8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

1/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

Blood pressure management in patients with atherosclerotic

cardiovascular disease

Last literature review version 18.2: May 2010 | This topic last updated: June 17, 2010

INTRODUCTION — Hypertension is the most frequent major risk factor for premature

cardiovascular disease (CVD), being more common than cigarette smoking, dyslipidemia, and

diabetes, the other major risk factors. In the INTERHEART study of patients from 52 countries,

hypertension accounted for 18 percent of the population attributable risk of a first myocardialinfarction (MI) [1]. (See "Cardiovascular risks of hypertension".)

The impact of hypertension on the risk of the development of a cardiovascular event such as

myocardial infarction, stroke or cardiovascular death is directly related to the level of blood

pressure. In addition, the majority of individuals with hypertension have one or more other risk

factors [2,3], which augment the cardiovascular risk at any level of blood pressure (figure 1) [4].

The excess risk of a future cardiovascular event attributable to hypertension is greater in

individuals with established CVD, diabetes mellitus, or chronic kidney disease compared to those

at lower risk. The 2003 Seventh Joint National Committee (JNC 7) report on high blood pressure

cited ischemic heart disease, heart failure, diabetes, chronic kidney disease, and cerebrovascular

disease as "compelling indications" for the treatment of hypertension [5]. Other considerations

include peripheral arterial disease and traditional major coronary risk factors such as cigarette

smoking and family history (table 1).

For those patients in whom a decision is made to lower blood pressure, the two most important

issues are the choice of antihypertensive agent(s) and the goal blood pressure (BP). The goal BP

in patients at increased risk for a cardiovascular event will be reviewed here. Goal BP in the

general population and in the specific settings of diabetes, proteinuric chronic kidney disease, and

heart failure are discussed separately. (See "What is goal blood pressure in the treatment of

hypertension?" and "Treatment of hypertension in patients with diabetes mellitus" and

"Antihypertensive therapy and progression of nondiabetic chronic kidney disease" and "Treatment

of hypertension in patients with heart failure".)

The choice of antihypertensive drug, assuming that the patient does not have an indication for a

particular class of drugs, are presented elsewhere. (See "Choice of therapy in essential

hypertension: Recommendations", section on 'Importance of attained blood pressure' and

"Indications and contraindications to the use of specific antihypertensive drugs".)

CLINICAL TRIALS — The benefit of BP reduction in patients at increased risk of a cardiovascular

event has been investigated in a number of major clinical trials. Some of these trials compared an

ACE inhibitor or ARB to placebo, while other trials compared two or more antihypertensive agents,

at least one of which was usually an ACE inhibitor or an ARB.

Based upon trial design, inclusion criteria, and patient population, the degree of blood pressure

lowering varied significantly in these trials. The findings in the major trials will be briefly reviewed

followed by recommendations for the goal BP.

Trials comparing blood pressure goals — Only three large trials, ACCORD BP, Cardio-Sis, and

Official reprint from UpToDate®

www.uptodate.com 

©2010 UpToDate®

AuthorsGeorge L Bakris, MDGuy S Reeder, MD

Section EditorsJuan Carlos Kaski, MD, DM,DSc, FRCP, FESC, FACC

Norman M Kaplan, MD

Deputy EditorGordon M Saperia, MD, FACC

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

2/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

HOT have directly compared blood pressure goals to test the hypothesis that lower attained blood

pressures (below the usual goal of less than 140/90 mmHg) improves patient outcomes. ACCORD

BP and Cardio-Sis, but not HOT, were limited to patients at increased cardiovascular risk other

than hypertension itself. In addition, HOT did not achieve systolic pressures below the usual goal

since the mean attained BP was 140/81 mmHg in the lowest group. As a result, the HOT trial will

not be further discussed here. The best data come from the ACCORD BP trial. (See "What is goal

blood pressure in the treatment of hypertension?", section on 'HOT trial' and "Treatment of

hypertension in patients with diabetes mellitus", section on 'HOT trial'.)

ACCORD BP trial — The ACCORD BP trial randomly assigned 4733 patients with type 2

diabetes who had cardiovascular disease or at least two additional risk factors for cardiovascular

disease to systolic blood pressure targets of either less than 120 mmHg or less than 140 mmHg

[6]. The mean attained blood pressures were 119 and 134 mmHg, respectively, compared to

139/76 mmHg at baseline.

