Evidence Based Medicine Conference
Marcus Muehlbauer
03-12-10
Title: Usual vs. tight control of systolic blood pressure in non-diabetic patients with
hypertension (Cario-Sis): an open-label randomized trial
Lancet, August 15, 2009, Vol. 374
I. Background
Hypertension is one of the most common worldwide diseases afflicting humans. Because of the
associated morbidity and mortality and the cost to society, hypertension is an important public
health challenge. Over the past several decades, extensive research and patient education,
have led to decreased mortality and morbidity rates from the multiple organ damage arising
from years of untreated hypertension. Hypertension is the most modifiable risk factor for
coronary heart disease, peripheral vascular disease, congestive heart failure, stroke and endstage renal disease.
Clinically important question which should have been answered (but was not) is:
Does a tighter BP control decrease overall mortality of coronary heart disease, peripheral
vascular disease, congestive heart failure, stroke and end-stage renal disease?
II. Study design:
 Randomised, open-label, multi-center , controlled trial.
 Stratification was done by centre.
 Intention to treat analysis.
 Primary endpoint was the rate of left ventricular hypertrophy
(LVH) 2 years after randomisation.
 Secondary endpoint was all cause morbidity
during the 2 year period.
Unfortunately the primary endpoint of this study is LVH which is shown to be linked to increased
risk of premature death and morbidity (Framingham Heart Study) but instead of the goldstandard (echocardiogram) EKG criteria with a positive predictive value of only 66% was used.
Am J Hypertens (2005) 18, 100A–100A
III. Methods:
 Enrollment of 1111 non-diabetic patients 55 years or older
with systolic BP >150mmHg and at least one risk factor.
 Risk factors:
- tobacco abuse
- total cholesterol >5.2mmol/L
- HDL cholesterol <1 mmol/L
- LDL cholesterol >3.4 mmol/L
- family history of premature cardiovascular disease in first degree
relative
- previous TIA or stroke, CAD or PVD
 Randomisation in
tight control group (syst. BP <130mmHg; n=558)
usual control group (syst. BP <140mmHg; n=553)
 Use of open-label medication
The study design and methods were well done (randomized, intention to treat) although the
sample size was somewhat small. One critique point is that medication was “down-titrated” in
usual control group patients who dropped below 130 mmHg (contradicting current guidelines).
IV. Results
 Blood pressure difference between the 2 groups averaged 3.8mmHg systolic
(p<0.0001) and 1.5mmHg diastolic (p<0.041) 135.6/78.7mmHg (usual) and
131.9/77.4mmHg (tight)
 Significant reduction of LVH prevalence in tight vs. usual control group
(p=0.008)
 Significant reduction of composite outcomes only for new onset atrial fibrillation
and coronary revascularization and not for the important mortalities as mentioned
above (see clinically important question)
V. Discussion:
Unfortunately the outcomes were only significantly better for LVH prevalence (diagnosed with
EKG only). There was no significant difference in overall mortality once atrial fibrillation and
coronary revascularization were excluded and therefore no recommendation for a tighter blood
pressure control can be made alone from this study. Hopefully the patients will be followed
along so that data will be available for the important endpoints (overall mortality of coronary
heart disease, peripheral vascular disease, congestive heart failure, stroke and end-stage renal
disease). Another weakness is the population which was strictly white and extrapolation to other
countries is difficult.
On a positive note it was the first study after almost a decade to investigate blood pressure
control in non-diabetics. Expiring patents may allow us to treat hypertension more costeffectively in the future and according to this study at least the side-effect profile for tighter
control was acceptable (although there are publications which suggest a so called J-curve
phenomenon: Higher mortality in pts. with tight BP control).
Original paper discussed:
Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (CardioSis): an open-label randomised trial.
Verdecchia P, Staessen JA, Angeli F, de Simone G, Achilli A, Ganau A, Mureddu G, Pede S, Maggioni AP,
Lucci D, Reboldi G; Cardio-Sis investigators.
Lancet. 2009 Aug 15;374(9689):525-33. Erratum in: Lancet. 2009 Sep 12;374(9693):880.