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Statins and Blood Pressure
Prof. Maciej BanachHead, Department of Hypertension,
Medical University of Lodz, PL
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Small HDL subfractions areindependent predictors ofnew onset hypertension?More potent than sdLDL?
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The prevalence of hypercholesterolemia (≥ 190 mg/dl) in patients ≥65 years old in Poland
M – men, W - women
56%
66%62%
M W All
POLSENIOR Registry (Sept. 2011)
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The changes of hipercholestrolemia prevalence in Poland in years 2002-2011
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Hipercholesterolemia control in Poland (Natpol 2011 registry)
NATPOL 18-79 18 mlnPOLSENIOR 80+ >1 mln
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The predicted changes of number of patients with hypercholesterolemia in Poland in years 2011-2035
10
15
20
2010 2015 2020 2025 2030 2035
Million of peo
ple
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The ratio of patients receiving statins in PolandAn
ti‐cholesterol treatment
Anti‐cholesterol treatment
Age [years] Age [years]
Women Men
Distribution smoothed using kernel density estimator function; thin lines are local confidence limits
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The prevalence of hypercholesterolemia depending on the hypertension occurrence
56%
80%
54%
80%
56%
78%
37%
80%
34%
83%
39%
76%
0%
20%
40%
60%
80%
100%
18‐39 60‐79 18‐39 60‐79 18‐39 60‐79
Total Women Men
HAnon‐HA
Age:
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0 1000 2000 3000 4000 5000 6000 7000 8000
Chałas
Ergonomia
Wykorzystywanie seksualne dzieci
Związki rakotwórcze w pracy
Brak antykoncpecji
Zmiany klimatu
Narkotyki
Ekspozycja na ołów
Szczególne zawody
Zawodowe czynniki ryzyka wypadków
Brak sterylnego sprzętu medycznego
Niedobór witaminy A
Niedobór cynku
Zanieczyszczenie w miastach
Niedobór żelaza
Dym z paliw stałych w pomieszczeniach
Brak czystej wody i środków higieny
Alkohol
Brak aktywności fizycznej
Spożywanie warzyw i owoców
Stosunki seksualne bez zabezpieczeń
Niedożywienie
Podwyższone stężenie cholesterolu
Tytoń
Ciśnienie tętnicze
No. of deaths (1000x)
Hypertension is the most common direct causeof death in the world
Dane wg. WHO 2011
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The prevalence of hypertension in Poland
72%78% 76%
M W All
All over 65
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The prevalence of hypertension (≥140/90 mmHg)
NATPOL 18-79 9,5 mlnPOLSENIOR 80+ 0,95 mlnALL 18+ 10,45 mln
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Hypertension control in Poland
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The improvement of HT control in Poland in years 2002-2011
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The predicted changes of number of patients with hypertension in Poland in years 2011-2035
4
9
14
19
2010 2015 2020 2025 2030 2035
Milion
y osób
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The factors that influenced the CAD mortality reduction in Poland in years 1991-2005
P. Bandosz et al. Br. Med. J., 2011
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Statin Evidence: Expanding BenefitsAcute coronary event
4S
CARE/LIPID
4 moNo history of CAD Unstable CAD
3 mo
t = 0
6 mo
Stable CAD
Secondary preventionPrimary prevention
AFCAPS / TexCAPS/WOSCOPS MIRACL
Hypertension
ASCOT-LLA
HPS
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Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Hypertensionn = 8457 (41%)