After a mean follow up of 4.7 years, there was no significant difference in the annual rate of the

primary composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or death from

cardiovascular causes (1.87 versus 2.09 percent, hazard ratio 0.88, 95% CI 0.73-1.06). The

annual rate of stroke, a prespecified secondary outcome, was significantly lower in those with a

lower targeted BP (0.32 and 0.53 respectively; hazard ratio 0.59, 95% CI 0.39-0.89). Significantadverse events occurred in significantly more patients in the group assigned to the lower blood

pressure goal (3.3 versus 1.3 percent). ACCORD BP is discussed in detail elsewhere. (See

"Treatment of hypertension in patients with diabetes mellitus", section on 'ACCORD BP trial'.)

Cardio-Sis trial — Cardio-Sis evaluated different blood pressure goals in 1111 patients with a

systolic pressure ≥150 mmHg and at least one additional cardiovascular risk factor but without

diabetes [7]. The patients were randomly assigned to a systolic target of less than 130 mmHg

(tight-control) or less than 140 mmHg (usual-control). The mean attained blood pressures were

132/78 versus 135/79 mmHg. Although the composite secondary outcome occurred significantly

less often in the tight-control group (4.8 versus 9.4 percent; hazard ratio 0.50, 95% CI

0.31-0.79), the benefit was primarily due to a reduction in rates of new onset atrial fibrillation orcoronary revascularization.

Cardio-Sis has important limitations, including a short duration of follow-up (two years), a weak

primary end point that assessed a risk marker (electrocardiographic left ventricular hypertrophy)

not cardiovascular events, and a composite secondary end point that included unusual end points

for a hypertension trial.

Placebo-controlled trials with a mean baseline BP less than 140/90

mmHg — Placebo-controlled trials, such as HOPE, EUROPA, PEACE, CAMELOT, TRANSCEND, and

NAVIGATOR evaluated the hypothesis that ACE inhibitors or ARBs might have a direct and

clinically significant cardiovascular benefit in patients with a mean baseline BP less than 140/90

mmHg. In addition, CAMELOT and ACTION compared long-acting dihydropyridine calcium channel

blockers to placebo.

Some, but not all, of these trials demonstrated benefit from active therapy. However, patients

treated with active therapy also had lower attained blood pressures, which provided another

mechanism than angiotensin inhibition to explain any observed benefits. Some support for the

attained blood pressure being most important came from the CAMELOT trial in which

enalapril and amlodipine produced similar outcomes that were nonsignificantly better than

placebo [8].

The following provides a brief summary of the results of the major trials. In the ACCORD BP trial

described above, an attained systolic pressure of 119 mmHg provided no significantcardiovascular benefit and more drug-induced side effects compared to an attained systolic

pressure of 134 mmHg [6]. This finding is not inconsistent with the following trials that suggest

that an attained systolic pressure between 130 and 134 mmHg may provide better cardiovascular

outcomes than an attained systolic pressure between 135 and 139 mmHg.

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

3/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

Trials demonstrating benefit — Significant benefit was demonstrated with active therapy

compared to placebo in the following trials:

HOPE trial — The HOPE trial evaluated 9297 patients over the age of 55 who were at high risk

due to prior cardiovascular disease and/or diabetes mellitus with one other coronary risk factor:

at 4.5 years, cardiovascular mortality occurred in 8.1 percent and nonfatal MI in 4.8 percent [9].

The mean BP at entry was 139/79 mmHg. The patients were randomly assigned to ramipril (10

mg once daily) or placebo, given before sleep.

The primary end point was any cardiovascular event (cardiovascular death, MI, or stroke). The

trial was prematurely terminated after a 4.5-year follow-up because ramipril therapy was

associated with the following significant benefits:

- A reduction in the primary end point (14.0 versus 17.8 percent for placebo, relative risk [RR]

0.78, 95% CI 0.70-0.86) (figure 2) and in each of the individual components of the primary end

point, including cardiovascular mortality (6.1 versus 8.1 percent) [9].

- A reduction in nonfatal MI (5.6 versus 7.2 percent) and stroke (3.1 versus 4.5 percent) that

was independent of other therapies, including beta blockers, lipid lowering agents, and

aspirin [10,11].

- These benefits were seen in all subgroups, including women and men and patients with

diabetes [12,13].

(See "Treatment of hypertension in patients with diabetes mellitus".)

The benefit of ramipril in the HOPE trial was initially thought to be independent of its

antihypertensive activity, as the difference between the two groups during the course of the trial

was only 3.3/1.4 mmHg (average 135/76 mmHg with ramipril) [14]. However, the actual

difference in BP was probably substantially greater. Ramipril was given before bedtime and the

office BP was measured about 10 to 18 hours later. In a subset of 38 patients with peripheral

arterial disease, ambulatory monitoring was performed at baseline and at one year [15]. The

24-hour ambulatory pressure was significantly reduced with ramipril, largely due to a more

prominent fall in BP during the night (17/8 mmHg compared to placebo).

