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Blood Pressure Reduction and Cardiovascular Outcomes:Past, Present, and Future

Giuseppe Mancia, MD

Hypertension has not always been recognized as a harbinger of cardiovascularcomplications and premature death. Only 70 years ago, hypertension was consideredthe body’s adaptation to sclerotic blood vessel disease and essential to maintain organperfusion; thus, treatment was regarded as undesirable. Epidemiologic studies havesince established a strong linear relation between blood pressure and cardiovasculardisease (CVD), and randomized trials have documented that blood pressure reduc-tions by antihypertensive drugs confer cardiovascular protection, making the hyper-tension-related risk a reversible risk. There is now a consensus that blood pressureshould be reduced to <140/90 mm Hg in all patients and that a more aggressive bloodpressure target (<130/80 mm Hg) should be pursued in those in whom the cardio-vascular risk is high. Despite this, blood pressure control remains elusive in mostindividuals in the hypertensive population, which makes improvement of bloodpressure control in this population a priority goal. This goal may meet with newchallenges, however. Optimal blood pressure control may have to include the mea-surement of blood pressure every day, given the fluctuations of blood pressure andtheir prognostic importance independent of and in addition to that of classicallymeasured blood pressure values. © 2007 Elsevier Inc. All rights reserved. (Am J
Cardiol 2007;100[suppl]:3J–9J)
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ypertension is universally accepted as among the strongestrognostic markers of cerebrovascular disease and cardio-ascular disease (CVD) and of premature death,1–3 withlood pressure values bearing a continuous linear relationith the incidence of cardiac and cerebrovascular events. It

s also universally accepted that the hypertension-relatedisk is not irreversible because when elevated blood pres-ure is reduced by treatment, the long-term outcome ismproved. This view of hypertension, however, is relativelyecent. Well into the 20th century, high blood pressure wasiewed as a useful and necessary adaptation by the bodyhat did not require treatment.4 Over the past 70 years, ourttitude toward hypertension and its management hashanged radically and is, in fact, still changing. This articleriefly reviews these changes and mentions further possiblehanges that may occur in the future.

ypertension: The Past

n the early 1930s, it was widely believed that high bloodressure was an important compensatory mechanism for arimary disease that reduced the caliber of the small vessels.

Department of Medicine, University of Milan-Bicocca, San Gerardoospital, Milan, Italy.

Address for reprints: Giuseppe Mancia, MD, Department of Medicine,niversity of Milan-Bicocca, San Gerardo Hospital, Via Donizetti 106,

-20052 Monza-Milan, Italy.
uE-mail address: [email protected].
002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.05.008

n a textbook of the time, a leading US cardiologist statedhat hypertension was “essential” in forcing blood throughclerotic arteries to maintain the perfusion of target organs.4

his reflected the opinion of many physicians that hyper-ension should not be treated because of the risk for under-erfusion and vital organ damage. Indeed, President Frank-in D. Roosevelt’s sudden, high-profile death in 1945 fromerebral hemorrhage was considered by many unrelated tohe high blood pressure values consistently recorded by hishysicians during the previous 10 years.5 As with mostlinicians at the time, the President’s physicians failed to seeny association between a blood pressure value persistently200/100 mm Hg and an increased risk for cardiovascular

r cerebrovascular complications.Over the following decades, clinical perception gradually

tarted to change as 2 lines of evidence began to merge:1) hypertension was associated with an increased incidencef cardiac and vascular morbid and fatal events because ofrofoundly harmful effects on the cardiovascular system,nd (2) lowering blood pressure conferred protectiongainst these effects.

The Framingham Heart Study was among the first large-cale epidemiologic studies to establish a definitive linketween hypertension and CVD. Drawing from 36 years ofata, this community-based US study in otherwise healthyndividuals showed unequivocally that high blood pressurencreased the risk of CVD, demonstrating a striking corre-ation between hypertension and an increase in coronaryisease, stroke, peripheral arterial disease, and heart fail-
re.6
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At about the same time that the link between hyperten-ion and CVD was being forged, the first studies wereublished showing that reduction in blood pressure couldave protective effects on patients with malignant hyperten-ion, with a reduction of their otherwise extremely high ratef mortality within a few years time.7 The first landmarktudy in this area, however, was the Veterans Administra-ion Cooperative Study, which was published in the 1960s.8

his long-term, randomized, double-blind, placebo-con-rolled study involved men with severe hypertension as-igned to triple therapy with a diuretic, a centrally actinggent, and a vasodilator, or to placebo. The study reportedmarked blood pressure reduction in the treatment group

ompared with the control group. At 5-year follow-up, theisk of developing cardiovascular complications was re-uced from 55% in untreated patients to just 18% in patientseceiving antihypertensive therapy.