with CHD1458 (7%)
no CHD1822 (9%)
with CHD4042 (20%)
no CHD2701 (13%)
with CHD1978 (10%)
no CHD3982 (19%)
no CHD2860 (14%)
with CHD5595 (27%)
with MI8510 (41%)
no MI4876 (24%)
20,536patients
PATIENT POPULATION
Statin Evidence: Heart Protection Study
CHDn = 13,379 (65%)
Diabetesn = 5963 (29%)
PVDn = 6748 (33%)
CVDn = 3280 (16%)
J1
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Slide 17
J1 Dr. J. Genest, 4/6/2002
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Vascular event
Major coronary eventNonfatal MICoronary death
Stroke
Revascularization
ANY MAJOR VASCULAR EVENT
27% risk reductionP <.0001
25% risk reductionP <.000124% risk reductionP <.000124% risk reductionP <.0001
Simvastatin Placebobetter better
0.4 0.6 0.8 1.0 1.2 1.4Risk ratio and 95% CI
Statin Evidence: Heart Protection Study
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
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Statin Evidence: Heart Protection Study
24% risk reductionP < .0001
Simvastatin Placebobetter betterBaseline level
LDL-C (mg/dL)<100 (2.6 mmol/L)>100 < 130>130 (3.4 mmol/L)
ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
Risk Ratio and 95% CI
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
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Statin Evidence: ASCOT-LLA
ASCOT is a multicenter, international trial that involves 2 treatment comparisons in a factorial design:
• A Prospective, Randomized, Open, Blinded End point (PROBE) design comparing 2 antihypertensive regimens
• A double-blind, placebo-controlled trial of atorvastatin 10 mg in a large prospective cohort of those hypertensive patients studied (lipid-lowering arm [ASCOT-LLA])
ASCOT is composed of almost 20,000 hypertensive patients with multiple risk factors for CHD
Sever PS, et al. Lancet. 2003;361:1149-1158.
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Statin Evidence: ASCOT-LLA
Eligibility criteria for ASCOT-LLA
• SBP >160 mm Hg and/or DBP >100 mm Hg (untreated) or SBP >140 mm Hg and/or DBP >90 mm Hg (treated)
• TC <250 mg/dL (<6.5 mmol/L) and triglycerides <400 mg/dL (<4.5 mmol/L)
• 40-79 years of age
• 3+ CVD risk factors
• No history of CHD
Sever PS, et al. Lancet. 2003;361:1149-1158.
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Atorvastatin 10 mgPlacebo
Baseline 164/95 mm HgTreated 138/80 mm Hg
130140150
160170
0 1 2 3
SBP
(mm
Hg)
LLA Close-out
DB
P (m
m H
g)
7580859095
100
0 1 2 3Years
LLA Close-out
Blood Pressure Changes
Statin Evidence: ASCOT-LLA
Sever PS, et al. Lancet. 2003;361:1149-1158.
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Statin Evidence: ASCOT-LLATo
tal c
hole
ster
ol
(mm
ol/L
)LD
L ch
oles
tero
l (m
mol
/L)
6
0 1 2 3
200
150
100
(mg/
dL)50 mg/dL
(1.3 mmol/L)38.7 mg/dL
(1.0 mmol/L)
2
4
Atorvastatin 10 mgPlacebo
150
75
125
100 (mg/
dL)
YearsLLA Close-out
1
2
3
4
0 1 2 3
38.7 mg/dL (1.0 mmol/L)
46.5 mg/dL (1.2 mmol/L)
Sever PS, et al. Lancet. 2003;361:1149-1158.
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Atorvastatin 10 mg Number of events 89Placebo Number of events 121
0
1
2
3
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cum
ulat
ive
Inci
denc
e (%
)
HR = 0.73 (0.56-0.96)P = .0236
27% reduction
Statin Evidence: ASCOT-LLA
Primary Endpoint:Nonfatal MI and Fatal CHD
Secondary Endpoint:Fatal and Nonfatal Stroke
0
1
2
3
4
0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5Years
Cum
ulat
ive
Inci
denc
e (%
)
Atorvastatin 10 mg Number of events 100Placebo Number of events 154
36% reduction
HR = 0.64 (0.50-0.83)P = .0005
Sever PS, et al. Lancet. 2003;361:1149-1158.
