Paraskevi 11 Rizzo

Manfredi Rizzo, MD, PhD Faculty of Medicine Dpt of Internal Medicine and Medical Specialties University of Palermo, Italy & Adjunct Professor School of Medicine Department of Internal Medicine University of South Carolina, USA & Head Unit of Atherosclerosis, Diabetes and Cardiovascular Prevention Euro-Mediterranean Institute of Science and Technology, Italy

Lipid-lowering treatment in elderly patients

1. Life expectancy

Life expectancy 1600-2000

Science 2002;296:1029

2. Lipids in the elderly

Changes of Cholesterol Levels with Age ?

• Total cholesterol levels increase with age primarily from an increase in the LDL-cholesterol • Multiple studies have shown that a high LDL and low HDL in the elderly is associated with significant CHD risk

cumulative mortality for cardiovascular disease

CV mortality and LDLc in the elderly LDL

0.5

low

0.4

intermediate high

0.3 0.2 0.1

p log rank = 0.16

0.0

85

86

87

88

89

age (years) Arch Intern Med 2003; 163:1549

cumulative mortality for cardiovascular disease

CV mortality and HDLc in the elderly 0.5

HDL

0.4

low intermediate

0.3

high

0.2 0.1 p log rank = 0.006

0.0

85

86

87

88

89

age (years) Arch Intern Med 2003; 163:1549

Lipoprotein alterations in the elderly: sdLDL as a risk factor for type-2 diabetes Density (g/ml) 1.025

1.034

1.060

1.044

Healthy female Male CAD patient

1.065

LDL-I 27.5

27.0

III

II 25.5

IV 24.2

21.8

LDL Particle Size (Diameter nm) Austin M et al. Circulation 1995;92:1770-17778.

Rizzo M, Berneis K. Low-density-lipoproteins size and cardiovascular risk assessment QJM 2006; 99: 1-14.

3. The lesson from International Scientific Guidelines

“As a rule, statin therapy should be employed more cautiously in older persons, particularly older thin or frail women, but it is not contraindicated in these or other high-risk patients.�

4. The lesson from clinical trials

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) • 5804 patients aged 70–82 years with a history of vascular disease or with cardiovascular risk factors • Randomized to pravastatin 40 mg/d or placebo • Baseline TC 155–348 mg/dL • Follow-up 3.2 years (mean)

• Primary endpoint (composite): coronary death, nonfatal MI, fatal or nonfatal stroke

Shepherd J et al. Lancet 2002;360:1623–1630.

PROSPER: Kaplan–Meier Analysis of Time to Primary Endpoint Proportion with Event (%)

20

Placebo

15

p=0.014

10

Pravastatin

5

0

0

0.5 1.0 1.5 2.0 2.5 3.0 Follow-up (years)

Shepherd J et al. Lancet 2002;360:1623–1630.

3.5 4.0

Major Endpoints: PROSPER Pravastatin (%)

Placebo (%)

14.1

16.2

0.85

0.014

10.1

12.2

0.81

0.006

4.7

4.5

1.03

0.81

Nonfatal MI

7.7

8.7

0.86

0.10

Nonfatal stroke

4.0

4.1

0.98

0.85

Transient ischemic attack

2.7

3.5

0.75

0.051

15.7

18.0

0.85

0.012

Endpoint

Hazard ratio

p

Primary endpoint: CHD death/MI/stroke Secondary endpoints: CHD death/MI Fatal or nonfatal stroke Other outcomes:

All CV events

Shepherd J et al. Lancet 2002;360:1623–1630.

The Heart Protection Study (HPS) • 20,536 subjects, aged 40-80 years, with coronary disease, other occlusive arterial disease, or diabetes • Randomized 40 mg simvastatin daily or placebo • Baseline TC 135 mg/dL

• Follow-up 5 years (mean) • Primary endpoint: all-cause mortality decreased by 14.7% and cardiovascular events decreased by about 25% among erderly individuals (75–80 years) Heart Protection Study Collaborative Group. Lancet. 2002 Jul 6;360(9326):7-22.

The MIRACL study: a randomized controlled trial • 3086 patients, 18 years or older with unstable angina or non-Q-wave acute myocardial infarction • Randomized to atorvastatin 80 mg/d • Baseline TC 206 mg/dL

• Follow-up 16 weeks • Primary endpoint: risk reduction in cardiovascular end point (death, nonfatal acute MI, resuscitated cardiac arrest or hospitalization for symptomatic myocardial ischemia).

