UPDATES IN PHARMACOTHERAPY OF

THE ELDERLY

UPDATES IN PHARMACOTHERAPY OF

THE ELDERLY

Miran F. Kenda

Slovenian Society of CardiologySlovenian Heart House

Ljubljana, Slovenia

20 % of population in North America and Europe is over 65 years old

Cardiovascular diseases are growing in this age group

Many patients over 65 are still very fit and active

We move this age limit to 75 years

Miran F. Kenda

Slovenian Society of CardiologySlovenian Heart House

Ljubljana, Slovenia

20 % of population in North America and Europe is over 65 years old

Cardiovascular diseases are growing in this age group

Many patients over 65 are still very fit and active

We move this age limit to 75 years

World Population

Aged >75 Years (Millions)

World Population

Aged >75 Years (Millions)

300

200

100

019501950 19601960 19701970 19801980 19901990 20002000 20102010 20202020 20302030

YearYear

Aging World Populations Aging World Populations

www.census.gov/prod/2001/p95-01-1.pdf

Cardiovascular diseases in

the elderly

Cardiovascular diseases in

the elderly• 2nd most common disease in elderly• 1st most common are depression and

dementia• aging process itself • many comorbidites• complex approach to diagnostic

procedures and treatment• important to improve quality of life

• 2nd most common disease in elderly• 1st most common are depression and

dementia• aging process itself • many comorbidites• complex approach to diagnostic

procedures and treatment• important to improve quality of life

Age of patients in major placebo controlled cardiovascular trials

Age of patients in major placebo controlled cardiovascular trials

666717RamiprilHOPE

584444Simvastatin4S

602647BisoprololCIBIS-II

643991Metoprolol CR/XL

Merit HF

581094CarvedilolUS Carvedilol

Mean age

NDrugTrial

HF in the elderlyHF in the elderly

• mostly diastolic dysfunction• complex diagnostic process because of

comorbidites• treatment more complex than in

younger patients• frequent monitorings• complications of treatment (renal

insufficiency, bleeding, cognitive impairment, etc.)

• mostly diastolic dysfunction• complex diagnostic process because of

comorbidites• treatment more complex than in

younger patients• frequent monitorings• complications of treatment (renal

insufficiency, bleeding, cognitive impairment, etc.)

Number of comorbid factors per patient

n = 86 094 HF patients, 85 ± 9 years SAGE database

1 - 31 - 3 27 %27 %4 - 5 4 - 5 41 %41 %> 5> 5 32 %32 %

Gambassi G Am Heart J 2000 ;139:85-93

COMORBIDITIES 86 094 residents with heart failure, 85 ± 9 years

Gambassi G Am Heart J 2000 ;139:85-93

36%

30%

20%

20%

17%

Dementia

Falls

AF

Anemia

19%COPD

Depression

9%Cancer

4%Parkinson

1%ESRD (Dialysis)

HOPE Study Investigators New Engl J Med 2000;342:154-160.

HOPE (ramipril) - subgroup analysisHOPE (ramipril) - subgroup analysis

No. of Incidence of MI, RR on ramipril patients stroke or CV death (95% CI)

on placebo (%)

Overall 9297 17.8

CVD 8162 18.7

No CVD 1135 10.2

Diabetes 3577 19.8

No diabetes 5720 16.5

Age < 65 yr 4169 14.2

Age 65 yr 5128 20.7

Men 6817 18.7

Women 2480 14.4

Hypertension 4355 19.5

No hypertension 4942 16.3

0.6 0.8 1.0 1.2

Ţ Ramipril was beneficial in all subgroups analysed

Ţ Ramipril was beneficial in all subgroups analysed

EUROPA - sub-groups analysis

EUROPA - sub-groups analysis

RRR (%)RRR (%)

0.50.5 1.01.0 2.02.0

Perindopril betterPerindopril better Placebo betterPlacebo better

Previous MIPrevious MI

No previous MINo previous MI

22.422.4

12.112.1

Age 56 yrsAge 56 yrs

Age 57 - 65Age 57 - 65

Age > 65 yrsAge > 65 yrs

27.327.3

14.314.3

18.218.2

MaleMale

FemaleFemale

19.319.3

22.022.0

ACE inhibitors and elderlyACE inhibitors and elderly

• Observation studies suggest that elderly with LVSD are as likely to benefit from ACE-i as younger patients

• ACE-i are underused in older persons despite guideline recommendations

• In spite of common comorbidites, polypharmacy and cognitive impairment, the judicious use of ACE-i in eligible older patients will likely improve health outcomes