EUROPA trial — The EUROPA trial of 13,655 patients with stable coronary heart disease and no

heart failure was similar in design to HOPE except that the patients were at lower risk, with lower

rates of hypertension (27 versus 47 percent), diabetes, and cerebrovascular and peripheral

arterial disease [16]. The mean BP at entry was 137/82 mmHg and only 27 percent had a history

of hypertension.

The patients were randomly assigned to perindopril (8 mg once daily) or placebo. The primary

end point was cardiovascular death, MI, or cardiac arrest. At a mean of 4.2 years, there was a

significant reduction in the primary end point with perindopril therapy (8 versus 10 percent,

relative risk reduction 20 percent, 95% CI 9-29 percent). There was at least a trend toward a

similar benefit in each of the components of the primary end point and the effect was consistent

in all predefined subgroups [17,18]. Perindopril therapy was associated with a BP ofapproximately 128/78 mmHg, a value that was a mean of 5/2 mmHg lower than seen with

placebo.

CAMELOT trial — The CAMELOT trial compared amlodipine (10 mg/day) or enalapril (20

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

4/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

mg/day) to placebo in 1991 patients with known coronary disease [8]. The primary endpoint was

a composite of cardiovascular death and cardiovascular events. The mean baseline BP was 129/78

mmHg and both amlodipine and enalapril produced greater average reductions in BP than placebo

(4.8/2.5 and 4.9/2.4 versus 0.7/0.6 mmHg). (See "Choice of therapy in essential hypertension:

Recommendations", section on 'Importance of attained blood pressure'.)

Most of the events comprising the primary end point were due to coronary revascularization or

hospitalization for angina, and only these components were significantly reduced by

amlodipine (an antianginal drug) compared to enalapril and placebo. There was a nonsignificant

difference in the rate of "hard" cardiovascular end points (all-cause mortality, nonfatal MI, or

stroke) with amlodipine or enalapril compared to placebo (hazard ratio 0.70 and 0.71,

respectively, compared to placebo, 95% CI 0.41-1.21). A benefit this large, if real, would be

clinically important. However, the upper limit of the confidence interval indicates the possibility of 

harm.

Trials showing no benefit — The following trials showed no benefit from active therapy

compared to placebo even though lower blood pressures were attained.

PEACE trial — In the PEACE trial, 8290 patients with stable coronary disease were randomly

assigned to trandolapril (4 mg daily) or placebo [19]. The patients were at lower cardiovascular

risk and were more likely to have been treated with blood pressure and lipid lowering therapy

than the HOPE and EUROPA cohorts. The mean baseline BP in the PEACE trial was 133/78 mmHg.

The primary end point was a composite of cardiovascular death, nonfatal MI, or revascularization.

At 4.8 years, there was no difference in the incidence of the primary end point with

trandolapril compared to placebo (21.9 versus 22.5 percent, hazard ratio 0.96; 95% CI

0.88-1.06) even those there was a greater reduction in mean BP with trandolapril (4.4/3.6 versus

1.4/2.4 mmHg in the placebo group, mean difference 3.0/1.2 mmHg).

The lack of benefit of trandolapril in PEACE may have been due in part to a lower average

baseline BP than in HOPE or EUROPA and more aggressive baseline management of other aspectsof coronary risk (such as coronary revascularization and lipid lowering) that may have mitigated

the benefit of further BP reduction. The net effect was that the rate of cardiovascular death,

nonfatal myocardial infarction, or stroke in the placebo group in PEACE was lower than in the

ramipril and placebo groups in HOPE and in the placebo group in EUROPA and the rate of 

all-cause mortality in PEACE was similar to that of an age- and sex-matched cohort from the

general population.

TRANSCEND trial — The TRANSCEND trial randomly assigned 5926 high-risk patients who

were similar to those in HOPE but did not tolerate ACE inhibitors to either telmisartan 80 mg/day

or placebo; the mean baseline blood pressure was 141/82 mmHg [20]. At a median follow-up of

56 months, the mean blood pressure was 4.0/2.2 mmHg lower in the telmisartan group. Despite

this, there was no statistically significant difference between the two groups in the primary

composite outcome of cardiovascular death, myocardial infarction, stroke, or hospitalization for

heart failure (15.7 versus 17.0 percent, hazard ratio 0.92, 95% CI 0.81-1.05). Compared to

HOPE, there was a significantly higher rate of use of statins, beta blockers, and antiplatelet

agents in TRANSCEND.

NAVIGATOR trial — In the NAVIGATOR trial, 9306 patients with impaired glucose tolerance

and either established cardiovascular disease (24 percent) or one or more risk factors for

cardiovascular disease were randomly assigned to valsartan (160 mg/day) or placebo [21]. In

addition, all patients participated in a lifestyle intervention program. The mean blood pressure at

baseline was 140/83 mmHg.

