Major antihypertensive intervention trials conducted outside the United States

Major Anti Conducted ~e~z~t~rf

ertensive Intervention Trials tside the United States

~~~2s.~~~

Five antihype~ension trials launched outside of the United States have bepn designed to address one of hvo vital issues. The first is whether or not there is an optimal leve! of blood pressure that cliniciane should aim for to minimize the risk of cardiovascular disease. This has been add by the Swedish Fkhandla Blodbyck Bathe l BBB t Trial and the international Hypestension Optimal Treatment (HOT1 Shady. The BBB Trial rwealed interesting trends, but no definitive conclusion% The oegaing HOT Study will have to be cumpleted before this particular issue can be adequately addressed However, preliminary adysis of a subgroup stody has revealed that the HOT treatment regimens are as effe&ive in the elderly as in yowngex Patients. The secxmd important issue, which is the quest%m of ubetlw traditional antihypertensive writs are mom effective &an the newer agent8 in reducing cardiovascular risk is the curreM focus of ttwee

on(;oing studies. Investigabxs in the Gpopil Preventiou P&ect (CAPPP) am cemPar& captopril to &blo&er and die& e

-s chntcai tnvestigattons d antihypertensive drugs have been Launched outside of the United States. This arti& will provide a brief overview of five such crials. most of which a* still in progress, that have been designed to address one of two vital issues. 2% objettive of the first two studies was to determine whether or not there is an optimal level of blood pressure that clinicians should aim for to minimize the risk of cardiovascuIar disease. The investigators in the re-

maining studies set art to di%vwt whetbu tradibona1 antihypwtcmsive agmts f B-Maters and diumt-

T&e

twatemeofb 1996;921SS-1?15 KEYWOSDQ

H

ity and mortality

2siudy,urdia~a-~

(Tabk llle

1).

PROBE

5esign

The shzdy protocol for most of these studies was PROBE, which fiXPRWpCh?lj Open trial with BIinded endpoint Evaluation.’ Randomization is the crucial factor in alI types of intervention studies because it reduces bias. However, the PROBE design has important diffm when mm-

A,,,-Al,L‘l,ST

TAABLE 1. SOME OF THE ENLWOINT STUDIES IN WY

ONGOING

HARD

HY~~~NSiON

Comment

Reference

ate drug variety studies addition

IY%-L’OL

9. NO 8, .-ART 2

efftzts on lipid profiles, renal function, and a of other variables. Thus, each of the following is expected to reveal important information in to data that relate to the primary objective.

STUDIES

OF OPTIMAL BLOOD LEVELS

PRESSURE

The 5BB Study The BBB Study was designed to determine if there is an optimal blood pressure level that physicians should aim for when treating patients with hypertension? BBB stands for Behandla Blodtryck Battre, which is Swtdish for “treat hypertension better.” The BB5 study was conducted at 142 medical centers in Sweden. The protocol was PROBE, and participants pared to the traditional double-blind study. The priincluded men and women who were being treated for mary difference is, of course, that the medication is hypertension and who had diastolic blood pressures of open in the PROBE design, which can be advanta90 to 100 mm Hg on three consecutive occasions. Each geous if many different therapeutic modalities are bepatient was random&d to maintain his or her usual ing compared. In the double-blind study, there needs therapy or to receive intensified treatment that was to be exclusion criteria against every possible therapy aimed at a diastolic blood pressure of ~80 mm Hg. that the patients can be randomized to. In an open There were approximately 1000 patients in each treattrial, exclusion criteria are only needed against the ment group, and each was followed for about 4 years. specific drugs that are being administered. Because of The study physicians were entirely free to u.se whatthis, the PROBE design is much more similar to ciiniever therapy they chose to bring the blood pressure ~231practice. down in patients randomized to the intensified treatThe cost is also very different. The double-blind ment group. A particular drug class was not dt&gnated study is more expensive to conduct because of the for this group, nor were doctors restricted to pharmacobl~ding procedure that is required in each of the logic therapy. The point was to intensify therapy cnrnsteps. In addition, some investigators