EDITORIAL
Cholesterol Can be Lowered in Older Persons
Should we care?
Scarso/incerto
valore predittivo
del colesterolo e
pochi dati da RCT
nei vecchi.
Pluripatologia e
importanti
“competing” cause
di mortalità
Scetticismo verso
inquinanti
“commerciali”
della medicina
JAGS 1990
Age and Ageing 1999; 28: 313-315
Cholesterol and long-term mortality after acute
myocardial infarction in elderly patients
Mario Bo, Umberto Fiandra, Gianfranco Fonte,
Marco Bobbio, Fabrizio Fabris
No. (%) by total cholesterol, mg/dl
Normo/Hyper
cholesterolemia
<164
165-188
189-220
>220
<230
>=230
p
All-cause
mortality
52 (67.5)
54 (72.0)
44 (57.9)
48 (63.2)
114
(69.5)
84
(60.0)
<0.05
CHD
mortality
23 (29.9)
26 (34.7)
20 (26.3)
21 (27.6)
53
(34.6)
37
(29.8)
<0.05
304 patients (192 men, mean age 73.3+-5.7 years), mean survival time 1758.1+- 113.8 days
Prospective Association Between Low and High Total and
Low-Density Lipoprotein Cholesterol and Coronary Heart
Disease in Elderly Men
J.David Curb, MD et al.
J Am Geriatr Soc 52:1975-1980, 2004
3 Age- and risk factor-adjusted RR of CHD
1.8
2
1.5
1
2.6
Total Cholesterol
1.1
1.5
LDL Cholesterol
1.2
1.0
0
<160 160-179 180-199 200-219 220-239 240+
<80 80-99 100-119 120-139 140-159 160+
CONCLUSION…the U-shaped associations between TC and LDL-C and CHD imply
a complex relationship between lipids and CHD in late life…the results indicate that
elevated lipid levels should continue to be treated in healthy elderly individuals, as they
are in those who are younger
J Am Geriatr Soc 52:1975-1980, 2004
BRIEF REPORTS
Low-Density Lipoprotein Cholesterol and Mortality in
Older People
1887 women and 1223 men 65 years+ (mean age 73.8); mean follow-up 11.1 years
Death per 1000
patient-years
100
TOTAL
CARDIOVASCULAR
40
MEN
WOMEN
80
30
60
40
20
80
120
160
200
80
120
160
200 mg/dl LDL
CONCLUSION: This study adds to the uncertainty of the role of elevated levels of LDL-C as a risk
factor for mortality in old people.
J. Am. Geriatr. Soc. 2005
Prospective population-based
cohort study; 5750 adults aged
55 to 99; median follow up
13.9 years
Leiden Plus Study on 599 patients aged >=85 years
Conclusions. In old age, larger declines in BMI, total cholesterol levels, and blood
pressure and weaker increases in HDL cholesterol levels associate with mortality.
We identified distinct clustering in the dynamics of these traditional metabolic risk
factors and indicators of health and disease in a profile that is suggestive of underlying
wasting disease.
<175
176-199
.5
Cumulative
mortality
200-226
>226
.4
.3
CONCLUSION: Low
cholesterol level is a robust
predictor of mortality in the
nondemented elderly and may be
a surrogate of frailty or
subclinical disease…
Participants taking lipidlowering drugs were only
one-quarter as likely to die as
those not taking drugs
.2
.1
0.0
2
4
6
8 years
Lowest levels. Several prospective population studies have suggested that the mortality
benefit associated with lower TC plateaus at levels around 180 mg/dl…
Lowered by treatment. Lowered TC, either by behavioral intervention or – much more
potently – by drug therapy, is a question distinct from naturally low TC. The evidence
that pharmacologic therapy of dyslipidemia in higher risk middle-aged men results in a
total mortality benefit is extensive and convincing…. The benefits of statins…appear
proportional to the degree of improvement in the TC/HDL ratio, and by far the largest
reductions in event rates reported occurred with combination statin and niacin therapy,
with the attendant profound lowering of the TC/HDL ratio….Only consideration of HDL
cholesterol allows much predictive power at middle or older ages.