After a median follow-up of five years, there was no significant difference in the incidence of

either an extended composite outcome of death from cardiovascular causes, nonfatal MI, nonfatal

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

5/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable

angina (14.5 versus 14.8 percent respectively) or a core composite outcome that excluded

unstable angina and revascularization (8.1 percent in both groups). The mean blood pressure

decreased significantly more in the valsartan group (6.3/4.4 versus 3.8/3.0 mmHg).

ACTION trial — In the ACTION trial, 7665 patients with chronic stable angina (52 percent had

a prior MI) were randomly assigned to long-acting nifedipine 60 mg daily or placebo [22]. The

mean baseline blood pressure of 137/80 mmHg, and at study end was significantly lower in the

nifedipine group (130/75 versus 136/78 mmHg).

The primary end point was survival free of major cardiovascular events, including death of any

cause, acute MI, refractory angina, new overt HF, debilitating stroke, and peripheral

revascularization. At a mean follow-up of 4.9 years, nifedipine therapy had no effect on the

incidence of the primary end point (4.60 versus 4.75 percent per year, hazard ratio 0.97) or

all-cause mortality alone (1.64 versus 1.53 percent per year, hazard ratio). Nifedipine did reduce

the need for coronary angiography and interventions.

Meta-analysis and limitations — Cardiovascular outcomes were evaluated in a 2009

systematic review of seven trials that compared either an ACE inhibitor or an angiotensin receptor

blocker to placebo in patients with ischemic heart disease and preserved left ventricular systolic

function [23]. Six trials of ACE inhibitor therapy (including HOPE, EUROPA, CAMELOT, and PEACE)

significantly reduced both total mortality (risk ratio 0.87, 95% CI 0.81-0.94) and nonfatal MI (risk

ratio 0.83, 95% CI 0.73-0.94).

However, two important trials described above, both of which showed no benefit, were not

included in the meta-analysis:

TRANSCEND used the ARB telmisartan [20]. When TRANSCEND was included with the ACE

inhibitor trials in the meta-analysis, the total mortality benefit was less prominent but still

statistically significant (risk ratio 0.91)

NAVIGATOR, which used valsartan, was published after the meta-analysis [21]. If this trial

were included in the meta-analysis, it would make the mortality benefit even smaller and perhaps

no longer statistically significant. However, a potentially important limitation to NAVIGATOR is

that the difference in blood pressure between the two groups was only 2.5/1.4 mmHg, which may

be insufficient to affect cardiovascular risk.

One could consider the possibility that ACE inhibitors are beneficial in patients at increased

cardiovascular risk and that ARBs might not be. However, this has not been proven to be true in

patients with other disorders, such as heart failure and proteinuric chronic kidney disease.

Additional support for the lack of a specific beneficial effect of ACE inhibitors comes from the

CAMELOT trial in which enalapril and amlodipine produced identical outcomes compared toplacebo [8].

While the meta-analysis provides some support for the use of ACE inhibitors in patients with

stable ischemic heart disease or those at very high risk, our authors and reviewers believe that

any benefit achieved comes from blood pressure lowering. Thus, we do not recommend the

preferential use of ACE inhibitors or angiotensin receptor blockers in patients with cardiovascular

disease unless there is a specific indication such as heart failure, prior myocardial infarction, or

proteinuric chronic kidney disease.

Are lower blood pressures harmful? — There is a blood pressure threshold for all patients

below which tissue perfusion is reduced to vital organs. As long as the blood pressure is lowered

gradually, this threshold does not appear to occur at current blood pressure goals. The ACCORD

BP trial of patients with type 2 diabetes who had cardiovascular disease or at least two additional

risk factors for cardiovascular disease found that cardiovascular outcomes at 4.7 years were

similar in patients with attained systolic pressures of 119 and 134 mmHg [6]. (See 'ACCORD BP

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

6/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

trial' above.)

Coronary heart disease without heart failure — For patients with coronary heart disease

without heart failure, it is possible that a lower limit exists for desirable diastolic pressure

because much of coronary filling occurs during diastole. Observations from the Framingham study

and a post hoc analysis from the INVEST trial suggested an increase in risk for patients with

cardiovascular at a diastolic pressure below 70 to 75 mmHg [24,25].

