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 Efficacy
Mean Blood Pressure
Nifedipine GITS
Hydrochlorothiazide
& Amiloride
180
173 mmHg
mmHg
160
138 mmHg
140
Systolic
120
100
99 mmHg
82 mmHg
80
Diastolic
60
Week 0
2
4
8 12 18 36
70 87
Year
1
121 138
Year
2
173 190
Year
3
225 242
Year
4
Nifedipine GITS
Cumulative Proportion Surviving
Overall Mortality
Hydrochlorothiazide
& Amiloride
1.01
1.00
p = 0.72
0.99
0.98
0.97
0.96
0.95
0.94
0.93
0.92
0
400
800
1,200
Time (Days)
1,600
2,000
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
0.5
0.6 0.7 0.8 0.9 1.0
Nifedipine GITS
better
1.1 1.2 1.3 1.4 1.5
Hydrochlorothiazide
& Amiloride better
Overview: Individual and Combined Endpoints
Relative Risk and 95% Confidence Interval
p
0.91
Stroke
0.61
1.27
Myocardial Infarction
0.17
0.74
Sudden Death
0.43
1.09
Other Cardiovascular Death
0.85
2.17
Heart Failure
0.023
1.11
All Primary Endpoints
0.34
All Cardiovascular Morbidity
and All-Cause Mortality
0.96
0.62
All Primary and Secondary Endpoints
0.2
0.4
0.6 0.8
Nifedipine GITS
better
1.0 1.2 1.4 1.6 1.8
Hydrochlorothiazide
& Amiloride better
Sudden Death and Death of ”Unknown Cause”
Number of Endpoints
60
Sum: 39
50
57
18
Death of ”Unknown Cause”:
Insufficient Information
16
Death of ”Unknown Cause”:
Probably Cardiovascular*
18
40
10
30
12
20
10
23
17
Sudden Death
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
Cardiovascular Endpoints
per 1,000 Patient Years
(Risk reduction estimated from Framingham data)
30
34
50%*
* > 35%
risk reduction
estimated from
MONICA data
20
17
10
0
Predicted
Observed
from cardiovascular
risk profiling at baseline
in all INSIGHT
patients
Hypertension Trials

Short term

Mortality/Morbidity based

Surrogate End-points “intriguing”
Side-arm Studies and Additional Analyses
Side-arm
studies
Additional
analyses
Diabetes
Intima media
thickness
INSIGHT
Coronary
calcification
Renal
function
High-risk
patients
Emergence
Nifedipine GITS
Hydrochlorothiazide
& Amiloride
of New Diseases*
% of Patients
6
5.6
5.3
4
4.3
3.0
2
2.1
1.3
0
Gout1
p < 0.01
Peripheral
Vascular Disorder1
p < 0.01
Diabetes2
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
IntimaMedia
Thickness
in the
Trial
International Nifedipine once-daily Study:
Intervention as a Goal in Hypertension Treatment
IMT Change from baseline (mm)
Impact on Intima-Media Thickness
0.040
HCTZ/
Amiloride
Progression
0.030
0.020
0.010
0
Nifedipine
GITS
-0.010
Regression
0
1
2
Follow-up (years)
3
4
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
Maximum
Total Calcium Score
150
HCTZ/Amiloride
Nifedipine GITS
146
125
120
100
101
79
75
75
50
Baseline
96
102
75
Year 1
Year 2
Year 3
Renal Function
Estimated Glomerular Filtration Rate (GFR)
80
p < 0.05 (for trend)
75
ml/min
Nifedipine GITS
70
Hydrochlorothiazide
& Amiloride
65
60
Baseline
Year 1
Year 2
Year 3
Last Visit
Conclusions

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