…all individuals presenting with an acute vascular event of any type in any arterial
territory irrespective of age in a population of 91106 in Oxfordshire, UK, in 2002-05
…2024 acute vascular events occurred in 1657 individuals: 918 (45%) cerebrovascular
(618 stroke, 300 TIA); 856 (42%) coronary vascular (159 STEMI, 316 NSTEMI, 218 UA,
163 SCD); 188 (9%) peripheral vascular (43 aortic, 53 embolic visceral or limb ischemia,
92 critical limb ischemia)…event and incidence rates rose steeply with age in all arterial
territories, with 80% cerebrovascular, 73% coronary and 78% peripheral vascular events
in 12886 (14%) individuals aged 65 years or older; and 54%, 47% and 56%,
respectively, in the 5919 (6%) aged 75 years or older….although case fatality rates
increased with age, 47% of non-fatal events occurred at age 75 years or older
Lifetime risks of fatal and nonfatal events according to aggregate burden of risk factors in men and women
Men
Women
51° CONGRESSO NAZIONALE SIGG
“La longevità del Paese: risorse e problema”
Firenze, 29 novembre-3 dicembre 2006
PAZIENTE ANZIANO E DISLIPIDEMIE: QUALE
TRATTAMENTO E’ PIU’ EFFICACE?
L’evidenza che colesterolo totale ed LDL non sono predittivi di mortalità
cardiovascolare e totale nell’insieme dei soggetti anziani non significa
necessariamente che non vi sia spazio per i benefici di una terapia
ipocolesterolemizzante in questi pazienti. Occorre quindi chiedersi se
Vi sono evidenze che l’intervento ipocolesterolemizzante si associ
ad un beneficio in termini di morbilità/mortalità negli anziani?
In caso di risposta affermativa, quali sono le priorità per un
trattamento ottimale in questa fascia di età?
DISLIPIDEMIE
FUMO
DIABETE
IPERTENSIONE
ETA’
SESSO
FAMILIARITA’
OBESITA’
SEDENTARIETA’
S.METABOLICA
INFIAMMAZIONE
IPERCOAGULABILITA’…
…il punto quindi non è tanto l’ipercolesterolemia in sé
quanto la possibilità della prevenzione delle
manifestazioni cliniche aterosclerotiche attraverso
l’impiego di farmaci ipocolesterolemizzanti che hanno
dimostrato importanti benefici nei soggetti ad alto
rischio CV…occorre quindi valutare se esistano delle
evidenze in questo senso e quali siano gli interventi
efficaci in questo ambito nell’anziano…
1250 women and 664 men 65 years
and older (71.1); mean follow-up 7.3
years; 382 CV events and 362 deaths
Association of drug therapy to lower cholesterol levels with incident CV events
Association of drug therapy to lower cholesterol levels with mortality
…statin use was associated with similar lower risk of incident CV events
among participants 74 years and older and among participants aged 65
to 73 years…
1.5 million veterans in 10 hospitals
Risk score (0-6): age>70; DM; previous
MI; hypertension; LDL-C>100 mg/dl;
current smoking
statin nonusers
statin users
OR 0.54 (0.42-0.69)
p<0.0001
Age distribution at death among statin users
and nonusers. Age at death was 2.1 years older
among statin users (p<0.0001)
Graded relation between risk of death and
benefit of statin therapy. For risk scores >1,
reduction in death was highly significant
Predictors of death
STATINS
Observational study in acute care hospitals in US from april
1998 to june 2001
23013 Medicare patients aged 65 and older who did and did
not receive a discharge prescription for statin
8452 of patients (40%) were aged 80 and older
5513/23013 (24%) in the overall sample and 1310/8452 of
those aged 80 and older (15.5%) received a statin at
discharge
NO STATINS
65-69
Unadjusted Kaplan Meier estimates of 3 year
survival in patients prescribed statins at
discharge versus patients not prescribed
statins at discharge
70-74
75-79
CONCLUSION-Statin therapy is associated
with lower mortality in older patients with AMI
younger than 80 but not in those aged 80 and
older, as a group. This finding questions whether
statin efficacy data in younger patients can be
broadly applied to the very old and indicated the
need for further study of this group.
