Should there be gender differences when treating raised blood pressure and cholesterol?

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Should there be gender differences when treating
raised blood pressure and cholesterol?

• Neil R Poulter
• International Centre for Circulatory Health NHLI,
  Imperial College London
• Hong Kong, April 2006

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Risk Factors for CHD
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Summary report
Sex differences in coronary heart disease Why
are women so superior? The 1995 Ancel Keys
Lecture Elizabeth Barrett-Connor,
MD Circulation 1997 95-252-264
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Summary

• Potentially beneficial mechanisms of
  oestrogen can
• be shown ( some harmful)
• Endogenous oestrogen levels do not predict
  CHD
• Lack of oestrogen (menopause) does not ? CHD
  rates
• Pre-menopausally exogenous oestrogen
  increases
• CVD rates
• Post-menopausally exogenous oestrogen
• provides no CVD benefit
• Conclusion
• 1 of 8 criteria for assessing a causative link
  between oestrogen and CVD protection are
  partially satisfied (laboratory)
• 7 OF 8 ARE NOT!

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Men are bad!

• Smoking
• Diet - fibre
• - vitamins
• Lipids (TCHDL)
• Blood pressure
• Blood viscosity
• Uric acid
• BUT - Exercise?
• - alcohol?
• - fibrinogen?

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Nondiabetic women Nondiabetic men Diabetic
men Diabetic women
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Health Survey for England 98
? 140/90 mmHg ? 160/95 mmHg
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Protocol for Prospective Collaborative Overviews
of Major Randomised Trials of Blood
pressure-lowering Treatments

• WHO-ISH Blood Pressure Lowering Treatment
• Trialists Collaboration
• Registry of gt30 randomised trials of BP lowering
• Each trial gt1,000 patient years per limb
• 1st analyses (1999) on 64,000 patients
• 2nd analyses (2003) on 195,000 patients
• 8,000 strokes
• 12,000 CHD events
• J Hypertens 199816127-137

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ACE-I and CCBS vs DIURETIC/?-BLOCKER
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MORE vs LESS BP LOWERING
HOT UKPDS ABCD
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Therefore, achieved blood pressure, not choice
of initial therapy, should be the over-riding
concern of clinicians treating hypertension
Brown, Lancet 2001
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Blood Pressure Lowering Treatment Trialists
CollaborationSecond cycle of overview analyses
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Conclusions I

• Similar net effects on total cardio-vascular
  events of
• ACE inhibitors
• Calcium antagonists
• Diuretics/beta-blockers
• ARBs also effective in reducing total
  cardiovascular events

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Conclusions III

• Size of blood pressure difference between
  randomised groups closely associated with
  reduction in risk (except for heart failure)
• Size of blood pressure reduction appears to be a
  more important determinant of outcome than drug
  choice

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Study design
19,257 hypertensive patients
ASCOT-BPLA
PROBE design
atenolol bendroflumethiazide
amlodipine perindopril
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Summary of all end points
Unadjusted Hazard ratio (95 CI) 0.90
(0.79-1.02) 0.87 (0.76-1.00) 0.87
(0.79-0.96) 0.84 (0.78-0.90) 0.89
(0.81-0.99) 0.76 (0.65-0.90) 0.77
(0.66-0.89) 0.84 (0.66-1.05) 1.27
(0.80-2.00) 0.68 (0.51-0.92) 0.98
(0.81-1.19) 0.65 (0.52-0.81) 1.07
(0.62-1.85) 0.70 (0.63-.078) 0.85
(0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92)
Primary Non-fatal MI (incl silent) fatal
CHD SecondaryNon-fatal MI (exc. Silent) fatal
CHD Total coronary end pointTotal CV event and
proceduresAll-cause mortalityCardiovascular
mortalityFatal and non-fatal strokeFatal and
non-fatal heart failure Tertiary Silent
MI Unstable anginaChronic stable
anginaPeripheral arterial diseaseLife-threatenin
g arrhythmiasNew-onset diabetes
mellitusNew-onset renal impairment Post hoc
Primary end point coronary revasc procs CV
death MI stroke
0.50
0.70
1.00
1.45
2.00
Atenolol ? thiazide better
Amlodipine ? perindopril better
The area of the blue square is proportional to
the amount of statistical information
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Total CV events and procedures among subgroups
p value 0.0283 lt0.0001 0.0001 0.0030 0.01
62 lt0.0001 lt0.0001 0.0227 0.0015 0.0001 0.00
56 lt0.0001 0.0019 0.0001 lt0.0001 0.0055 0.00
15 0.0002 lt0.0001
Heterogeneity p 0.5205 0.1138 0.6753 0.7
816 0.2889 0.6364 0.4863 0.7130 0.9417
DiabetesNo diabetes Current smokerNon-current
smoker ObeseNon-obese Older (gt60 years)Younger
(60 years) FemaleMale LVH according to ECG or
ECHONo LVH according to ECG or ECHO Previous
vascular diseaseNo previous vascular
disease Renal dysfunctionNo renal
dysfunction With metabolic syndromeWithout
metabolic syndrome All patients
0.60
0.70
0.80
0.90
1.00
1.50
Amlodipine ? perindopril better
Atenolol ? thiazide better
The area of the blue square is proportional to
the amount of statistical information
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Landmark statin trials effect of therapy on
clinical events
mmol/L (mg/dL)
Shepherd JM. N Engl J Med 199533313011307.
Downs JR. JAMA 199827916151622. Sever. Lancet
200336111491158. HPS Group. Lancet
2002360722. 4S Group. Lancet
199434413831389. Sacks FM. N Engl J Med
199633510011009. LIPID Group. N Engl J Med
199833913491357.
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Event rates plotted against LDL cholesterol
levels during statin therapy in
secondary-prevention studies
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• Efficacy and safety of cholesterol-lowering
  treatment prospective meta-analysis of data from
  90 056 participants in 14 randomised trials
• Cholesterol Treatment Trialists (CTT)
  Collaborators
• Lancet 20053661267-1278

