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

Risk Factors for CHD

Oral contraceptives

Clotting factors

Homocysteine

Central obesity

Birth weightLeft ventricular hypertrophy

OTHERDiabetes & glucose intolerance

Lack of exercise

GeneticLow HDL cholesterol

Family historySmoking

SexHigh blood pressure

AgeHigh LDL cholesterol

NON-MODIFIABLEMODIFIABLE

Summary report

Sex differences in coronary heart disease

Why are women so superior?

The 1995 Ancel Keys LectureElizabeth Barrett-Connor, MD

Circulation 1997; 95-252-264

• 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!

Summary

• Smoking• Diet - fibre - vitamins• Lipids (TC:HDL)• Blood pressure• Blood viscosity• Uric acid

BUT … - Exercise?- alcohol?-

fibrinogen?

Men are bad!

Nondiabetic women

Nondiabetic men

Diabetic men

Diabetic women

Health Survey for England ‘98

Prevalence of high blood pressure, by age

0

10

20

30

40

50

60

70

80

16-24 25-34 35-44 45-54 55-64 65-74 75+

Age Group

Pe

r c

en

t

MenWomenMenWomen

140/90 mmHg

160/95 mmHg

Protocol for Prospective Collaborative Overviews of Major Randomised Trials of Blood pressure-lowering

Treatments

WHO-ISH Blood Pressure Lowering TreatmentTrialists’ Collaboration

Registry of >30 randomised trials of BP loweringEach trial >1,000 patient years per limb1st analyses (1999) on 64,000 patients2nd analyses (2003) on 195,000 patients

• 8,000 strokes• 12,000 CHD events

J Hypertens 1998;16:127-137

ACE-I and CCB’S vs DIURETIC/-BLOCKER

OR (95%CI)

End point ACE-I CCB

Stroke 1.05 0.87 (0.77-0.98)

CHD 1.00 1.12 (1.00-1.26)

Ht failure 0.92 1.12 (0.95-1.33)

Major CV events 1.00 1.02

CV death 1.00 1.05

Total death 1.03 1.01

MORE vs LESS BP LOWERING*

End point OR (95% CI)

Stroke 0.80

CHD 0.81

Ht Failure 0.78 (0.53-1.15)

Major CV events 0.85

CV death 0.90 (0.75-1.09)

Total death 0.97 (0.85-1.11)

* HOT: UKPDS: ABCD

“Therefore, achieved blood pressure, not choice of initial therapy, should be the over-riding concern of clinicians treating hypertension”

Brown, Lancet 2001

Blood Pressure Lowering Treatment Trialists’ CollaborationSecond cycle of overview analyses

Institutefor

InternationalHealth

Similar net effects on total cardio-vascular events of: ACE inhibitors Calcium antagonists Diuretics/beta-blockers

ARBs also effective in reducing total cardiovascular events

Conclusions I

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

Conclusions III

Study design

atenolol ± bendroflumethiazide

amlodipine ± perindopril

19,257 hypertensive

patients

PROBE design

ASCOT-BPLA

Investigator-led, multinational randomised controlled trial

placeboatorvastatin 10 mg Double-blind

ASCOT-LLA10,305 patients

TC ≤ 6.5 mmol/L (250 mg/dL)

Summary of all end points

The area of the blue square is proportional to the amount of statistical information

Amlodipine perindopril better Atenolol thiazide better0.50 0.70 1.00 1.45

Primary Non-fatal MI (incl silent) + fatal CHD

SecondaryNon-fatal MI (exc. Silent) +fatal CHDTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure

Tertiary Silent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment

Post hoc Primary end point + coronary revasc procsCV death + MI + stroke

2.00

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)

Total CV events and procedures among subgroups

0.60 0.70 0.80 0.90 1.00 1.50Amlodipine perindopril better Atenolol thiazide better