The favorable results obtained by the Veteran Adminis-ration study8 prompted the planning and performance ofther trials that exported considerable knowledge on theeneficial effect of antihypertensive treatment. Findingshowed that the cardiovascular protection associated withntihypertensive treatment was not limited to severe hyper-ension, but it included moderate and mild hypertension asell. In addition, in patients with hypertension who were

ged �65 years, the reduction of cardiovascular morbid andatal events was no less than in younger patients. Finally, ithowed that the clinical benefits of reducing blood pressureere not confined to cardiovascular complications. In the

arly 1980s, Parving et al9 were among the first to show thatlood pressure lowering could slow the rate of renal dete-ioration in patients with diabetic nephropathy by almost0%.

enefits of Lowering Blood Pressure

n a review of several thousand patients with hypertensionreated before 1990 mainly with diuretics or �-blockers for

mean duration of 5 years, a reduction in systolic bloodressure (SBP) of 10–12 mm Hg or in diastolic bloodressure (DBP) of 5–6 mm Hg resulted in a decrease in thencidences of stroke, coronary artery disease (CAD), con-estive heart failure, and cardiovascular death of 35%–0%, 20%–25%, 45%–55%, and 20%–25%, respectively.10

he question arising from these data was whether theserotective effects were owing to the specific protectiveroperties of the drugs used or, rather, whether they origi-ated from the lowering of blood pressure, per se. This wasddressed by studies performed in the 1990s, which haverovided several lines of evidence in favor of the latterypothesis. In these studies, the following conclusions wereade:

1. A reduction of cardiovascular complications has been
documented in trials in which antihypertensive treat- c
ment was based on drugs other than diuretics and�-blockers (ie, angiotensin-converting enzyme [ACE]inhibitors, calcium antagonists, and angiotensin IIantagonists).11

2. A meta-analysis12 of all studies published up to 2003on 162,000 patients with hypertension treated withdifferent blood pressure–lowering regimens hasshown a strongly proportional reduction in the inci-dence of stroke, CVD, CAD, cardiovascular mortal-ity, and total mortality with progressively greaterblood pressure reductions by treatment (Figure 1).

3. Retrospective analyses of data obtained in random-ized trials have shown that patients whose blood pres-sure is maintained at �140/90 mm Hg during treat-ment have a considerably better cardiovascularprognosis than those whose blood pressure remainsabove these values. In the Valsartan AntihypertensiveLong-Term Use Evaluation (VALUE) study, patientswhose blood pressure was controlled to a target of�140/90 mm Hg after 6 months’ treatment had sig-nificantly fewer cardiovascular events, stroke, myo-cardial infarction, or death from any cause (p �0.01for all comparisons) than patients whose blood pres-sure was not controlled to these values, regardless ofwhether they were treated with an angiotensin II re-ceptor blocker (ARB) or a calcium antagonist.12

4. Regardless of the type of treatment used, a greaterblood pressure reduction has been reported to be moreprotective against the cardiovascular and renal se-quelae of hypertension. A recent meta-analysispooled the effect of different blood pressure–loweringregimens in patients with diabetes mellitus (n �3,395). The results showed that intensive regimens thatproduced additional systolic/diastolic blood pressure re-ductions of 6.0/4.6 mm Hg over less intensive reduc-tions conferred correspondingly greater reductions in therisk for major cardiovascular events (p � 0.03) andcardiovascular death (p � 0.02).13

Lower blood pressure targets also have more favorableenal-protective effects in patients with renal disease. Aecent review of studies evaluating the renoprotective ef-ects of ARBs or ACE inhibitors in �70,000 patients withnd-stage renal disease found that intensive SBP reduc-ion (equating to a reduction of 6.9 mm Hg) markedlylowed not only the progression to end-stage renal failureut also the progression of microalbuminuria, a well-nown marker for renal, as well as cardiovascular, sur-ival.14

enefits of Aggressive Blood Pressure Reduction

vidence is available that in high-risk individuals with hy-ertension, greater blood pressure reductions by treatment
onfer a greater degree of cardiovascular protection com-