Other analyses from placebo-controlled trials of hypertension found a similar J-shaped curve for

diastolic and systolic pressures in both treated and untreated groups and for both cardiovascular

and noncardiovascular mortality (figure 3A-B) [26,27]. These findings indicate that the worse

outcomes at lower pressures are independent of antihypertensive therapy as long as the BP is

lowered slowly. This issue is discussed in detail elsewhere. (See "What is goal blood pressure in

the treatment of hypertension?", section on 'J-shaped diastolic curve' and "What is goal blood

pressure in the treatment of hypertension?", section on 'J-shaped systolic curve'.)

Heart failure — For patients with heart failure due to systolic dysfunction, many experts

consider the goal of therapy to be the lowest blood pressure that is not associated with symptoms

of hypotension or evidence of hypoperfusion (eg, worsening prerenal azotemia). In some patients

with severe HF, this may be a systolic pressure as low as 90 mmHg.

Most patients with systolic HF are treated with inhibition of the renin-angiotensin system (eg,

angiotensin converting enzyme inhibitors or angiotensin II receptor blockers), beta blockers, and,

in selected patients, an aldosterone antagonist. These agents have favorable effects on survival in

HF that are independent of their effects on blood pressure. (See "Treatment of hypertension in

patients with heart failure".)

Isolated systolic hypertension — Although there are no convincing data, there may be a

threshold diastolic BP below which adverse cardiovascular outcomes might increase in elderly

patients with isolated systolic hypertension. When treating such patients, we and others

(including JNC 7 [5]) suggest a minimum posttreatment diastolic pressure of 60 mmHg overall or

perhaps 65 mmHg in patients with known coronary artery disease unless symptoms that could beattributable to hypoperfusion occur at higher pressures. (See "Treatment of hypertension in the

elderly, particularly isolated systolic hypertension", section on 'Goal blood pressure'.)

Prior stroke — The efficacy of lowering the BP with antihypertensive therapy has been

evaluated in patients with a prior stroke, many of whom have a history of prior hypertension. This

issue is discussed in detail separately. (See "Treatment of hypertension in patients who have had

a stroke".)

GOAL BLOOD PRESSURE — Regardless of the goal BP, blood pressure reduction should be

gradual in all patients in the absence of a hypertensive emergency. In addition, patients with

isolated systolic hypertension or stenotic arterial lesions (carotid or coronary) may be at increased

risk for ischemic manifestations at lower blood pressure goals. Thus, such patients should be

monitored carefully for possible signs of hypoperfusion, such as angina or neurologic dysfunction,

and for elevations in serum creatinine, which are more likely to occur in patients with bilateral

renal artery stenosis. (See "Treatment of hypertension in the elderly, particularly isolated systolic

hypertension", section on 'Goal blood pressure' and "Treatment of bilateral atherosclerotic renal

artery stenosis", section on 'Medical therapy'.)

Patients with known atherosclerotic cardiovascular disease — As many of the relevant

studies included patients with atherosclerotic cardiovascular disease (CVD) other than coronary

heart disease, such as those with peripheral arterial or cerebrovascular disease, our

recommendations are for all patients with atherosclerosis.

The 2003 JNC 7 report recommended a goal BP of less than 140/90 mmHg in patients with

coronary heart disease (CHD), similar to that in the general hypertensive population [5]. In

contrast, guidelines published in 2007 by the American Heart Association and the European

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

7/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

Society of Hypertension/European Society of Cardiology set a goal of less than 130/80 mmHg for

patients with atherosclerotic CVD [2,28,29].

However, there is no compelling evidence supporting a goal of less than 130/80 mmHg in

patients with atherosclerotic CVD as evidenced from the clinical trial data presented above:

In the ACCORD BP trial, there was no significant difference in cardiovascular outcomes at a

mean attained systolic pressure of 119 compared to 134 mmHg [6]. It is theoretically possible

that outcomes were better at a blood pressure between 125 and 129 mmHg and then becameworse at lower pressures. Subgroup analyses in the future may address this issue. (See 'ACCORD

BP trial' above.)

The placebo-controlled trials cited above provide some (HOPE, EUROPA, and possibly

CAMELOT trials) but not consistent support (PEACE, TRANSCEND, ACTION, NAVIGATOR, and

ACCORD BP trials) for administering additional antihypertensive therapy in patients with a

baseline blood pressure already below 140/90 mmHg. A meta-analysis of most of these trials

showed significant benefit from angiotensin inhibition compared to placebo [23]. (See

'Placebo-controlled trials with a mean baseline BP less than 140/90 mmHg' above.)

It is difficult to reach a confident conclusion about the optimal goal blood pressure in patientswith atherosclerotic CVD from the above observations. Patients in the two major positive trials

(HOPE and EUROPA) had baseline systolic pressures of 139 and 137 mmHg, respectively, whereas

a major negative trial PEACE had a baseline pressure of 133 mmHg.