• Observation studies suggest that elderly with LVSD are as likely to benefit from ACE-i as younger patients

• ACE-i are underused in older persons despite guideline recommendations

• In spite of common comorbidites, polypharmacy and cognitive impairment, the judicious use of ACE-i in eligible older patients will likely improve health outcomes

CarvedilolCarvedilol(n=696)(n=696)CarvedilolCarvedilol(n=696)(n=696)

PlaceboPlacebo(n=398)(n=398)PlaceboPlacebo(n=398)(n=398)

SurvivalSurvival

DaysDays00 5050 100100 150150 200200 250250 300300 350350 400400

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

Risk reduction=65%Risk reduction=65%Risk reduction=65%Risk reduction=65%

P<0.001P<0.001P<0.001P<0.001

Packer et al (1996)Packer et al (1996)

CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)

0 200 4000 200 400 600 600 800 8000 200 4000 200 400 600 600 800 800

1.01.0

0.80.8

0.60.6

00

1.01.0

0.80.8

0.60.6

00

BisoprololBisoprololBisoprololBisoprolol

PlaceboPlaceboPlaceboPlacebo

Time after inclusion (days)Time after inclusion (days)Time after inclusion (days)Time after inclusion (days)

P<0.0001P<0.0001P<0.0001P<0.0001

SurvivalSurvivalSurvivalSurvival

Risk reduction=34%Risk reduction=34%Risk reduction=34%Risk reduction=34%

The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)

Months of follow-upMonths of follow-up

Mortality (%)Mortality (%)

00 33 66 99 1212 1515 1818 2121

2020

1515

1010

55

00

PlaceboPlacebo

Metoprolol CR/XLMetoprolol CR/XL

P=0.0062P=0.0062

Risk reduction=34%Risk reduction=34%

US Carvedilol ProgramUS Carvedilol Program

blockers in CHF –all-cause mortality

blockers in CHF –all-cause mortality

CIBIS-IICIBIS-IICIBIS-IICIBIS-II MERIT-HFMERIT-HFMERIT-HFMERIT-HF60 years

58 years

64 years

SENIORS

Study of Effects of Nebivolol Intervention

on Outcomes and Rehospitalisation inSeniors with Heart Failure

A randomised, double-blind, placebo-controlled study

Eur Heart J 2005;26:215-25.

Inclusion criteriaInclusion criteria

• age 70 years (average 76,1)• N=2,128 (1,067 nebivolol, 1,061 placebo)

• clinical diagnosis of chronic heart failure and either of:

a) documented LVEF < 35% within previous 6 months

orb) hospital admission within previous

1 year for congestive HF

• age 70 years (average 76,1)• N=2,128 (1,067 nebivolol, 1,061 placebo)

• clinical diagnosis of chronic heart failure and either of:

a) documented LVEF < 35% within previous 6 months

orb) hospital admission within previous

1 year for congestive HF

All cause mortalityor CV hospitalisationAll cause mortality

or CV hospitalisation

Death or CV hospitalisationby subgroup

Death or CV hospitalisationby subgroup

Conclusions Conclusions

• Nebivolol significantly reduced death or hospitalisation in elderly heart failure patients

• The effect was similar regardless of ejection fraction, age or gender

• Partly nebivolol greater effectiveness could be attributed to its action through NO vasodilatatory and other effects

• Nebivolol significantly reduced death or hospitalisation in elderly heart failure patients

• The effect was similar regardless of ejection fraction, age or gender

• Partly nebivolol greater effectiveness could be attributed to its action through NO vasodilatatory and other effects

The HYpertension in the

Very Elderly Trial

The HYpertension in the

Very Elderly Trial

N. Beckett, R. Peters, A. Fletcher, C. Bulpitt on behalf of the HYVET committees and investigators

ClinicalTrials.gov: NCT00122811

The Trial:International, multi-centre, randomised double-blind placebo controlled

Inclusion Criteria: Exclusion Criteria:Aged 80 or more, Standing SBP < 140mmHgSystolic BP; 160 -199mmHg Stroke in last 6 months+ diastolic BP; <110 mmHg, DementiaInformed consent Need daily nursing care

Primary Endpoint: All strokes (fatal and non-fatal)

Target blood pressure

150/80 mmHg

All stroke(30% reduction)

Total Mortality(21% reduction)

Heart Failure(64% reduction)

0 20.50.20.1

HR 95% CI

0.70 (0.49, 1.01)

0.61 (0.38, 0.99)

0.79 (0.65, 0.95)

0.81 (0.62, 1.06)

0.77 (0.60, 1.01)

0.71 (0.42, 1.19)

0.36 (0.22, 0.58)

0.66 (0.53, 0.82)

All Stroke

Stroke Death

All cause mortality

NCV/Unknown death

CV Death

Cardiac Death

Heart Failure

CV events

ITT – Summary

ConclusionsConclusions• Antihypertensive treatment based on indapamide

(SR) 1.5mg (± perindopril) reduced stroke mortality and total mortality in a very elderly cohort.