believe that pared to the other treatment group. comphance is better in a PROBE study, because s-me The BBB Study was designed to answer three yuespatients may prefer to take a brand-name medication, tions. First, is it possible to lower the diastolic blood rather than a drug Iabeled X, Y, or Z. pressure further in well treated patients? Second, will There is one clear disadvantage to the I’KOBE deincreasing the medication inerease the incidence and sign. Doctors can introduce a bias because they are severity of side effects to an unacceptabie level? The told which medication the patient is receiving. This final and most important question is this: will further of course, does not happen in the double-blind trial. reductions in blood pressure affect cardiovascular morHowever, even in the double-blind protocol, it is difbidity and mortality? ficult to make antihy~rtensive trials entirely blinded Results from the BBB Study, which were published It would, for example, be easy to realize that a tiatient in 1992, showed that it is indeed possible to further has taken a D-biocker, because the patients pulse reduce blood pressure in well treated patients.’ Be would be slow-a classic effect of &blocker therapy. tween the hvo groups, a difference in diastolic pressure Patient complaints of specific side erfects will give the of 7 mm Hg was obtained, and this difference was physician another clue. Thus, it is difficult to achieve maintained for over 3 years. The results also showed full “blindness“ even in double-blind studies. that adverse effects did not increase in patients who were randomized to intensii%xI therapy. In fact, a sigSobstudies Each of studies presented in fhis article nificant decxeasc was observed in these patients. Thii has a primary objective. However, within each there is observation was very surprising; it may indicale that also a nuder of s&studies that are being conducted. hypertension is an even more malevolent condition Although these substudies will not be discussed, they than was once believed, and that some adverse effects inchtde such ssecondary objjves as the effRh of ~3- may actually disappear when hypertension is more efblockers on hypertensive patients with diabetes mellifectively controlled. tam, rn~u~e~ of ambulatory blood pressure levels Unfor~na~ly, no difference in c~diavascuIar marIn VICIOUS ~b~ups, ~~~~i~phic studies to debidity and mart lity was observed between the two termine Lte effect of the varicx drugs on left vemricugroups. The fr , number of stroke and myacardial inlar h~~hy~ as well as various diagnostics to evdutarctions were B in one group and 29 in the other (Ta-

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lSSti-VWI.. 9, NO. 8. PART 2

TABLE 2 CARDIOVASCULAR MORBIDITY MORTALITY IN THE BBB STUDY Group A Stroke Mycadial SiIent F&d

infarction

Stroke + myocardial

infarction

A~~a~NStON

AND Gmp

B

8 20 3 8

11 18 4 3

28

29

Data from Honscon L?

ble 21. The reason that no difference was found has been attributed to the statistical power of the shldy, which was too low to determine how blood pressurr? reductions affect cardiovascular morbidity and mortality. However, a positive response to the fi& hvo questions mentioned above encxmraged investig&xs to become involved in a larger-sale trial called the Hyper tension Optimal Treatment fHCll7 Stody. The HOT Study The HCX Study is the largest mtervention antihypertensive trial 50 far. This study was

We have analyzed

I-year

data from the elderly

sub-

TRIALS HELD OUT?XDE THE US

47s

A/N-AUCUST

TABLE

TABLE f THE CAPPP STUDY OVERVIEW 475 cenlers

in Sweden and Finland 25-66 years BPCJ >100 mm Hg n = 10,BW liyear duration to det& a 2O‘Z different in CV rtxwtdity UP < .05, pwer t3iB) ACE1 tr non-ACE1 Rx El. angmkwn mmvrfm”~ mqmt tabihrfur. BPD. L&9 pm CAPPP Cmup n