80-84
85+
Adjusted hazard ratio (HR) of 3 year mortality for patients
prescribed statins at discharge versus patients not prescribed
statins at discharge by 5-year age increments.
20536 pazienti (75% maschi), 40-80 anni
(28%>70), col.tot.>134 mg/dl, alto rischio CV:
storia di CAD; altre malattie ats ostruttive o
precedenti rivascolarizzazioni; DM (tipo 1 e 2);
ipertesi se maschi >65 anni
ANY DEATH
ANY MAJOR
CV EVENT
•
•
•
5804 patients (2804 men), 70-82 years with history of, or risk factors for, vascular disease
Pravastatin 40 mg/day vs placebo, follow-up 3.2 years
Primary end-point: composite of coronary death, non-fatal MI, fatal and non-fatal stroke
Placebo
(2913)
Pravastatin
(2891)
Hazard ratio
(95%CI)
Primary end-point
473 (16.2%)
408 (14.1%)
0.85 (0.74-0.97)
CHD death or non-fatal MI
356 (12.2%)
292 (10.1%)
0.81 (0.69-0.94)
Fatal/non-fatal stroke
131 (4.5%)
135 (4.7)
1.03 (0.81-1.31)
All CV end-points
523 (18%)
454 (15.7%)
0.85 (0.75-0.97)
CHD deaths
122 (4.2%)
94 (3.3%)
0.76 (0.58-0.99)
Cancer
91 (3.1%)
115 (4%)
1.28 (0.97-1.68)
306 (10.5%)
298 (10.3%)
0.97 (0.83-1.14)
All-cause mortality
CHD, non-fatal MI, fatal/non fatal stroke
CHD death or non-fatal MI
Fatal/non-fatal stroke
Studio osservazionale su 7220 pazienti con CAD definita angiograficamente, seguiti per
un periodo di 3.3 anni in relazione all’uso di statine in rapporto all’età
Mortalità in pazienti che assumevano
(colonne bianche) e non assumevano
(colonne nere) statine
Analisi multivariata dell’effetto delle
statine sulla mortalità complessiva
nei pazienti di 80+ anni
9 trials, 19569
pazienti, range età
basale 65-82 anni
(A)
(C)
RRR 22%, NNT 28
RRR 26% , NNT 28
(D)
(B)
RRR 25%, NNT 58
RRR 30%, NNT 34
Bayesian
Forest
Plot for
Mortality
(A)
Bayesian
Forest
PlotAll-Cause
for Non-Fatal
MI (C)
and Coronary
(B)
Bayesian Heart
ForestDisease
Plot forMortality
Stroke (D)
Studio osservazionale su pazienti >80 anni con
diagnosi di IMA tra il 1999 e il 2003. Analisi di
sopravvivenza ed eventi in relazione all’uso di
statine sul campione totale (popolazione A, 14907
pazienti) e dopo aver escluso quelli deceduti
entro 14 giorni (popolazione B) ed entro un anno
(popolazione C)
51351 pazienti >60 anni in
RCT con statine,
prevenzione primaria e
secondaria
EDITORIAL
Statin Therapy in Older Persons
Pertinent Issues
LDL lowering therapy undoubtedly should be one therapeutic modality for
secondary prevention in older persons with CHD
The issue of LDL lowering drugs for older persons without CHD is more problematic.
LDL lowering drugs should be reserved for persons who are deemed to be at higher
risk. In younger elderly (65-75 years) use of statin therapy even in primary prevention
is justifiable; in the older persons (>75 years) statins should be used more cautiously
(Grundy S., Arch.Intern. Med. 2002, 162, 1329)
..il rischio di rabdomiolisi è principalmente determinato dalla dose di statina
piuttosto che dall’entità della riduzione del colesterolo LDL…
.. il maggior determinante del beneficio associato all’uso delle statine è
l’entità della riduzione del colesterolo LDL piuttosto che il tipo o la dose di
statina usata… il maggior determinante della tossicità (peraltro assai
modesta) delle statine non è l’entità della riduzione del colesterolo LDL quanto
la dose di statina usata… sembra pertanto prudente non usare dosi di
statine superiori a quelle necessarie a raggiungere l’obiettivo LDL
desiderato
..l’insieme delle evidenze rassicura sul fatto che l’impiego delle statine non è
associato ad un maggior rischio di cancro rispetto al placebo…
Major CV events
In-hospital death
CYP3A4
Amiodarone
Clarithromicin, Erythromicin
Cyclosporine
Diltiazem, Nifedipine,
Verapamile, Lacidipine
Itraconazole, Ketoconazole
Bioav
Lipophil Protein
Midazolam
%Nefazodone
bind.
