21 August 2009
The Cardio-Sis study found that tight control of systolic hypertension (<130mmHg) decreased the likelihood of left ventricular hypertrophy and a composite of clinical events, compared with usual control (<140mmHg), in non-diabetic patients with hypertension and at least one additional risk factor for cardiovascular disease. However, this is based on a disease-oriented primary outcome and the study may have been underpowered to detect a difference in the secondary, patient-oriented outcome because the number of clinical events was low and the follow-up was only two years.
Level of evidence: Level 3 (disease-oriented evidence) according to the SORT criteria.
Clinicians should continue to follow the NICE hypertension guideline, which states that the aim of treatment is to reduce blood pressure to 140/90mmHg or below in all people with readings of 160/100mmHg or more, or more than140/90mmHg if they have cardiovascular (CV) disease, their risk of CV disease is more than 20% over ten years, or they have target organ damage. Treatment thresholds and targets are lower for people with diabetes.
Drug treatment should be considered alongside lifestyle interventions to reduce blood pressure and the risk of CV disease. NICE advises that patients should be given information about the benefits and side effects of drugs so that they can make informed choices about their treatment. The patient decision aid on the hypertension section of NPC might help with this.
What is the background to this?
There is a continuous relationship between blood pressure and risk of CV disease so hypertension diagnostic criteria and treatment targets are to some extent arbitrary. Guidelines differ in both aspects but generally recognise that the lower the blood pressure the better. Randomised controlled trials have shown that in the majority of the people in the trials, current targets are not unrealistic.
Because there is limited data about how far systolic hypertension should be lowered in patients with hypertension, this Italian randomised open-label study tested the hypothesis that tight control of systolic blood pressure (<130mmHg) would be beneficial compared with usual control (<140mmHg). The study enrolled 1,111 non-diabetic patients aged 55 years or older with systolic blood pressure greater than 150mmHg (mean 163/90mmHg) and one additional risk factor for CV disease, who had been receiving antihypertensive treatment for at least 12 weeks. Patients were randomised to tight (n=558) or usual control (n=553) and followed up every 4 months for a median of two years. Seven different antihypertensive treatments could be added in on an open-label basis, tailored to the patients’ needs (see study details below).
What does this study claim?
At two-year follow-up, systolic blood pressure was less than 130mmHg in 27% of patients in the usual-control group , compared with 72% in the tight-control group (P<0.0001). 17% of patients in the usual-control group had signs of left ventricular hypertrophy (LVH) on electrocardiogram (ECG) (the primary endpoint), compared with 11% of the tight-control group (odds ratio [OR] 0.63, 95%CI 0.43 to 0.91; P=0.013). A secondary composite CV endpoint (see study details below) occurred in 9% of patients in the usual-control group and 5% of the tight-control group (hazard ratio [HR] 0.50, 95%CI 0.31 to 0.79; P=0.003).
Adverse reactions were rare, generally mild and occurred at a similar rate in both groups. The number of antihypertensive drugs used in each group was not significantly different throughout the study: in both groups, two drug classes were used at randomisation and three were used at two-year follow-up. Also, at two years, 35% of patients were taking statins and 24% were taking aspirin.
The Cardio-Sis study showed that it was possible to achieve a target systolic blood pressure below 130mmHg using, on average, three antihypertensive drugs. In addition, reducing blood pressure below this target resulted in a lower likelihood of the primary, disease-oriented outcome, LVH on ECG. LVH is a controversial choice as a sensitive surrogate marker for subsequent cardiovascular events. Although the composite CV secondary endpoint was also statistically significantly reduced, the number of clinical events was very small because of the small sample size and limited follow-up. This means that the study was probably not powered to determine conclusively whether reducing systolic hypertension to 130mmHg reduces CV events.
As an accompanying Comment points out, these results have some utility because this is the first time a well-conducted randomised trial has evaluated the CV effects of lowering systolic blood pressure below 130mmHg in patients with hypertension and at least one other CV risk factor. The HOT study has been the benchmark study in hypertension target studies for some time, along with the UKPDS intensive vs. less intensive control of blood pressure arm. Whilst the secondary composite outcome data in this study are persuasive they should be regarded as hypothesis – generating, and before guidelines are changed a systolic blood pressure treatment goal of 130mmHg should be evaluated in adequately powered double blind randomised trials with patient-orientated outcomes as the primary end point.