• Patients >65 years had a 14% decrease in CV end point (although not significantly) and those >80 years a 34% risk reduction (p = 0.05) Schwartz GG et al. JAMA. 2001;285(13):1711-8.

Carol L. Howe. Barry D. Weiss. Hyperlipidemia in Older Adults: To Treat or Not to Treat? Interprofessional care improves the outcomes of older adults with complex health problems, May 2010

5. Did we include the elderly in our clinical trials with lipid-lowering drugs ?

Men and Women aged 21-65 years

Men aged 18-60 years

Men and Women aged 18+ years (mean 59 yrs)

Adult Men and Women (mean 59 yrs)

Men and Women aged 18-65 years

6. Any Barrier ?

Which barriers ?

• Barriers to treatment

– Misconception that benefit of treatment will take years: really is shown in 6 months • improved endothelial dysfunction in days

– Fear of increased risk of side effects in the elderly: no studies have shown this • side effects are the same in the elderly as the

young

Why would we undertreat?

• Ageism • Exclusion of older adults from clinical trials • Assumption that the older adult may not want “aggressive” treatment • Ideas based upon Life Expectancy • Concern for Polypharmacy • Concern that relative efficacies may be less for certain treatments in older subgroups • Overestimation of Risks of Treatment and underestimation of Benefits of Treatment

Ageism • Coined in 1969 by Dr. Robert Butler (first director of the National Institute on Aging) • “Systematic stereotyping of and discrimination against people because they are old” • Still used in clinical training But… • Age is NOT EQUAL to frailty !

Exclusion of Older Adults from Clinical Trials • 1/3 of original research papers in 1997 and 15% in 2004 excluded older people without justification.

• Potential concerns: – More comorbid illnesses, more difficulty to follow, higher drop out – Increased risks with treatment – Polypharmacy – Protocol restrictions on comorbidities – Older population as “vulnerable” study group – Barriers for transportation and mobility

Assumption that Older Adult May Not Want “Aggressive” Therapy • The literature suggests that we tend to underestimate “Quality of Life” equivalents for others.

• There is data showing that physicians tend to assume that older adults do not want certain treatments. Yet, older patients, when asked, actually do want such care.

Ideas Based upon Life Expectancy • “Average Life Expectancy” can be misleading: – Overall average 77 years in 2002

– But, a 70-year-old woman on average can expect to live another 18 years!

– 10% of 90 year olders will live to 100

% Eligible AMI patients given ASA (Annals Emergency Medicine 2005)

100 90 80 70 60 50 40 30 20 10 0

<50 (n=169)

50-59

60-69

70-79

80-89 (n=461)

>90

% Eligible AMI patients given reperfusion (Annals Emergency Medicine 2005)

90 80 70 60 50 40 30 20 10 0

<50 (n=62)

50-59 (n=96)

60-69 (n=107)

70-79 (n=117)

80-89 (n=69)

>90 (n=9)

Likelihood of Statin Prescription: Ages 66 â&#x20AC;&#x201C; 74

Low CV Risk

Intermediate Risk

High Baseline Risk

(7.8% 3 year Mortality)

(12.8% 3 year Mortality)

(34.4 % 3 year Mortality)

37.7%

26.7%

23.4%

Likelihood of Statin Prescription: Ages 75 â&#x20AC;&#x201C; 80

Low CV Risk

Intermediate Risk

High Risk

(13.7% 3 year Mortality)

(21% 3 year Mortality)

(43% 3 year Mortality)

29%

19%

15%

Likelihood of Statin Prescription: Age > 80

Low Risk

Intermediate Risk

High Risk

(25% 3 year Mortality)

(40% 3 year mortality)

(60 % 3 year Mortality)

13%

6%

4%

Treatment-Risk Paradox â&#x20AC;˘ Those at the highest risk of certain outcome (CV mortality) are often those NOT treated because of fear of risk of treatment.

â&#x20AC;˘ Highest risk population may see the greatest ABSOLUTE benefit in reduction of events given the high baseline risk.

CONCLUSION â&#x20AC;˘ There is a need to include much more older adults in clinical trials. â&#x20AC;˘ Age is only one factor;

frailty and age are not the same thing !