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Statin Evidence: ASCOT-LLA
Secondary Endpoint:All CV Events and Procedures
Secondary Endpoint:All Coronary Events
0
2
4
6
8
10
12
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Years
Cum
ulat
ive
Inci
denc
e (%
) 21% reduction
HR = 0.79 (0.69-0.90)P = .0005
Atorvastatin 10 mg Number of events 389Placebo Number of events 486
Atorvastatin 10 mg Number of events 178Placebo Number of events 247
0
1
2
3
4
5
6
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Years
Cum
ulat
ive
Inci
denc
e (%
) 29% reduction
HR = 0.71 (0.59-0.86)P = .0005
Sever PS, et al. Lancet. 2003;361:1149-1158.
Sept. 2002 : The Data Safety Monitoring Board (DSMB) recommended that the double-blind,cholesterol-lowering study treatment arm be terminated since the results were outside of thestopping rules of the trial. The Steering Committee endorsed the recommendation of the DSMB,and the lipid arm was closed after a median follow-up period of 3.3 years.
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ESC 2011: 11-year follow-up of ASCOT-LLA Trial
Sever P S et al. Eur Heart J 2011;eurheartj.ehr333
15%14%
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I admit statins may lower BP by some few mmHg – which is fine and different from NSAIDS, glitazones and some other
drugs. But for me the most important thing with statins in hypertensive patients is the fact that they prevent the
endpoints – the reason why we had to abort the atorvavastatin arm of ASCOT prematurely
– 36 and 27 % reductions in MI and stroke, respectively.
Prof. Sverre E. KjeldsenNov. 17th, 2009
Statin Evidence: ASCOT-LLA
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BRISIGHELLA HEART STUDY (2004)
Borghi C et al. Am Heart J 2004; 148:285-92.
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Statins in hypertensive patientsRecommendations
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Statins in hypertensive patientsRecommendations
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Lipids and Blood Pressure Meta-analysis Collaboration (LBPMC) Group
Mohammad Abdollahi (Iran/Canada), Ali Ahmed (USA), Wilbert S. Aronow (USA), MaciejBanach (PL), George Howard (USA), Jolanta Malyszko (PL), Dimitri P. Mikhailidis (UK),Krzysztof Narkiewicz (PL), Stephen Nicholls (USA/Australia), Shekoufeh Nikfar (Iran),Michael J. Pencina (USA), Roja Rahimi (Iran), Manfredi Rizzo (IT), Kausik K. Roy (UK),Jacek Rysz (PL), Peter P. Toth (USA), Nathan D. Wong (USA), Alberto Zanchetti (IT).
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Statins and blood pressure
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Statins and blood pressure
Scopus, PubMed, Web of Science (WoS), and the Cochrane CentralRegister of Controlled Trials were searched for studies thatinvestigated the effect of statins on BP either in normotensive or inhypertensive subjects;
Data were collected for the years 1966 to 2012 (up to January 2012); All randomized controlled clinical trials (RCTs) that investigated the
effect of statins on BP were considered. Studies and abstracts thatwere presented at meetings were also considered;
In some of these studies, BP was not measured as primary outcomeand some were not designed to evaluate the effects of statins on BP;but BP was measured as a side or secondary outcome;
We excluded studies with other factors (drugs other thanhypotensives, concomitant diseases), which could have influenced BP;
Changes in systolic and diastolic BP were the key outcomes ofinterest.
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The effects of statins on blood pressure in normotensive or hypertensive subjects – a meta-analysis
9033 potentially relevant reports identified and screened for retrieval from electronic search3540 PubMed197 Cochrane Library2286 Web of Science3010 Scopus
7140 excluded because of duplication;1841 reports excluded on basis of title and abstract
52 reports retrieved34 reports excluded upon full-text search:n=9: crossovern=3: renal transplant recipientsn=1: patients with cirrhosisn=1: cohortn=6: BP not measuredn=8: measured BP not reportedn=2: no placebo groupn=3: standard deviation not reportedn=1: BP measured during exercise test
18 eligible clinical trials included in the meta-analysis 5628 subjects (4692 normotensiveand 936 hypertensive patients)
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Statins and blood pressure - normotensive patients
Materially the effect was consistent with the overall effect whenthe largest study (n = 2069 in the statin group), single genderstudy, as well as trials with diabetic and non-diabetic patientswere excluded from the analysis (p = 0.22, p = 0.93, p = 0.83and p = 0.17, respectively).