Based upon these observations:

We recommend a goal blood pressure of less than 140/90 mmHg compared to higher values

in all patients with atherosclerotic CVD.

In patients with a systolic pressure of 135 to 139 mmHg, we suggest (a weaker

recommendation) an attempt to lower the systolic pressure below 135 mmHg by either adding

one antihypertensive drug or increasing the dose of a drug already being given (that is not at

maximal recommended dose) without producing significant side effects. However, given the

available data, it would not be wrong to stop at a goal less than 140 mmHg.

Antihypertensive therapy should be accompanied by management of other risk factors. (See

"Secondary prevention of cardiovascular disease: Risk factor reduction".)

Patients at high risk for atherosclerotic cardiovascular events — A separate issue related to

goal blood pressure, is whether the recommendations in the preceding section on patients with

atherosclerotic cardiovascular disease apply to patients who are at risk (eg, smoker,

hyperlipidemia) but do not have documented disease. No studies have been performed to assess

goal blood pressure in these patients [2] and, given the weak evidence supporting of goal of lessthan 135/85 mmHg in patients who already have cardiovascular disease, we recommend a goal

blood pressure equivalent to that in the general hypertensive population (less than 140/90

mmHg) in patients at increased cardiovascular risk. (See "What is goal blood pressure in the

treatment of hypertension?".)

Patients with diabetes mellitus or chronic kidney disease — Patients with diabetes mellitus

and chronic kidney disease are also at increased cardiovascular risk. Issues related to goal blood

pressure in these disorders are discussed separately. (See "Treatment of hypertension in patients

with diabetes mellitus", section on 'Goal blood pressure' and "Antihypertensive therapy and

progression of nondiabetic chronic kidney disease", section on 'Goal blood pressure'.)

SUMMARY AND RECOMMENDATIONS — Trials of antihypertensive therapy in patients with

different levels of risk for a cardiovascular event have shown benefit, particularly in individuals

with atherosclerotic cardiovascular (CVD) disease or those at very high risk, such as patients with

diabetes or chronic kidney disease. The higher the starting blood pressure, the more likely benefit

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

8/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

from treatment will be seen. For patients with hypertension, the minimum goal of therapy (less

than 140/90 mmHg) is well established. (See "What is goal blood pressure in the treatment of

hypertension?".)

However, whether there is benefit from a lower goal blood pressure (such as less than 135/85 or

even 130/80 mmHg) for those with atherosclerotic CVD (coronary artery disease, peripheral

arterial disease, abdominal aortic aneurysm, diabetes, and/or cerebrovascular disease) has not

been well defined.

For hypertensive patients with established atherosclerotic CVD (see 'Patients with known

atherosclerotic cardiovascular disease' above:

We recommend antihypertensive therapy to lower the blood pressure to less than 140/90

mmHg compared to higher pressures (Grade 1B).

We suggest a goal blood pressure of less than 135/85 mmHg, rather than less than 140/90

mmHg, for patients in whom this goal can be attained by either adding one antihypertensive drug

or increasing the dose of a drug already being given (that is not at maximal recommended dose)

without producing significant side effects (Grade 2C). However, a goal blood pressure of less

than 140/90 mmHg is reasonable for patients who do not want to increase the intensity of

antihypertensive therapy.

For hypertensive patients at high risk for atherosclerotic CVD (see 'Patients at high risk for

atherosclerotic cardiovascular events' above:

We recommend a goal blood pressure less than 140/90 mmHg compared to higher values,

similar to that in the general hypertensive population (Grade 1C).

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

Yusuf, S, Hawken, S, Ounpuu, S, et al. Effect of potentially modifiable risk factors associatedwith myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet 2004; 364:937.

1.

Mancia, G, De Backer, G, Dominiczak, A, et al. 2007 Guidelines for the management ofarterial hypertension: The Task Force for the Management of Arterial Hypertension of theEuropean Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).Eur Heart J 2007; 28:1462.

2.

Mancia, G, Parati, G, Borghi, C, et al. Hypertension prevalence, awareness, control andassociation with metabolic abnormalities in the San Marino population: the SMOOTH study. JHypertens 2006; 24:837.

3.

Jackson, R, Lawes, CM, Bennett, DA, et al. Treatment with drugs to lower blood pressure andblood cholesterol based on an individual's absolute cardiovascular risk. Lancet 2005;365:434.

4.

Chobanian, AV, Bakris, GL, Black, HR, Cushman, WC. The Seventh Report of the JointNational Committee on Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure: The JNC 7 Report. JAMA 2003; 289:2560.

5.

Cushman, WC, Evans, GW, Byington, RP, et al. Effects of intensive blood-pressure control intype 2 diabetes mellitus. N Engl J Med 2010; 362:1575.