• NNT (2 years) = 94 for stroke and 40 for mortality

• Large and significant benefit in reduction of heart failure events and for combined endpoint of cardiovascular events

• Benefits seen early

• Treatment regime employed was safe

• Antihypertensive treatment based on indapamide (SR) 1.5mg (± perindopril) reduced stroke mortality and total mortality in a very elderly cohort.

• NNT (2 years) = 94 for stroke and 40 for mortality

• Large and significant benefit in reduction of heart failure events and for combined endpoint of cardiovascular events

• Benefits seen early

• Treatment regime employed was safe

Extending Benefits of Pravastatin to the Elderly:

PROSPER Study

PROSPER Study Group. Lancet. 2002; 360:1623-30.

Extending Benefits of Pravastatin to the Elderly:

PROSPER Study

PROSPER Study Group. Lancet. 2002; 360:1623-30.

PROSPER - summary of results PROSPER - summary of results

· Pravastatin achieved a 15% RRR (p= 0.014) in the primary endpoint over 3.2 years of follow-up in elderly (mean age 75+ years)

· Pravastatin significantly reduced CHD events by 19% (p= 0.006); CHD mortality decreased by 24% (p= 0.043)

· No effect on stroke or cognitive function was observed in 3.2 years; TIAs decreased by 25% (p=0.051)

· Pravastatin achieved a 15% RRR (p= 0.014) in the primary endpoint over 3.2 years of follow-up in elderly (mean age 75+ years)

· Pravastatin significantly reduced CHD events by 19% (p= 0.006); CHD mortality decreased by 24% (p= 0.043)

· No effect on stroke or cognitive function was observed in 3.2 years; TIAs decreased by 25% (p=0.051)

PROSPER Study Group. Lancet. 2002; 360:1623-30.PROSPER Study Group. Lancet. 2002; 360:1623-30.

Lipid lowering interventions in the elderly Lipid lowering interventions in the elderly

· have a proven correlation with a significant reduction in morbidity and mortality

· the improvement in CV risk, according to clinical studies of statins, cannot be attributed solely to a reduction in cholesterol levels

· more prudent to give small/medium doses of statins:· the half life of statins is prolonged· the pts may be taking other drugs metabolised to the same cytochrome

· combination of ezetimibe and statin is well tolerated and lead to a significant reduction in LDL-C levels compared with statin monotherapy in all age groups

· have a proven correlation with a significant reduction in morbidity and mortality

· the improvement in CV risk, according to clinical studies of statins, cannot be attributed solely to a reduction in cholesterol levels

· more prudent to give small/medium doses of statins:· the half life of statins is prolonged· the pts may be taking other drugs metabolised to the same cytochrome

· combination of ezetimibe and statin is well tolerated and lead to a significant reduction in LDL-C levels compared with statin monotherapy in all age groups

Review: Kalantzi KI, et al. Hellenic J Cardiol 2006;47:93-9.

Prevalence of atrial fibrillation (AF)Prevalence of atrial fibrillation (AF)

0

4

8

12

16

20

30 40 50 60 70 80 90

Framingham

CHS

Rochester

W. Australia

age (years)age (years)

pre

vale

nce (

%)

Risk of stroke in patients with AF Risk of stroke in patients with AF

• age < 65 years, no risk factors• age < 65 years, no risk factors low risklow risk

• age 65 -75 years with no risk factors or• 1 risk factor: CAD, DM, AH

• age 65 -75 years with no risk factors or• 1 risk factor: CAD, DM, AH

intermediate riskintermediate risk

• age >75 years• more than 1 risk factor : stroke, TIA, AF, HF

• age >75 years• more than 1 risk factor : stroke, TIA, AF, HF

high riskhigh risk

< 2 %/year

2-7 %/year

8-18 %/year

Anticoagulation in patients with AF Anticoagulation in patients with AF

low risklow risk

intermediate riskintermediate risk

high riskhigh risk

ASAASA

ASA or varfarin ( INR 2,5; 2,0-3,0)

ASA or varfarin ( INR 2,5; 2,0-3,0)

varfarin(INR 2,5; 2,0-3,0) varfarin(INR 2,5; 2,0-3,0)