Quinidine
Sildenafil
Warfarin
Clinical Pharmacokinetics of STATINS
Tmax
hours
ATORVA
2-3
Metab.
pathw.
Active
metab.
T 1/2
hours
Urinary/
Fecal
excret.
12
Yes
80-90
CYP 3A4
Yes
15-30
2/70
FLUVA
0.5-1
20-30
Yes
>99
CYP 2C9
No
0.5-2
6/90
PRAVA
1-1.5
18
No
43-55
Sulfation
No
1-3
20/71
SIMVA
1-2.5
5
Yes
94-98
CYP 3A4/5
Yes
2-3
13/58
3
20
No
88
CYP 2C9
Yes
(minor)
21
10/90
ROSUVA
CYP2C9
Alprenolol
Diclofenac
Fluvastatin
Phenitoin
Tolbutamide
Warfarin
Pharmacol.Ther. 1999, 84, 413-428
J.Clin.Pharmacol. 2002, 42, 963-970
ELDERLY & SAFETY OF STATINS
Patients at highest risk for CHD include older individuals, patients after
transplantation and patients with hypertension, diabetes or multivessel disease…who
are also the most likely to need multiple medications and thus are at greatest
risk for drug-drug interaction
FACTORS INCREASING THE RISK OF MYOPATHY
•
•
Patient characteristics: older age; female sex; renal insufficiency; hepatic
disease; hypothyroidism; grapefruit juice; polypharmacy
Statin properties: high systemic exposure; lipophilicity; high bioavailability; limited
protein binding; potential for drug-drug interactions metabolized by CYP pathways
(CYP3A4)
WHEN PRESCRIBING STATINS CONSIDER:
•
•
•
•
Personal characteristics: advanced age (women and patients >80 years), frailty,
small body frame, alcohol abuse, muscle disorders, grapefruit juice
Disease burden: multisystem disease (chronic RF with diabetes), hypothyroidism,
antecedent liver or muscle disease
High-risk clinical situations: perioperative period
Medication burden
poiché l’anziano è estremamente sensibile e vulnerabile agli
effetti avversi delle terapie mediche, la prevenzione
cardiovascolare nel vecchio non può prescindere dal
•Mantenimento e miglioramento dell’autonomia funzionale
•Mantenimento della performance psico-cognitiva
•Prevenzione del danno iatrogeno
•Prevenzione delle cadute
Età estremamente
avanzata e/o ridotta
spettanza di vita
Dipendenza e non
autonomia
Estrema fragilità
Severe comorbilità
irreversibili
Valutazione rischio CV
globale
FRAIL /DISABLE
Isolati fdr dopo i
75 anni
Valutazione spettanza di
vita, comorbilità e
politerapia, stato
funzionale e cognitivo,
fragilità, tono dell’umore,
volontà individuale…
DM e/o plurimi fdr
dopo i 75 anni
DM e/o plurimi fdr
prima dei 75 anni
Precedenti
clinici CV
FIT
In sintesi:
• La terapia con statine non ha indicazione razionale negli anziani con
ridotta spettanza di vita, dipendenza funzionale, fragilità o severe
comorbilità croniche irreversibili.
• Negli anziani «robusti» la terapia con statine può essere utile e
dovrebbe essere impiegata per ridurre le recidive vascolari dopo un
evento coronarico.
• Negli anziani «robusti» ad alto rischio di ma senza precedenti CV
una terapia con statine già in atto e ben tollerata può essere
continuata fino ai 75 – 80 anni con le più basse dosi efficaci a
condizione che non vi sia rischio di interazioni e tossicità. Non vi sono
invece sostanziali evidenze circa l’opportunità di iniziare una
prevenzione primaria con statine dopo i 75 anni.