6.

Verdecchia, P, Staessen, JA, Angeli, F, et al. Usual versus tight control of systolic blood

pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomisedtrial. Lancet 2009; 374:525.

7.

Nissen, SE, Tuzcu, EM, Libby, P, et al. Effect of antihypertensive agents on cardiovascularevents in patients with coronary disease and normal blood pressure: the CAMELOT study: arandomized controlled trial. JAMA 2004; 292:2217.

8.

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

9/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

16 19/11/2010 12:08

Yusuf, S, Sleight, P, Pogue, J, et al. Effects of an angiotensin-converting-enzyme inhibitor,ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes PreventionEvaluation Study Investigators. N Engl J Med 2000; 342:145.

9.

Dagenais, GR, Yusuf, S, Bourassa, MG, et al. Effects of ramipril on coronary events inhigh-risk persons: results of the Heart Outcomes Prevention Evaluation study. Circulation2001; 104:522.

10.

Bosch, J, Yusuf, S, Pogue, J, et al. Use of ramipril in preventing stroke: double blindrandomised trial. BMJ 2002; 324:699.

11.

Lonn, E, Roccafonte, R, Yi, Q, et al. Effect of long-term therapy with ramipril in high-riskwomen. J Am Coll Cardiol 2002; 40:693.

12.

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetesmellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes PreventionEvaluation (HOPE) Study Investigators. Lancet 2000; 355:253.

13.

Sleight, P, Yusuf, S, Pogue, J, et al. Blood-pressure reduction and cardiovascular risk inHOPE study. Lancet 2001; 358:2130.

14.

Svensson, P, de Faire, U, Sleight, P, et al. Comparative effects of ramipril on ambulatory andoffice blood pressures: a HOPE Substudy. Hypertension 2001; 38:E28.

15.

Fox, KM. Efficacy of perindopril in reduction of cardiovascular events among patients with

stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentretrial (the EUROPA study). Lancet 2003; 362:782.

16.

Daly, CA, Fox, KM, Remme, WJ, et al. The effect of perindopril on cardiovascular morbidityand mortality in patients with diabetes in the EUROPA study: results from the PERSUADEsubstudy. Eur Heart J 2005; 26:1369.

17.

Brugts, JJ, Boersma, E, Chonchol, M, et al. The cardioprotective effects of theangiotensin-converting enzyme inhibitor perindopril in patients with stable coronary arterydisease are not modified by mild to moderate renal insufficiency: insights from the EUROPAtrial. J Am Coll Cardiol 2007; 50:2148.

18.

Braunwald, E, Domanski, MJ, Fowler, SE, et al. Angiotensin-converting-enzyme inhibition instable coronary artery disease. N Engl J Med 2004; 351:2058.

19.

Yusuf, S, Teo, K, Anderson, C, et al. Effects of the angiotensin-receptor blocker telmisartanon cardiovascular events in high-risk patients intolerant to angiotensin-converting enzymeinhibitors: a randomised controlled trial. Lancet 2008; 372:1174.

20.

McMurray, JJ, Holman, RR, Haffner, SM, et al. Effect of valsartan on the incidence ofdiabetes and cardiovascular events. N Engl J Med 2010; 362:1477.

21.

Poole-Wilson, PP, Lubsen, PJ, Kirwan, BA, et al. Effect of long-acting nifedipine on mortality

and cardiovascular morbidity in patients with stable angina requiring treatment (ACTIONtrial): randomised controlled trial. Lancet 2004; 364:849.

22.

Baker, WL, Coleman, CI, Kluger, J, et al. Systematic review: comparative effectiveness ofangiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemicheart disease. Ann Intern Med 2009; 151:861.

23.

D'Agostino, RB, Belanger, AJ, Kannel, WB, Cruickshank, JM. Relation of low diastolic bloodpressure to coronary heart disease death in presence of myocardial infarction: TheFramingham study. BMJ 1991; 303:385.

24.

Messerli, FH, Mancia, G, Conti, CR, et al. Dogma disputed: can aggressively lowering bloodpressure in hypertensive patients with coronary artery disease be dangerous?. Ann InternMed 2006; 144:884.

25.

Boutitie, F, Gueyffier, F, Pocock, S, et al. J-shaped relationship between blood pressure andmortality in hypertensive patients: new insights from a meta-analysis of individual-patientdata. Ann Intern Med 2002; 136:438.

26.

Staessen, J, Bulpitt, C, Clement, D, et al. Relation between mortality and treated blood

pressure in elderly patients with hypertension: report of the European Working Party onHigh Blood Pressure in the Elderly. BMJ 1989; 298:1552.

