SIGN 97: Risk estimation and the prevention of cardiovascular disease

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10 Blood pressure lowering

Elevated blood pressure (BP) increases the risk of CHD, heart failure, stroke and renal failure.249 Systematic reviews of trials of antihypertensive drugs versus placebo have shown that blood pressure lowering is associated with reductions in CHD, stroke, heart failure, and cardiovascular and total mortality.250 Evidence level 1++

A dietary pattern low in total fat, saturated fatty acids, and dietary cholesterol, and rich in fruits, vegetables, and low-fat dairy products can produce blood pressure reductions exceeding 11/5 mm Hg in people at higher cardiovascular risk.251 Weight loss, the restriction of dietary sodium, and regular intake of oily fish may enhance these effects (see section 4).252,253 Evidence level 1+

10.1 Blood pressure thresholds for intervention with drug therapy

The relationship between blood pressure and cardiovascular risk is approximately linear between the values of 115/70 and 170/100 mm Hg. Within this range, treatment results in similar relative benefitsregardlessofthebaselinebloodpressure.254 People at greater cardiovascular risk derive the most absolute benefit from treatment and are subject to lower intervention thresholds. Evidence level 2++

Lowering blood pressure has been shown to reduce the risk of both cardiovascular and total mortality, without adverse effect on quality of life. Trials of antihypertensive drugs show a similar relative reduction in coronary heart disease risk of 15-25% and reduction in ischaemic stroke risk of 30-40%.179,255-259 One Health Technology Assessment shows that the risk from pre-existing vascular disease strongly outweighs any other risk factor calculation, and concludes that all such patients should be offered, and will benefit from, blood pressure lowering. Lowering diastolic blood pressure by 5 mm Hg reduces the risk of stroke by an estimated 34% and ischaemic heart disease by 21% from any pre-treatment level and there is no threshold.260 Evidence level 1++, 4

The British Hypertension Society guideline38 indicates that the following lifestyle activities are associated with a potential reduction in blood pressure:

Evidence level 4

[Good practice point] All individuals with a persistent blood pressure =140/90 mm Hg or a family history of hypertension should receive lifestyle advice to help reduce their blood pressure and CVD risk. Lifestyle advice should continue even when drug therapy is initiated.

10.1.1 Blood pressure thresholds for individuals with symptomatic cardiovascular disease

Randomised controlled trials show a benefit in treating people with established cardiovascular disease or diabetes irrespective of baseline blood pressure.255,257,261 Evidence level 1++

AIndividuals with sustained systolic blood pressures >140 mm Hg systolic and/or diastolic blood pressures >90 mm Hg and clinical evidence of cardiovascular disease should be considered for blood pressure lowering drug therapy.

People with established cardiovascular disease, who also have chronic renal disease or diabetes with complications, or target organ damage may be considered for treatment at the lower threshold of systolic >130 mm Hg and/or diastolic >80 mm Hg.28 These individuals are assumed to be at even greater risk of cardiovascular events and are targeted with more aggressive thresholds for treatment. Data regarding the optimal treatment regimen of older individuals are sparse. Treatment decisions should balance potential benefits in the context of other comorbidities. Blood pressure lowering will reduce stroke and CHD, although no benefit on overall mortality has yet been demonstrated.262 Evidence level 1++, 4

The Joint British Societies' guideline on the prevention of cardiovascular disease defines target organ damage as any of the following:28

AIndividuals with established cardiovascular disease, who also have chronic renal disease or diabetes with complications, or target organ damage may be considered for treatment at the lower threshold of systolic >130 mm Hg and/or diastolic >80 mm Hg.

10.1.2 Blood pressure thresholds for individuals without symptomatic

The following good practice points are based on the recommendations from the JBS2 and British Hypertension Society guidelines:28,38 Evidence level 4

[Good practice point]

Persistent blood pressure elevation =160 mm Hg systolic and/or =100 mm Hg diastolic causes sufficient CVD risk on the basis of blood pressure levels alone to require drug therapy to reduce blood pressure.28,45 Evidence level 2++, 4

BIndividuals with blood pressure greater than 160/100 mm Hg should have drug treatment and specific lifestyle advice to lower their blood pressure and risk of cardiovascular disease.

10.2 Target values for blood pressure lowering

The relationship between blood pressure and cardiovascular risk is continuous and there has been a lowering of targets over recent years as evidence of benefit and safety has accumulated. The evidence for diastolic blood pressure targets179 is more robust than that for systolic BP, although for most patients above 50 years, systolic BP appears to be more important for the prediction of adverse CVD outcomes.254

Evidence for an optimal level of diastolic blood pressure, drawn from a large meta-analysis of antihypertension intervention trials, indicates that the further the diastolic blood pressure can be reduced, the greater the reduction in cardiovascular risk without any convincing evidence of a J-curve relationship.263 The Hypertension Optimal Treatment (HOT) trial reported that the optimal target blood pressure in patients with a diastolic BP of 100-115 mm Hg was 139/83 mm Hg. Reduction of BP below the optimal level caused no harm.179 Evidence level 1++

The cost effectiveness of different targets for the reduction in BP was analysed using clinical data from the HOT trial.264 The trial randomised patients to three target groups for diastolic BP, with the hypothesis that the lower the target, the better the outcome but the higher the drug costs. The clinical trial showed no statistical difference in the number of events avoided for the three target groups. Significant reductions in event rates were found in a subset analysis of people with diabetes, which limited the cost effectiveness analysis to this group. The study concluded that in patients with diabetes, compared to maintenance doses of calcium channel blockers, intensive treatment to a lower blood pressure target (=80 mm Hg), was cost effective.

[Good practice point] Treatment targets defined by the Joint British Societies state optimal blood pressure control for patients at high cardiovascular risk (established cardiovascular disease or asymptomatic patients with a ten year risk of CVD =20%) as <140/85 mm Hg.

