Beta-Bl.Admission?

Low potential for troubleIf mild edema

Avoid if low clearance

If other Indicationor “stress”

Thiazides

Thiazidediuretics

ACE inhibitors

β-blockers

Angiotensinreceptor

antagonists

Calcium antagonists

α-blockers

CombinationCombination

A forefather of nephrology and hypertensionA forefather of nephrology and hypertension

Franz Volhard 1872 - 1950

Franz Volhard 1872 - 1950

• Speculated that „pale“

hypertension is mediated by

factors secreted by the kidney

• This was later proven by Goldblatt

• Volhard also pioneered the salt-

free diet

• A man of varied interests

• Speculated that „pale“

hypertension is mediated by

factors secreted by the kidney

• This was later proven by Goldblatt

• Volhard also pioneered the salt-

free diet

• A man of varied interests

News from the renin angiotensin aldosterone systemNews from the renin angiotensin aldosterone system

Escape

Angio-

tensinogen

Renin

Aliskiren Adapted from Wood JM, et al. 2003

Adapted from Wood JM, et al. 2003

Aliskiren – a novel renin inhibitorAliskiren – a novel renin inhibitor

Aliskiren – a novel renin inhibitorAliskiren – a novel renin inhibitor

Oparil S, et al., The Lancet 2007; 370:221-229Oparil S, et al., The Lancet 2007; 370:221-229

“These findings provide a

clear rationale for further

studies to investigate the

potential effects of long-

term treatment with the

combination of aliskiren

and valsartan,and

combinations of aliskiren

with other ARBs, on

possible benefits beyond

treating hypertension”

“These findings provide a

clear rationale for further

studies to investigate the

potential effects of long-

term treatment with the

combination of aliskiren

and valsartan,and

combinations of aliskiren

with other ARBs, on

possible benefits beyond

treating hypertension”

Aliskiren: HyperkalemiaAliskiren: Hyperkalemia

> 6.0

1.5

1.1

1.1

5.5Ramipril 10 mg +Aliskiren 300 mg

2.2Aliskiren 300 mg

2.6Ramipril 10 mg

> 5.5

Novartis dataNovartis data

• In patients with renal impairment:

– changes in aliskiren exposure did not correlate with the

severity of renal disease or with creatinine clearance

– steady-state clearance of aliskiren was 60–70% of the values

for matched healthy control subjects

“… adjustment of the initial aliskiren dose is not necessary in patients

with hypertension and renal impairment”

• Low potential for interactions, long half-life

• In patients with renal impairment:

– changes in aliskiren exposure did not correlate with the

severity of renal disease or with creatinine clearance

– steady-state clearance of aliskiren was 60–70% of the values

for matched healthy control subjects

“… adjustment of the initial aliskiren dose is not necessary in patients

with hypertension and renal impairment”

• Low potential for interactions, long half-life

Aliskiren and renal impairmentAliskiren and renal impairment

Vaidyanathan S, et al. Clin Pharmacokinet.2007;46(8):661-75.

Vaidyanathan S, et al. Clin Pharmacokinet.2007;46(8):661-75.

Direct renin inhibitorsDirect renin inhibitors

Direct renin inhibitors: the dawn of a new era, or just a variation on a theme?

Segall et al. NDT 2007

Direct renin inhibitors: the dawn of a new era, or just a variation on a theme?

Segall et al. NDT 2007

“DRIs may find their place as adjunctive therapies, in combinations with ACE inhibitors or

ARBs, or less commonly still, in patients intolerant to these.”

“DRIs may find their place as adjunctive therapies, in combinations with ACE inhibitors or

ARBs, or less commonly still, in patients intolerant to these.”

“Renin inhibition may offer protection of target organs such as

the kidney … beyond what can be achieved with

current antihypertensive therapies … this drug class may have

great potential.”

“Renin inhibition may offer protection of target organs such as

the kidney … beyond what can be achieved with

current antihypertensive therapies … this drug class may have

great potential.”

Dominik N. Mueller and Friedrich C. Luft. Clin J Am Soc Nephrol 1: 221–228, 2006Dominik N. Mueller and Friedrich C. Luft. Clin J Am Soc Nephrol 1: 221–228, 2006

Future studies:

The latest gadgetThe latest gadget

Management of Uncontrollable Hypertension With a

Carotid Sinus Stimulation Device

Markus G. Mohaupt, Juerg Schmidli, Friedrich C. Luft

Hypertension published online Sep 24, 2007

Management of Uncontrollable Hypertension With a

Carotid Sinus Stimulation Device

Markus G. Mohaupt, Juerg Schmidli, Friedrich C. Luft

Hypertension published online Sep 24, 2007

"For they taught us

common sense

Tried to teach us

common sense

Truth and God 's own

common sense

Which is more than

knowledge."'

"For they taught us

common sense

Tried to teach us

common sense

Truth and God 's own

common sense

Which is more than

knowledge."' Rudyard Kiplingpoem dedicated to his teachers

Rudyard Kiplingpoem dedicated to his teachers