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 Lecture Elizabeth Barrett-Connor, MD Circulation 1997;

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  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 Treatment Trialists’ Collaboration Registry of >30 randomised trials of BP lowering Each trial >1,000 patient years per limb 1 st analyses (1999) on 64,000 patients 2 nd analyses (2003) on 195,000 patients 8,000 strokes 12,000 CHD events J Hypertens 1998;16:

ACE-I and CCB’S vs DIURETIC/  -BLOCKER

MORE vs LESS BP LOWERING* * 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’ Collaboration Second cycle of overview analyses Institute for International Health

 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 placebo atorvastatin 10 mg Double-blind ASCOT-LLA 10,305 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 better Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 2.00 Unadjusted Hazard ratio (95% CI) 0.90 ( ) 0.87 ( ) 0.87 ( ) 0.84 ( ) 0.89 ( ) 0.76 ( ) 0.77 ( ) 0.84 ( ) 1.27 ( ) 0.68 ( ) 0.98 ( ) 0.65 ( ) 1.07 ( ) 0.70 ( ) 0.85 ( ) 0.86 ( ) 0.84 ( )

Total CV events and procedures among subgroups Amlodipine  perindopril betterAtenolol  thiazide better Diabetes No diabetes Current smoker Non-current smoker Obese Non-obese Older (>60 years) Younger (≤60 years) Female Male LVH according to ECG or ECHO No LVH according to ECG or ECHO Previous vascular disease No previous vascular disease Renal dysfunction No renal dysfunction With metabolic syndrome Without metabolic syndrome All patients p value < < < < < < Heterogeneity p 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 Prevention WOSCOPS AFCAPS/TexCAPS ASCOT MI+CHD death MI+CHD death+ unstable angina MI+CHD death Study Baseline LDL* Ending LDL* Years of follow- up 1° Efficacy parameter RR reduction (%) Primary/Secondary Prevention HPS5.0MI+CHD death24 Secondary Prevention 4S CARE LIPID Total mortality MI+CHD death CHD death (192) 3.9 (150) 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 participants in 14 randomised trials  Cholesterol Treatment Trialists’ (CTT) Collaborators  Lancet 2005;366:

Proportional effects on major CV events/ mmol/L of LDL reduction Events RxControlHR (95% CI) Men Women ( ) 0.83 ( ) CTT Collaboration, Lancet 2005

Study design atenolol ± bendroflumethiazide amlodipine ± perindopril 19,257 hypertensive patients PROBE design ASCOT-BPLA Investigator-led, multinational randomised controlled trial placebo atorvastatin 10 mg Double-blind ASCOT-LLA 10,305 patients TC ≤ 6.5 mmol/L (250 mg/dL)

36% reduction Primary End Point: Nonfatal MI and Fatal CHD HR = 0.64 ( ) Atorvastatin 10 mgNumber of events100 PlaceboNumber of events 154 p=0.0005

Prespecified Subgroups: Primary End Point Area of squares is proportional to the amount of statistical information 0.84 ( ) 0.56 ( ) 0.56 ( ) 0.70 ( ) 0.59 ( ) 0.67 ( ) 0.67 ( ) 0.64 ( ) 0.64 ( ) 0.66 ( ) 1.10 ( ) 0.59 ( ) 0.80 ( ) 0.61 ( ) 0.61 ( ) 0.70 ( ) 0.77 ( ) 0.56 ( ) 0.64 ( ) Hazard Ratio Diabetes Nondiabetes Current smoker Noncurrent smoker Obese Nonobese LVH No LVH Older (>60 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 betterPlacebo better Risk Ratio Sever PS, et al. Lancet. 2003;361:

Diabetes Nondiabetes Current smoker Noncurrent smoker Obese Nonobese LVH No LVH Older (>60 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 betterPlacebo 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 * ≠ SubgroupMFMF CHD or stroke: Hx Hypertension Diabetes * 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