The goal of treatment of hypertension is to help reduce a person’s risk of CV disease. To do this, all modifiable reversible risk factors should be considered including, but not only, high blood pressure. These include supporting the person to stop smoking, have a balanced diet, take exercise, the management of dyslipidaemia etc. It may not be possible to achieve a target blood pressure but it is important to remember that any reduction in blood pressure is worthwhile. NICE guidance on hypertension advises that blood pressure should be reduced to 140/90mmHg or below in all people with readings of 160/100mmHg or more, or more than140/90mmHg if they also have CV disease, their CV disease risk is more than 20% over ten years, or they have target organ damage. Targets are lower in people who have diabetes especially if they have also got kidney, eye or cerebrovascular damage.
Although reducing hypertension to 130mmHg would result in fewer CV events on a population basis, the benefits are less clear for the individual patient. The greatest absolute benefits are gained in individuals and populations who have the highest blood pressures. Clinicians need to carefully consider whether a fourth, fifth or even sixth drug is really going to have a significantly worthwhile benefit compared to the risks, side effects and the inconvenience to the patient in taking it. A BMJ article has pointed out that guidelines are based on average findings and also that individual patients will have quite differing views on risk and acceptability of side effects. As the authors conclude, a patient’s blood pressure can be lowered until side effects are unacceptable or they wish to avoid further additions or changes to their medicines. NICE reinforces the need for patient centred care.
Verdecchia P, Staessen JA, Angeli F, et al, on behalf of the Cardio-Sis investigators.
Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet 2009;374:525–33
Open-label randomised trial in 44 centres in Italy.
1,111 non-diabetic patients with systolic blood pressure 150mmHg or higher and at least one additional CV risk factor (cigarette smoking, adverse lipid profile, family history of premature CV disease in first degree relative, previous transient ischaemic attack [TIA] or stroke, or established coronary or peripheral arterial disease) who had been receiving antihypertensive treatment for at least 12 weeks.
Intervention and comparison:
Patients were randomly assigned to a target systolic blood pressure of less than 140mmHg (usual control; n=553) or less than 130mmHg (tight control; n=558). Antihypertensive treatment was open-label and tailored to the patients’ needs. It could include a patient’s background treatment(s) plus a choice of seven drugs: furosemide 25mg daily, ramipril 5mg or 10mg daily, telmisartan 80mg daily, amlodipine 5mg or 10mg daily, bisoprolol 5mg daily, transdermal clonidine 2.5mg or 5mg daily and hydrochlorothiazide 12.5mg or 25mg daily.
The primary outcome was the prevalence of LVH on ECG at the final two-year visit. The main secondary outcome was a composite of all-cause mortality, fatal or non-fatal myocardial infarction (MI), fatal or non-fatal stroke, TIA, congestive heart failure NYHA III or IV requiring admission to hospital, angina pectoris with objective evidence of MI, new-onset atrial fibrillation, coronary revascularisation, aortic dissection, occlusive peripheral arterial disease, and renal failure requiring dialysis. Other secondary outcomes were the single components of this composite and the baseline-adjusted difference between the groups in achieved systolic blood pressure.
Over a median follow-up of 2 years systolic and diastolic blood pressure were reduced by a mean of 23.5/8.9mmHg in the usual-control group and by 27.3/10.4mmHg in the tight-control group. The primary endpoint occurred in 17.0% in the usual-control group and 11.4% of the tight-control group (OR 0.63, 95%CI 0.43 to 0.91; P=0.013). The composite CV endpoint occurred in 9.4% patients in the usual-control group and 4.8% in the tight-control group (HR 0.50, 95%CI 0.31 to 0.79; P=0.003). Side-effects were rare and did not differ significantly between the two groups.
Supported by Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) through grants from Boehringer-Ingelheim, Sanofi Aventis, and Pfizer.
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