1. The INSIGHT study - Reliable blood pressure control and additional benefits for hypertensive patients Anthony M Heagerty Department of Medicine Manchester Royal Infirmary, UK

2. International Nifedipine once-daily Study: Intervention as a Goal in Hypertension Treatment

3. Antihypertensive treatment based on diuretics (and beta blockers) had been shown to reduce cardiovascular disease. Cardiovascular protection by other antihypertensive drugs was not documented in prospective controlled trials. Questions were subsequently raised on protective ability of calcium antagonist-based treatment. Background of Trial

4. Study Objectives To compare the influence of nifedipine GITS vs conventional treatment on cardio- and cerebrovascular morbidity and mortality in hypertensive patients with additional risk factors. Primary Outcome Composite of myocardial infarction, sudden death, stroke, heart failure and other cardiovascular death Secondary Outcome Above plus non-cardiovascular deaths, new or worsening angina, transient ischaemic attacks, renal failure

5. Number of Patients 31573164 6321 randomised, eligible for intention-to-treat analysis 7434 enrolled Diuretic combination: Hydrochlorothiazide & Amiloride (”Active control”) Long-acting calcium antagonist Nifedipine GITS

6. mmHg 138 mmHg 82 mmHg 180 160 140 120 100 80 60 Systolic Diastolic 173 mmHg 99 mmHg Antihypertensive Efficacy Mean Blood Pressure Nifedipine GITS Hydrochlorothiazide & Amiloride 0248 1218367087121138173190225242 Year 1 Year 2 Year 3 Year 4 Week

7. Overall Mortality 04008001,2001,600 Time (Days) Cumulative Proportion Surviving 1.01 Nifedipine GITS Hydrochlorothiazide & Amiloride p = 0.72 1.00 0.99 0.98 0.97 0.96 0.95 0.94 0.93 0.92 2,000

8. Main Clinical Outcome Relative Risk and 95% Confidence Interval Primary Endpoints Myocardial Infarction, Sudden Death, Stroke, Heart Failure, Other Cardiovascular Death Sum of Primary and Secondary Endpoints All Cardiovascular Morbidity and All-Cause Mortality 1.01.11.21.31.40.9 0.8 p = 0.34 p = 0.62 0.70.60.5 1.5 1.11 0.96 Nifedipine GITS better Hydrochlorothiazide & Amiloride better

9. Overview: Individual and Combined Endpoints Relative Risk and 95% Confidence Interval All Cardiovascular Morbidity and All-Cause Mortality All Primary and Secondary Endpoints All Primary Endpoints p 0.62 Hydrochlorothiazide & Amiloride better 0.34 1.8 Nifedipine GITS better 1.01.21.41.60.80.60.40.2 0.96 1.11 Stroke Sudden Death 0.43 0.61 0.91 Other Cardiovascular Death 0.85 1.09 Heart Failure 0.023 2.17 Myocardial Infarction 0.17 1.27 0.74

10. Sudden Death and Death of ”Unknown Cause” *Based on opinion of Critical Events Committee, but lacking documentation of cardiac symptoms within 24 hours of death.  Failing to meet pre-specified definition of sudden death Nifedipine GITS Hydrochlorothiazide & Amiloride 12 Number of Endpoints 0 10 20 30 40 50 60 Sum:39 10 17 16 18 23 57 18 Death of ” Unknown Cause ” : Insufficient Information Death of ” Unknown Cause ” : Probably Cardiovascular* Sudden Death

11. Benefit Achieved by INSIGHT Treatment (Risk reduction estimated from Framingham data) Cardiovascular Endpoints per 1,000 Patient Years 34 17 0 10 20 30 Predicted from cardiovascular risk profiling at baseline Observed in all INSIGHT patients 50%* * > 35% risk reduction estimated from MONICA data

12. Short term Mortality/Morbidity based Surrogate End-points “intriguing” Hypertension Trials

13. Side-arm Studies and Additional Analyses INSIGHT Side-arm studies Additional analyses Intima media thickness Coronary calcification Diabetes Renal function High-risk patients

14. Emergence of New Diseases* % of Patients 0 2 4 6 1.3 3.0 2.1 5.3 Gout 1 Peripheral Vascular Disorder 1 p < 0.01 4.3 5.6 Diabetes 2 p = 0.02 *or Recurrence; 1 Reported by investigator; 2 WHO definition of random glucose measurement >11.0 mmol/l or use of anti-diabetic drugs Nifedipine GITS Hydrochlorothiazide & Amiloride

15. I ntima- M edia T hickness in the Trial International Nifedipine once-daily Study: Intervention as a Goal in Hypertension Treatment

16. Impact on Intima-Media Thickness Follow-up (years) IMT Change from baseline (mm) 0 -0.010 0 0.010 0.020 0.030 0.040 1234 HCTZ/ Amiloride Nifedipine GITS Progression Regression

17. Coronary Calcification Substudy International Nifedipine once-daily Study: Intervention as a Goal in Hypertension Treatment International Nifedipine Trial

18. 75 100 125 150 Baseline Year 1 Maximum Total Calcium Score HCTZ/Amiloride Nifedipine GITS Year 2Year 3 Effect on Maximum Total Calcium Score: Values in LAD (Left Anterior Descending Coronary Artery) Geometric Mean 79 101 120 146 75 96 102 50

19. Renal Function Estimated Glomerular Filtration Rate (GFR) Nifedipine GITS Hydrochlorothiazide & Amiloride 80 ml/min BaselineYear 1Year 2Year 3Last Visit 75 70 65 60 p < 0.05 (for trend)

20. Trials of antihypertensive drugs suggest equivalent efficacy in reducing stroke and MI. Surrogate end points such as IMT, vascular calcification and renal parameters are prognostically important. The Insight trial suggests Nifedipine may provide long-term cardiovascular protection Conclusions