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

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

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

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

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

mmHg 138 mmHg 82 mmHg Systolic Diastolic 173 mmHg 99 mmHg Antihypertensive Efficacy Mean Blood Pressure Nifedipine GITS Hydrochlorothiazide & Amiloride Year 1 Year 2 Year 3 Year 4 Week

Overall Mortality ,2001,600 Time (Days) Cumulative Proportion Surviving 1.01 Nifedipine GITS Hydrochlorothiazide & Amiloride p = ,000

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 p = 0.34 p = Nifedipine GITS better Hydrochlorothiazide & Amiloride better

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 Nifedipine GITS better Stroke Sudden Death Other Cardiovascular Death Heart Failure Myocardial Infarction

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 Sum: Death of ” Unknown Cause ” : Insufficient Information Death of ” Unknown Cause ” : Probably Cardiovascular* Sudden Death

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

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

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

Emergence of New Diseases* % of Patients Gout 1 Peripheral Vascular Disorder 1 p < 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

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

Impact on Intima-Media Thickness Follow-up (years) IMT Change from baseline (mm) HCTZ/ Amiloride Nifedipine GITS Progression Regression

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

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

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

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