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The INSIGHT study - Reliable blood pressure control and additional benefits for hypertensive patients. Anthony M Heagerty Department of Medicine Manchester Royal Infirmary, UK. I nternational N ifedipine once-daily S tudy: I ntervention as a G oal in H ypertension T reatment.
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The INSIGHT study -Reliable blood pressure control and additional benefits for hypertensive patients Anthony M Heagerty Department of Medicine Manchester Royal Infirmary, UK
I nternational N ifedipine once-daily S tudy: I ntervention as a G oal in H ypertension T reatment
Background of Trial • 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.
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 7434 enrolled 6321 randomised, eligible for intention-to-treat analysis 3157 3164 Long-acting calcium antagonist Nifedipine GITS Diuretic combination: Hydrochlorothiazide & Amiloride (”Active control”)
Antihypertensive EfficacyMean Blood Pressure Nifedipine GITS Hydrochlorothiazide & Amiloride 180 173 mmHg 160 138 mmHg 140 mmHg Systolic 120 99 mmHg 100 82 mmHg 80 Diastolic 60 12 18 36 70 87 121 138 173 190 225 242 Week 0 2 4 8 Year 1 Year 2 Year 3 Year 4
Nifedipine GITS Hydrochlorothiazide & Amiloride Overall Mortality 1.01 1.00 p = 0.72 0.99 0.98 0.97 Cumulative Proportion Surviving 0.96 0.95 0.94 0.93 0.92 0 400 800 1,200 1,600 2,000 Time (Days)
Main Clinical Outcome Relative Risk and 95% Confidence Interval p = 0.34 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 1.11 p = 0.62 0.96 0.9 1.0 1.1 1.2 1.3 1.4 1.5 0.5 0.6 0.7 0.8 Nifedipine GITS better Hydrochlorothiazide & Amiloride better
Overview: Individual and Combined Endpoints Relative Risk and 95% Confidence Interval p 0.91 0.61 Stroke 1.27 0.17 Myocardial Infarction 0.74 Sudden Death 0.43 1.09 Other Cardiovascular Death 0.85 2.17 0.023 Heart Failure 1.11 All Primary Endpoints 0.34 All Cardiovascular Morbidity and All-Cause Mortality All Primary and Secondary Endpoints 0.96 0.62 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Nifedipine GITS better Hydrochlorothiazide & Amiloride better
Sudden Death and Death of ”Unknown Cause” Sum: 39 57 60 Death of ”Unknown Cause”: Insufficient Information 18 50 18 40 10 Death of ”Unknown Cause”: Probably Cardiovascular* 16 Number of Endpoints 30 12 20 23 Sudden Death 17 10 0 Nifedipine GITS Hydrochlorothiazide & Amiloride *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
Benefit Achieved by INSIGHT Treatment (Risk reduction estimated from Framingham data) 34 30 50%* * > 35% risk reduction estimated from MONICA data 20 Cardiovascular Endpoints per 1,000 Patient Years 17 10 0 Observed in all INSIGHT patients Predicted from cardiovascular risk profiling at baseline
Short term Mortality/Morbidity based Surrogate End-points “intriguing” Hypertension Trials
Side-arm Studies and Additional Analyses Side-arm studies Additional analyses Diabetes Intima media thickness Renalfunction INSIGHT Coronary calcification High-riskpatients
Emergence of New Diseases* Nifedipine GITS Hydrochlorothiazide & Amiloride 6 5.6 5.3 4 4.3 % of Patients 3.0 2 2.1 1.3 0 Gout1 Peripheral Vascular Disorder1 Diabetes2 p < 0.01 p < 0.01 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
Intima- Media Thickness in the Trial International Nifedipine once-daily Study: Intervention as a Goal in Hypertension Treatment
Impact on Intima-Media Thickness 0.040 HCTZ/ Amiloride Progression 0.030 0.020 IMT Change from baseline (mm) 0.010 0 Nifedipine GITS -0.010 Regression 0 1 2 3 4 Follow-up (years)
International Nifedipine Trial Coronary Calcification Substudy International Nifedipine once-daily Study: Intervention as a Goal in Hypertension Treatment
Effect on Maximum Total Calcium Score: Values in LAD (Left Anterior Descending Coronary Artery) Geometric Mean 150 HCTZ/Amiloride Nifedipine GITS 146 125 120 Maximum Total Calcium Score 100 101 102 96 79 75 75 75 50 Year 1 Year 2 Year 3 Baseline
Renal FunctionEstimated Glomerular Filtration Rate (GFR) 80 p < 0.05 (for trend) 75 Nifedipine GITS ml/min 70 Hydrochlorothiazide & Amiloride 65 60 Baseline Year 1 Year 2 Year 3 Last Visit
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