The effect was maintained when trials with single gender,diabetic and non-diabetic patients were excluded from theanalysis (p = 0.27, p = 0.32 and p = 0.41, respectively).
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Statins and DBP – normotensive patients
After excluding the largest study (n = 2069 in the statin group), a significant effect of statins on DBP wasobserved (the difference was −2.27 mm Hg [95% CI: −4.1 to −0.44] [−1.73 mm Hg vs. 0.54 mm Hg —comparing statin and placebo groups, respectively; the weighted mean difference:−1.46; 95% CI:−2.88to−0.04, p = 0.04). However, given that these observations are based on a relatively small number of patientsin each of the studies included (e.g. n = 53 normotensive patients in the statin subgroup in the largest study),as well as small difference of final DBP in this group of patients, these findings should be treated with caution.
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Statins and blood pressure – hypertensive patients
The effect was maintained in this group when the largest (n = 253in the statin group), with long-term follow-up (2.5 and 3.3 years),and single gender studies, as well as trials with diabetic and non-diabetic patients were excluded from the analysis (p = 0.13, p =0.26, p = 0.13, p = 0.52, and p = 0.09, respectively). The lack ofefficacy of statins was also observed when analyzing only trials withthe duration of therapy longer than 2 years (the weighted meandifference was 1.28 with 95% CI = −1.33 to 3.89; p = 0.34).
The effect was maintained in this group when the largest (n = 253in the statin group), with long-term follow-up (2.5 and 3.3 years)and single gender studies, as well as trials with diabetic and non-diabetic patients were excluded from the analysis (p = 0.40, p =0.34, p = 0.39, p = 0.52, and p = 0.75, respectively). The lack ofefficacy of statins was also observed when analyzing only trials withthe duration of therapy longer than 2 years (the weighted meandifference was −0.11 with 95% CI = −1.27 to 1.05; p = 0.86).
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Statins and pulse pressure (PP)
Effect of statins on pulse pressure (PP) in normotensive patients
The weighted mean difference on pulse pressure (∆PP) in normotensivepatients from 11 included trials for statin therapy was 0.51 with 95% CI:−0.28 to 1.31 (p = 0.21).
Effect of statins on pulse pressure (PP) in hypertensive patients
The weighted mean difference on pulse pressure (∆PP) in hypertensivepatients for 8 included trials for statin therapy was 4.46 with 95% CI:−0.76 to 9.69 (p = 0.09).
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Statins and blood pressure –Conclusions
In conclusion, our meta-analysis provides reliableevidence against any substantial BP-loweringeffect of statins in both normotensive andhypertensive patients, suggesting that theestablished protective effects of these drugs onthe CV system do not materially depend onreductions in BP.
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Mean SBP in the statin group decreased by 2.62 mm Hg (95%confidence interval [CI], 3.41 to 1.84; P<.001) and DBP by0.94 mm Hg (95% CI, 1.31 to 0.57; P<.001).
In studies including hypertensive patients, the decrease in bloodpressures with statins was slightly greater (SBP, 3.07 mm Hg;95% CI, 4.00 to 2.15 and DBP, 1.04 mm Hg; 95% CI, 1.47 to0.61).
J Clin Hypertens (Greenwich). 2013 May;15(5):310-20.
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Comparison of the meta-analyses
9033 potentially relevant reports identified and screened for retrieval from electronic search3540 PubMed197 Cochrane Library2286 Web of Science3010 Scopus
7140 excluded because of duplication;1841 reports excluded on basis of title and abstract
52 reports retrieved34 reports excluded upon full-text search:n=9: crossovern=3: renal transplant recipientsn=1: patients with cirrhosisn=1: cohortn=6: BP not measuredn=8: measured BP not reportedn=2: no placebo groupn=3: standard deviation not reportedn=1: BP measured during exercise test
18 eligible clinical trials included in the meta-analysis