DiabetesNo diabetes

Current smokerNon-current smoker

ObeseNon-obese

Older (>60 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

p value

0.0283<0.0001

0.00010.0030

0.0162<0.0001

<0.00010.0227

0.00150.0001

0.0056<0.0001

0.00190.0001

<0.00010.0055

0.00150.0002

<0.0001

Heterogeneity p

0.5205

0.1138

0.6753

0.7816

0.2889

0.6364

0.4863

0.7130

0.9417

The area of the blue square is proportional to the amount of statistical information

Landmark statin trials: effect of therapy on clinical events

Shepherd JM. N Engl J Med 1995;333:1301–1307. Downs JR. JAMA 1998;279:1615–1622. Sever. Lancet 2003;361:1149–1158. HPS Group. Lancet 2002;360:7–22. 4S Group. Lancet 1994;344:1383–1389. Sacks FM. N Engl J Med 1996;335:1001–1009. LIPID Group. N Engl J Med 1998;339:1349–1357.

Primary PreventionWOSCOPSAFCAPS/TexCAPS

ASCOT

4.95.2

3.3

MI+CHD death MI+CHD death+ unstable angina

MI+CHD death

3136

36

StudyBaseline

LDL*Ending LDL*

Years of follow-

up

1° Efficacy parameter

RR reduction

(%)

Primary/Secondary PreventionHPS 5.0 MI+CHD death 24

Secondary Prevention4SCARELIPID

5.4

5.0

6.1

Total mortality

MI+CHD death CHD death

30

24

24

5.0 (192)

3.9 (150)

3.4 (131)

3.4 (131)

4.9 (188)

3.6 (139)

3.9 (150)

3.7 (142)

3.0 (115)

2.3 (90)

2.7 (104)

3.2 (122)

2.5 (98)

2.9 (112)

*mmol/L (mg/dL)

Event rates plotted against LDL cholesterol levels during statin therapy in secondary-prevention studies

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 2005;366:1267-1278

Proportional effects on major CV events/ mmol/L of LDL reduction

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

Study design

atenolol ± bendroflumethiazide

amlodipine ± perindopril

19,257 hypertensive

patients

PROBE design

ASCOT-BPLA

Investigator-led, multinational randomised controlled trial

placeboatorvastatin 10 mg Double-blind

ASCOT-LLA10,305 patients

TC ≤ 6.5 mmol/L (250 mg/dL)

0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cu

mu

lati

ve

Inc

ide

nc

e (

%)

36% reduction

Primary End Point: Nonfatal MI and Fatal CHD

HR = 0.64 (0.50-0.83)

Atorvastatin 10 mg Number of events 100

Placebo Number of events 154

p=0.0005

Prespecified Subgroups: Primary End Point

Area of squares is proportional to the amount of statistical information

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)

Hazard Ratio

DiabetesNondiabetesCurrent smokerNoncurrent smokerObeseNonobeseLVHNo LVHOlder (>60 years)Younger (≤60 years)FemaleMalePrevious vascular diseaseNo previous vascular diseaseRenal dysfunctionNo renal dysfunctionWith metabolic syndromeWithout metabolic syndrome

All patients

0.5 1.0 1.5

Atorvastatin better Placebo better

Risk Ratio

Sever PS, et al. Lancet. 2003;361:1149-1158.

DiabetesNondiabetesCurrent smokerNoncurrent smokerObeseNonobeseLVHNo LVHOlder (>60 years)Younger (≤60 years)FemaleMalePrevious vascular diseaseNo previous vascular diseaseRenal dysfunctionNo renal dysfunctionWith metabolic syndromeWithout metabolic syndrome

All patients

0.5 1.0 1.5

Atorvastatin better Placebo better

Subgroups: Total CV Events and Procedures

Area of squares is proportional to the amount of statistical information

Risk Ratio

HSE Lipids 2003: Treatment and control in subgroups

Treatment * 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 >5 mmol/l or on Rx

≠ <5.0 mmol/l

Case history

• 19 year old woman (JP)

• Current smoker (began 5 years ago)

Treatment plan

(a) Based on short-term absolute risk

- NO ACTION

(b) Based on long-term intuition

- ADVISE

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 RCT’s

The majority of CV events can be prevented by optimal treatment of raised BP and lipid levels supported by non-drug interventions.

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