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5JMancia/ Blood Pressure Reduction and Cardiovascular Outcomes: Past, Present, and Future

ared with the usual blood pressure–lowering effect. Inatients with diabetes and hypertension in the Hypertensionptimal Treatment (HOT) study, for example, the group inhich the DBP target with treatment was �80 mm Hg had

bout 50% fewer cardiovascular events than the group inhich the target was �90 mm Hg.15 This was also the case

n patients with hypertension and diabetic nephropathy re-ruited for the Irbesartan in Diabetic Nephropathy TrialIDNT) in whom congestive heart failure was much lessommon if SBP was reduced to �130 mm Hg comparedith on-treatment values around 140 mm Hg.16 Reduction

igure 1. Association between systolic blood pressure changes and cardioascular outcomes and death. (A) Calcium antagonist versus placebo; (B) anersus less intensive blood pressure lowering; (D) angiotensin II receptoralcium antagonist versus diuretic or �-blocker; and (G) ACE inhibitorermission from Lancet.11)

f SBP to �130 mm Hg conferred an additional cardiovas- c

ular-protective effect in individuals with hypertensionithout diabetes but who had a high cardiovascular riskecause of a history of CVD or cerebrovascular disease.17,18

n the Perindopril Protection Against Recurrent StrokePROGRESS) study,17 6,105 patients with and without hy-ertension considered to be at high risk for future cerebro-ascular events because of previous stroke or transient isch-mic attack were assigned to drug treatment (an ACEnhibitor, plus a diuretic, if needed, or placebo). After 4ears, the incidence of stroke was reduced by 28% and thencidence of major vascular events was reduced by 26%

r (CV) disease (CVD) risk in patients with hypertension at risk for majorin-converting enzyme (ACE) inhibitor versus placebo; (C) more intensive(ARB) versus control; (E) ACE inhibitor versus calcium antagonist; (F)

diuretic or �-blocker. CAD � coronary artery disease. (Reprinted with

vasculagiotensblockerversus

ompared with placebo. The benefit was apparent both in

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he group with and in the group without blood pressure140/90 mm Hg before treatment (Figure 2).These compelling results, together with those of other

tudies, have led international guidelines to recommend anggressive approach to lowering blood pressure for all pa-ients at high risk for CVD, with the target blood pressureeing set at �130/80 mm Hg.19–21 They have also led touidelines to recommend antihypertensive drug treatment ofigh-risk individuals when blood pressure is initially140/90 mm Hg.20

Achieving optimal blood pressure control is not easy,nd the difficulty is particularly pronounced for SBP con-rol. In a review of blood pressure control in major antihy-ertensive drug trials, Mancia and Grassi22 demonstratedhat even under stringently controlled study conditions withighly motivated patients and investigators, SBP remained140 mm Hg in about 50% of patients with hypertension

uring treatment. This was despite, in most instances, �2ntihypertensive agents being administered. In patients withiabetes and hypertension, SBP control was even poorer. Ino instance did the treatment SBP decrease below the targetalue of 130 mm Hg.22

The situation is even worse in “real-life” clinical prac-ice. In 4 recently published large surveys of hypertensiveare in Italy where patients are treated by general practitio-ers, specialists, or in specialist hypertension centers, targetlood pressure control rates were alarmingly low.22–26 Evenhe specialist centers succeeded in achieving a target bloodressure of �140/90 mm Hg in only 37.5% of patients, and2% of patients had uncontrolled blood pressure (�180/100m Hg).23 Control of SBP, in particular, was poor: one

hird of patients had blood pressure values �160/95 mmg. Surveys of general practitioners and specialists revealed

hat, in these settings, even fewer patients with hypertensionchieve targets: typically only 12%–22% of patients at-ained blood pressure targets of �140/90 mm Hg.24–26

gain, patients with diabetes and hypertension fared worse

igure 2. Effects of active blood pressure–lowering treatment versus placend without hypertension. CI � confidence interval. (Adapted with permi

han their counterparts without diabetes, with only 3% of d

atients in the Italian ForLife study achieving the more strin-ent target blood pressure of �130/80 mm Hg.25

Poor rates of blood pressure control are not confined totaly. Similar trends have been documented in surveys ofatients with hypertension in the United States, Canada,ermany, Spain, and the United Kingdom, with control

ates (ie, proportion with blood pressure �140/90 mm Hg)anging from 29% in the United States, 17% in Canada, and10% in European countries.27

Consequently, international and national societies aretriving to increase the proportion of patients with hyper-ension achieving target blood pressure in the general pop-lation by (1) encouraging the use of effective, properlyosed antihypertensive agents; (2) supporting the use ofombination treatments; (3) promoting well-tolerated/sim-le dosing regimens; (4) improving information exchangeetween physicians and patients; and (5) fighting the “clin-cal inertia” that prevents blood pressure targets from beingore aggressively pursued. However, even these improve-ents may not be sufficient because the criteria that define

optimal” target blood pressure control are likely to becomever more challenging in the future.