27.

Rosendorff, C, Black, HR, Cannon, CP, et al. Treatment of hypertension in the preventionand management of ischemic heart disease: a scientific statement from the American HeartAssociation Council for High Blood Pressure Research and the Councils on Clinical Cardiology

28.

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

10/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

of 16 19/11/2010 12:08

and Epidemiology and Prevention. Circulation 2007; 115:2761.

Graham, I, Atar, D, Borch-Johnsen, K, et al. European guidelines on cardiovascular diseaseprevention in clinical practice: executive summary. Eur Heart J 2007; 28:2375.

29.

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

11/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

of 16 19/11/2010 12:08

GRAPHICS

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

12/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

of 16 19/11/2010 12:08

Cumulative absolute risk of CVD at five years

Cumulative absolute risk of cardiovascular disease (CVD) at five

years according to systolic blood pressure and specified levels ofother risk factors. The reference category is a nondiabetic,nonsmoking 50 year-old woman with a serum total cholesterol (TC)of 154 mg/dL (4.0 mmol/L) and HDL-cholesterol of 62 mg/dL (1.6mmol/L). The CVD risks are given for systolic blood pressure levelsof 110, 130, 150, and 170 mmHg. In the other categories, theadditional risk factors are added consecutively. As an example, thediabetes category is a 50-year-old diabetic man who is a smokerand has a total cholesterol (TC) of 270 mg/dL (7 mmol/L) andHDL-cholesterol of 39 mg/dL (1 mmol/L). Adapted from Jackson, R,Lawes, CM, Bennett, DA, et al, Lancet 2005; 365:434

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

13/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

of 16 19/11/2010 12:08

Components of cardiovascular risk factors in patients with hypertension

Major risk factors

Hypertension

Cigarette smoking

Obesity (BMI ≥30 kg/m2)

Physical inactivity

Dyslipidemia

Diabetes mellitus

Microalbuminuria or estimated GFR 55 years for men, >65 years in women

Family history of premature coronary disease

Men -

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

14/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

of 16 19/11/2010 12:08

Ramipril improves the outcome in high risk patients

The HOPE trial randomized 9541 patients at high risk for a

cardiovascular event to ramipril or placebo; after a 4.5 yearfollow-up, ramipril significantly reduced the incidence of thecomposite endpoint of death from cardiovascular causes,myocardial infarction, or stroke (14.1 versus 17.7 percent forplacebo, relative risk 0.78, p

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

15/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

of 16 19/11/2010 12:08

Lack of true J-shaped curve in diastolic pressure

Age- and sex-adjusted mortality rates (per 1000 patient years,

bars show the 95 percent confidence intervals) according toachieved diastolic pressure in active treatment and control groups

in a meta-analysis of seven randomized clinical trials ofhypertensive patients. The number of events is shown below eachbar. Among treated patients, cardiovascular mortality initially fallsat achieved diastolic pressures below 106 mmHg and then risesagain at low diastolic pressures (upper right panel). However, asimilar relationship is seen with noncardiovascular mortality(bottom right panel) and in the control groups (left panels). Thus,the increase in mortality at low diastolic pressures probablyreflects underlying poor health rather than an adverse effect of

antihypertensive therapy. Data from Boutitie, F, Gueyffier, F, Pocock, S,et al, Ann Intern Med 2002; 136:438.

8/9/2019 Blood Pressure Management in Patients With Atherosclerotic CA..

16/16

od pressure management in patients with atherosclerotic cardiovas... http://www.uptodate.com/online/content/topic.do?topicKey=hyperten...

Lack of true J-shaped curve in systolic pressure

Age- and sex-adjusted mortality rates (per 1000 patient years, bars

show the 95 percent confidence intervals) according to achievedsystolic pressure in active treatment and control groups in ameta-analysis of seven randomized clinical trials of hypertensivepatients. The number of events is shown below each bar. Amongtreated patients, cardiovascular mortality initially falls at achievedsystolic pressures below 180 mmHg and then rises again at lowsystolic pressures (upper right panel). However, a similarrelationship is seen with noncardiovascular mortality (bottom rightpanel) and in the control groups (left panels). Thus, the increase inmortality at low diastolic pressures probably reflects underlyingpoor health rather than an adverse effect of antihypertensive

therapy. Data from Boutitie, F, Gueyffier, F, Pocock, S, et al, Ann Intern Med

2002; 136:438.

© 2010 UpToDate, Inc. All rights reserved. |  Subscription and License Agreement  | Support Tag:[ecapp1104p.utd.com-152.118.148.218-7D2683CB66-6-11177766]Licensed to: UpToDate Individual Web - Ginova Nainggolan