Myocardial revascularization in the elderly Myocardial revascularization in the elderly

· percutaneous angioplasty can be considered the technique of choice for rapid reperfusion in acute phase MI with elderly pts:

· PAMI Study – mortality/reinfarction rate of 5.1 % vs. 12% in the group treated with fibrinolysis (age over 70 years: mortality 2% in PCI group vs. 10% in the thrombolysis group)

· GUSTO-IIb – a trend towards mortality reduction at 30 days with primary PCI compared with thrombolysis in the over 70 years of age

· Primary Coronary Angioplasty Trial (meta-analysis) – primary PCI more effective in terms of mortality reduction at 30 days in pts over 70 years of age

· percutaneous angioplasty can be considered the technique of choice for rapid reperfusion in acute phase MI with elderly pts:

· PAMI Study – mortality/reinfarction rate of 5.1 % vs. 12% in the group treated with fibrinolysis (age over 70 years: mortality 2% in PCI group vs. 10% in the thrombolysis group)

· GUSTO-IIb – a trend towards mortality reduction at 30 days with primary PCI compared with thrombolysis in the over 70 years of age

· Primary Coronary Angioplasty Trial (meta-analysis) – primary PCI more effective in terms of mortality reduction at 30 days in pts over 70 years of age

Review: Filali T, Carrie D. Int Coron Adv 2006; 3:3-4.

Myocardial revascularization in the elderly Myocardial revascularization in the elderly · chronic coronary insufficiency:

· the treatment strategy must balance the benefit/risk ratio obtained with medical or surgical solutions

· very critical pts contraindicated for surgical revascularization may possibly benefit from rescue angioplasty designed to treat the culprit artery

· pts in more favourable condition must receive a complete percutaneous or surgical myocardial revascularization

· chronic coronary insufficiency:

· the treatment strategy must balance the benefit/risk ratio obtained with medical or surgical solutions

· very critical pts contraindicated for surgical revascularization may possibly benefit from rescue angioplasty designed to treat the culprit artery

· pts in more favourable condition must receive a complete percutaneous or surgical myocardial revascularization

Review: Filali T, Carrie D. Int Coron Adv 2006; 3:3-4.

TIMETIME

• 301 patients• 804 years old• 42% women• 153 invasive treatment• 148 medical treatment• follow-up 3,1 years

• 301 patients• 804 years old• 42% women• 153 invasive treatment• 148 medical treatment• follow-up 3,1 years

Circulation 2004;110:1213-8

TIMETIME

• Long-term survival was similar for patients

assigned to invasive and medical treatment.

• The benefits of both treatments in angina relief and improvement in QoL were maintained, but nonfatal events occured more frequently in

patients assigned to medical treatment.

• Irrespective of whether patients were catheterized initially or only after drug therapy

failure, their survival rates were better if they were revascularized within the first year.

• Long-term survival was similar for patients

assigned to invasive and medical treatment.

• The benefits of both treatments in angina relief and improvement in QoL were maintained, but nonfatal events occured more frequently in

patients assigned to medical treatment.

• Irrespective of whether patients were catheterized initially or only after drug therapy

failure, their survival rates were better if they were revascularized within the first year.

Elderly and revascularisation

Elderly and revascularisation

• Older patients do not represent a homogeneous group and age alone should not be a barrier to invasive revascularisation strategies.

• Careful evaluation of each patient’s fitness and preference for different management strategies must be considered.

• In well selected older adults revascularisation procedures could be rewarding.

• Older patients do not represent a homogeneous group and age alone should not be a barrier to invasive revascularisation strategies.

• Careful evaluation of each patient’s fitness and preference for different management strategies must be considered.

• In well selected older adults revascularisation procedures could be rewarding.

ConclusionsConclusionsBased on the results of recent studies, we can

conclude that pharmacotherapy in the elderly is necessary, but needs selection of appropriate medications, knowledge of their interactions, adequate dosage and of course more frequent monitoring of the patients.

Pharmacological treatment of older patients is at least as effective as it is in younger if all complex clinical specifics for the elderly are considered.

Based on the results of recent studies, we can conclude that pharmacotherapy in the elderly is necessary, but needs selection of appropriate medications, knowledge of their interactions, adequate dosage and of course more frequent monitoring of the patients.

Pharmacological treatment of older patients is at least as effective as it is in younger if all complex clinical specifics for the elderly are considered.

To be seventy years young is sometimes far more

cheerful and hopeful than to be forty years old.

To be seventy years young is sometimes far more

cheerful and hopeful than to be forty years old.

Oliver Wendell Holmes