ypertension: The Future

ecent research suggests that in the future, we may have toontrol blood pressure in different and more demandingays than have been considered previously. The specific

lements of blood pressure that are central to cardiovascularurvival are only just beginning to be understood. For ex-mple, SBP is emerging as a more prognostic indicator ofurvival than DBP.28 There is evidence to suggest that pulseressure may be a predictor of CVD independent of and inddition to SBP,29 and central (ie, aortic) blood pressure isegarded by many as clinically more relevant than the periph-ral or brachial blood pressure value.30 Finally, we know that

e incidence of stroke and major vascular events in high-risk patients withom Lancet.17)

bo on th

aily life changes in blood pressure have important implica-

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ions for outcome, the best examples being the relation be-ween the incidence of stroke or cardiovascular events and theorning magnitude of the blood pressure surge from nighttime

leep or the overall 24-hour blood pressure variability.31,32

There is mounting evidence to suggest that differenteasurements of blood pressure (ie, office, home, or am-

ulatory 24-hour) have independent prognostic values. Theressioni Arteriose Monitorate E Loro Associazioni (PAM-LA) study compared the prognostic value of ambulatory,ome, and office blood pressure measurements in a generalopulation of 2,051 individuals in Monza (Milan), Italy.33

ver an average period of 131 months, the study showedhat the risk for cardiovascular death increased exponen-ially with increasing in SBP, regardless of whether it waseasured in the office, at home, or over a 24-hour period

Figure 3). However, the increase in risk was steepest forighttime mean blood pressure, where each increase of 10m Hg in SBP increased the risk for cardiovascular death

y almost 40%. The next most predictive measurement was4-hour mean blood pressure, followed by daytime, home,

igure 3. Office, home, and 24-hour mean daytime and nighttime systoliche Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study

igure 4. Kaplan-Meier curves for cardiovascular and all-cause mortaliteasurements (office, home, and 24-hour ambulatory). (Adapted from Hy

nd office blood pressure. Thus, every 1-mm Hg increase in t

4-hour mean SBP carried a greater increase in risk forardiovascular death than did a similar increase in home orffice blood pressure.

An unexpected result from the PAMELA study was thebservation that each method of blood pressure measurementarries its own independent risk for cardiovascular mortalityFigure 4).34 Kaplan-Meier analyses showed that patientsith elevated blood pressure according to office, home, and4-hour ambulatory measurements carried the worst risk,hereas patients whose blood pressure was normal, or only

levated in 1 or 2 types of measurement, fared considerablyetter.

The implications of these findings from a treatmenterspective are that the best cardiovascular prognosis isikely to be achieved when office, home, and 24-hourmbulatory blood pressure are all optimally controlled. Its also important to use antihypertensive drugs that areapable of achieving effective daily reductions either asonotherapy or when given in combination with other

rugs. The database available for telmisartan suggests

pressure at entry as predictors of 11-year risk for cardiovascular death ininted with permission from Circulation.33)

no blood pressure (BP) elevations, or with elevations in 1, 2, or 3 BPion.34)

blood

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hat this may be the case for this drug.35 In a randomized,

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pen-label trial, telmisartan plus hydrochlorothiazide wasignificantly more effective than amlodipine plus hydro-hlorothiazide in reducing blood pressure over 24 hoursp �0.001), during the daytime (p �0.001), and duringhe early morning blood pressure increase (p �0.05)Figure 5).36

onclusion

he past 50 years have seen a complete reversal in our viewf hypertension from being a life-preserving compensationor vascular sclerosis to a life-threatening marker of in-reased CVD and cerebrovascular disease. Blood pressureeduction is now known to be essential for improving car-iovascular prognosis in hypertension. Despite the widehoice of available antihypertensive agents, the balance ofvidence suggests that the type of antihypertensive used tochieve blood pressure reduction is largely irrelevant.

The next 50 years are likely to witness important ad-ances in our understanding of what optimal blood pressureontrol really is. It is already apparent that everyday bloodressure values, as well as specific blood pressure phenom-na during the day and night, are relevant to survival. In theuture, it will be important to evaluate more extensively thebility of antihypertensive drugs to control these phenom-na and to determine how this improves protection againstVD.

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blood pressure reduction and cardiovascular outcomes: past, present, and future

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