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Proportional effects on major CV events/ mmol/L
of LDL reduction
Events Events
Rx Control HR (95 CI)
Men Women 5097 1257 6504 1490 0.78 (0.75-0.81) 0.83 (0.76-0.91)
CTT Collaboration, Lancet 2005
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Study design
19,257 hypertensive patients
ASCOT-BPLA
PROBE design
atenolol bendroflumethiazide
amlodipine perindopril
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Primary End Point
Nonfatal MI and Fatal CHD
Atorvastatin 10 mg Number of events 100 Placebo Nu
mber of events 154
36 reduction
HR 0.64 (0.50-0.83)
p0.0005
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Prespecified Subgroups Primary End Point
Hazard Ratio
Risk Ratio
0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.56
(0.37-0.85) 0.70 (0.51-0.96) 0.59
(0.39-0.90) 0.67 (0.49-0.92) 0.67
(0.35-1.29) 0.64 (0.49-0.84) 0.64
(0.47-0.86) 0.66 (0.41-1.06) 1.10
(0.57-2.12) 0.59 (0.44-0.77) 0.80
(0.45-1.42) 0.61 (0.46-0.81) 0.61
(0.44-0.84) 0.70 (0.47-1.04) 0.77
(0.52-1.12) 0.56 (0.40-0.79) 0.64 (0.50-0.83)
Diabetes Nondiabetes Current smoker Noncurrent
smoker Obese Nonobese LVH No LVH Older (gt60
years) Younger (60 years) Female Male Previous
vascular disease No previous vascular
disease Renal dysfunction No renal
dysfunction With metabolic syndrome Without
metabolic syndrome All patients
Atorvastatin better
Placebo better
0.5
1.0
1.5
Area of squares is proportional to the amount of
statistical information
Sever PS, et al. Lancet. 20033611149-1158.
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Subgroups Total CV Events and Procedures
Risk Ratio
Diabetes Nondiabetes Current smoker Noncurrent
smoker Obese Nonobese LVH No LVH Older (gt60
years) Younger (60 years) Female Male Previous
vascular disease No previous vascular
disease Renal dysfunction No renal
dysfunction With metabolic syndrome Without
metabolic syndrome All patients
Area of squares is proportional to the amount of
statistical information
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HSE Lipids 2003
Treatment and control in subgroups
Treatment Treatment Control ? Control ?
Subgroup M F M F
CHD or stroke Hx 71.1 55.8 51.7 28.8
Hypertension 32.7 22.4 22.9 11.1
Diabetes 50.9 50.0 33.3 31.9
Among those with TC gt5 mmol/l or on Rx ? lt5.0
mmol/l
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• Case history
• 19 year old woman (JP)
• Current smoker (began 5 years ago)

• Treatment plan
• Based on short-term absolute risk
• - NO ACTION

(b) Based on long-term intuition - ADVISE
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Summary

• Clinical guidelines relating to CVD need to
  incorporate a broad multifactorial approach
• Total (global) CV risk assessment will assist
  decision-making, but the shortcomings of the
  system used should be appreciated
• Intervention based on estimated total CV risk
  levels remains unvalidated in RCTs
• The majority of CV events can be prevented by
  optimal treatment of raised BP and lipid levels
  supported by non-drug interventions.

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Should there be gender differences when treating
raised blood pressure and cholesterol?

1. If treatment is based on estimated CV risk ? More
   man will be treated
2. For the same level of CV risk ? women benefit as
   much as men