[Good practice point] For individuals with established CVD and diabetes, chronic renal disease or target organ damage a lower blood pressure target of <130/80 mm Hg is recommended.

10.3 Selection of antihypertensive therapy

There are four major classes of antihypertensive drug (thiazides, angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists (ARB) and calcium channel blockers) which are about as effective as each other and more effective than beta-blockers at reducing cardiovascular morbidity and mortality per unit fall in blood pressure. There are some important cautions and contraindications for all of the antihypertensive drug classes.263,266,267 Evidence level 1++

In a meta-analysis, the five main categories of blood pressure lowering drugs all significantly reduce blood pressure from all pre-treatment levels. The extent of blood pressure reduction increased with pre-treatment blood pressure. The reductions were similar at standard dose for the five categories; average reduction was 9.1 mm Hg systolic and 5 mm Hg diastolic. The effect of combinations of two drugs on blood pressure was additive.260 The adverse effect profiles of drugs could be minimised by using half-standard or standard doses, rather than titrating any given drug to higher doses. This does not apply to ACE inhibitors or ARBs, where the adverse effects are present or absent, regardless of dose. The meta-analysis presents a rationale for polypharmacy, utilising modest doses of more than one antihypertensive agent in order to maximise control whilst minimising adverse effects. Evidence level 1++

The ASCOT-BPLA study recruited 19,257 patients, including many from Scotland, to treatment by two combinations of antihypertensive drugs.268 The study tested whether a newer antihypertensive combination treatment, comprising the calcium channel blocker (CCB) amlodipine and the ACE inhibitor perindopril, was more effective than an older combination regimen of the beta- blocker atenolol and the diuretic bendroflumethiazide. The trial was terminated early because of a large difference in mortality between the older drugs and the newer ones, favouring the amlodipine+perindopril combination. The trial showed that amlodipine+perindopril were significantly more effective at reducing strokes (327 vs 422; unadjusted hazard ratio (HR) 0.77, 95% CI 0.66 to 0.89, p=0.0003), total cardiovascular events (1362 vs 1602; HR 0.84, 95% CI 0.78 to 0.90, p<0.0001) and all cause mortality (738 vs 820; HR 0.89, 95% CI 0.81 to 0.99, p=0.025) than atenolol with bendroflumethiazide. Evidence level 1++

A large RCT of 33,357 patients reported on blood pressure lowering in individuals with high global risk and hypertension. A significant proportion of the subjects had overt vascular disease as manifested by previous cardiovascular events (MI, stroke), or ongoing symptoms (angina, intermittent claudication). All had moderate hypertension, on therapy or untreated. Extensive analysis of this trial and data subsets shows evidence of reduced event rate regardless of starting blood pressure, within the parameters of trial inclusion.269 Participants were randomised to receive a thiazide-like diuretic (chlorthalidone, 12.5 to 25 mg daily); a calcium channel blocker (amlodipine, 2.5 to 10 mg daily); or an ACE inhibitor (lisinopril, 10 to 40 mg daily). There was no significant difference between groups in combined fatal CHD or non-fatal myocardial infarction. Five year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, p=0.03) and lisinopril (2 mm Hg, p<0.001) groups compared with chlorthalidone, and five year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, p<0.001). For amlodipine vs chlorthalidone, outcomes were similar except for a higher six year rate of heart failure with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI 1.25 to 1.52). Evidence level 1++

[Good practice point] In any individual with hypertension, consideration should be given to using two or more antihypertensive agents, in half to standard doses, to achieve additive blood pressure lowering whilst minimising the adverse effect profile.

10.3.1 The British Hypertension Society algorithm

The British Hypertension Society AB/CD algorithm has been widely adopted for deciding drug therapy for an individual.38 The algorithm was substantially ratified by the ASCOT trial and AB/ CD has now been accepted by JBS2 as the best method of defining combination drug therapy.

The AB/CD algorithm was designed to improve blood pressure control based on age-related renin levels and appropriate combinations.

In June 2006 the National Institute for Clinical Health and Excellence (NICE) and the BHS jointly released a revised guideline that updated the clinical evidence base to include recent meta-analyses and RCTs and included a cost effectiveness analysis comparing the various blood pressure lowering drug classes.270 The results showed that:

The recommendations based on this evidence are summarised in the A/CD algorithm shown in

Figure1.Itincorporatesallclassesofantihypertensivedrugs.Althoughnotspecificallyvalidated by a clinical trial, the recommended drug combinations and sequencing are similar to those used in many clinical trials of blood pressure lowering drugs.

Figure 1: The British Hypertension Society A/CD algorithm for blood pressure

Figure 1: The British Hypertension Society A/CD algorithm for blood pressure

A = ACE inhibitor (* or ARB if intolerant to ACE inhibitor), C = calcium channel blocker

D = thiazide-type diuretic.

Beta blockers are not a preferred initial therapy for hypertension but are an alternative to ACE inhibitors in patients <55 years in whom ACE inhibitors or ARBs are not tolerated, or contraindicated (includes women of childbearing potential). Black patients are only those of African or Caribbean descent. In the absence of evidence, all other patients should be treated according to the algorithm as non-black.

10.4 Multiple risk interventions

One Cochrane review investigated the effects of multiple risk factor interventions on blood pressure, cholesterol and smoking in primary prevention.271 Individuals with the highest baseline blood pressure, smoking and cholesterol levels showed the largest reductions in event rates following intervention. Pooled effects suggest that multiple risk factor intervention has no 1+ effect on mortality. Multiple interventions appear to be more effective in high risk populations. Treating large numbers of individuals in low risk populations may result in small treatment benefits being outweighed by small treatment risks.272,273 Evidence level 1+

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