more years before the final results are in. As a substudy of CAPPP, investigators will be trying to determine if there is a relationship between a specific ACE gene aberration, which is hypothesized to contribute to hypertension, and the incidence of study endpoints. Toward this end, blood samples were taken from patients and stored so that eventual DNA analysis can determine if specific ACE gene subtypes are related to cardiovascular risk. The NORDIL Study The NORDIL Study is similar to the CAPPP in many regards. Patients have been randomized to receive the calcium antagonist diltiazem or conventional treatment with the goal of determining which regimen, if any, has a more favorable effect on cardiovascular risk (Table 41. NORDIL is being conducted in almost centers in Norway and Sweden. Recruitment is ongoing. Approximately 6,000 patients have already been randomized and investigators are aiming for a total study population of up to ll.GBO patients. The primary endpoints of the NORDlL Study are cardiovascular mortality, including fatal myocardial infarction, fatal stroke, sudden death, and other fatal cardiovascular disease. Other primary endpoints include acute myocardial infarction and acute stroke. Shady The STOP-Hypertension-2 Study has been designed to compare traditional treatment with novel therapies in elderly patients (Table 5). A PROBE design was used for this ongoing study, which is being conducted in 3BO centers in Sweden. The patient population includes hypertensive men and women, aged 70 to 84, with systolic blood pressure of 180 mm Hg or above and diastolic blood pressure

STUDY

of 105 mm Iig or above. By the time recruitment had been completed, 6,628 patients were enrolled, which was more than needed to give the study its intended statistical power. The patients in the study were comparable to those in the STOP Hypertension-l Study in terms of age, systolic blood pressure levels, and cholesterol IeveIs.’ The STOP Hypertension-l Study, which was published in 1991, was designed to compare placebo to active treatment with diuretics and @-blockers in 162 elderly hypertensive patients. The results showed that a 40% reduction in major cardiovascular endpoints was seen in the actively-treated group. There was also a 47% reduction in fatal and nonfatal stroke, and quite surprisingly, a significant reduction in total mortality. These encouraging results prompted investigators to launch the STOP 2 Study, whtch is expected to be completed by 1997. REFERENCES 1.

2.

3.

OVERVIEW

PROBE Study

Approximately 800 oxters in Sweden & Norway Men and women 50-69 years BPD >lDo -% S-year duration to detect a 20% difference in CV

5. THE STOP-PERVASION-2 STUDY OVERVIEW

300 centers in Sweden 70-84 years BP ~180 mm Hg Men and women or > 105 mm Hg n = 6,628 &year duration to detect a 25% different in CV mortality 12P < .05, power 90%) between &blockers/ diuretics u CaA Keiodipine. isradipine) ~1ACE1 (enalaprii, lisinonnl)

4.

3. THE NORDIL

9. NO 8. PART 2

PROBE Study

The STOP-Hypertension-2

TABLE

l!W&VOl.

5.

Hansson 8. Hedner T. Uahlof 8: Prospective Randomized Open Blinded End-point (PROBE) Study: a novel design for intervention trials. Blood Pressure 1992; 1:113-119. The BBB Smdy Group: The BBB Study: a pros@ive randomrzed study of intensified antihypertensive treatment. 1 Hypertcns 1988;693-697. Hansson L, for the BBB Study Group: Thr BBB Study: the rff& of intensified antihypertensive therapy treatment on the level of blood pressure, side effcrts, morbidity and mortality in “well-treated” hypertension patients. Blood Pressure 1994;3:248-254. The HOT Shtdy Group: The Hypertension Optimal lireatment tH9Tf Study. A prospective shady of the op timat therapeutic goal and the value of low-dose aspirin in antihypertensive treatment. Bload Pressure 1993; 2:113-119. Hansson L, Zanchetti A, for the HOT Study Croup: The Hypertension Optimal Treatment (HOT) Study: 1% month data on blood pressure and tolerability. With special referent to age and gender. Blood Pressure 1995; 4~312-318.

6.

The CAPPP Group: The Captroprii Prevention Project: a pro+ctive inteivention trial of angiotensin converting

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8.

1996~VOL 9, NO 8. PART 2

enzyme inhibition in the heatment of hypertension. J Hypertens 1~;8:985-~. 1 The NORDIL Shldy Group: The Nordil Diltiazem Study. An inkwention intervention study iiin hype&n! hypertensinn camparing catcium antagonist based treatment treatmentwun wiih cconventional therapy. Bleed Pressure 1993;2:332-321. Dahlof 8, Hansson L, Lindholm LH, et al: STOP-Hyper-

A~H~R~NSION

9,

TRIALS HELD OWSIDE

THE US

49s

tension-2: A ptmpe&ve intervention trial of “newer’ YBCWS “older” twatment alternatives in old patient with Blood Pressure 1993;2:136-141. hypertension 1993;2:136-141 ~~hi~f B, Li”db&, LH, ~~~~~ L, et ai: Mo,bidity and mortabty m the Swedish Trial in Old Patients with Hypertension (STOP-Hypntcnsion ). Lancet 1991;338: Hype 1281-12X5. 1281-rm~