analysis of recent papers in hypertension

VOL. IV NO. IV JULY/AUGUST 2002 THE JOURNAL OF CLINICAL HYPERTENSION 295

ANGIOTENSIN RECEPTOR BLOCKER COMPARED TO A β BLOCKER-BASED TREATMENT REGIMEN IN HYPERTENSIVEPATIENTS WITH LEFT VENTRICULARHYPERTROPHY: THE LIFE TRIALIn patients with hypertension, left ventricularhypertrophy (LVH) is a major independent riskfactor for stroke, myocardial infarction (MI), sud-den cardiac death, and cardiovascular mortality. Itis still uncertain if one specific class of blood pres-sure lowering agent is more effective than anotherin causing LVH regression. Controlled data indi-cate that angiotensin-converting enzyme (ACE)inhibitors and diuretics appear to be somewhatmore effective than calcium channel blockers and βblockers. It is clear that patients who experienceregression of LVH on treatment experience lesscardiovascular disease and death than patientswhose LVH does not regress. Both β blocker andangiotensin II type 1 receptor blocker (ARB) ther-apy antagonize the effects of angiotensin II andcause LVH regression. Accordingly, a study wasperformed in patients with essential hypertensionand LVH to specifically compare the effects ofthese two classes of antihypertensive agents on car-diovascular death, MI, and stroke as well as theirability to regress LVH independent of blood pres-sure reduction.

The Losartan Intervention for Endpoint Reductionin Hypertension (LIFE) study was an internationalmulticountry study that evaluated 9193 patients55–80 years of age (mean age, 67) with previouslytreated (72%) or untreated (28%) hypertension andECG evidence of LVH (ECG-LVH). Patients were eli-gible for the trial if their trough sitting systolic bloodpressure was 160–200 mm Hg and/or their diastolicblood pressure was 95–115 mm Hg after a 14-day

placebo washout period. Baseline characteristics, sim-ilar in the overall treatment group, found 54% werefemale, 92% white, 6% black, and 13% diabetic,with 16% having a history of coronary artery diseaseand 8% a history of cerebrovascular disease. Thosewith a history of an MI or stroke within the previous6 months, angina requiring treatment, or heart failurewere excluded.

Patients were double-blindly randomized in par-allel groups to either atenolol (A) (n=4558), orlosartan (L) (n=4605). The starting dose of bothdrugs was 50 mg once daily. After 2 months, if thetarget blood pressure of <140/<90 mm Hg was notmet, open-label hydrochlorthiazide, 12.5 mg, wasadded. If necessary, 100 mg once daily of L or Awere then used to reach the target blood pressurelevel, with additional therapies added (excludingACE inhibitors, other ARBs, or β blockers), if nec-essary. The primary end point was a composite endpoint including first evidence of cardiovasculardeath, MI, or stroke. Other pre-specified endpoints included total mortality, hospitalization forangina pectoris or heart failure, the need for coro-nary or peripheral revascularization, and the devel-opment of new-onset diabetes mellitus.

Mean blood pressure was reduced from 175/98mm Hg to 145.4/80.9 mm Hg in the A group and175/98 mm Hg to 144.1/81.3 mm Hg in the Lgroup. Heart rate was reduced 2 beats/min in the Lgroup and 8 beats/minute in the A group.

The mean dose of A was 79 mg once daily, with43% of the A patients requiring 100 mg, with or with-out additional therapy including hydrochlorthiazideand the mean dose of L was 82 mg once daily with50% of the L patients taking 100 mg, with or withoutadditional therapy. Only 9% of the L group and 10%of the A group were controlled with the initial dose ofblinded therapy and only 11% of all the participantswere controlled just with the blinded agent. Thus,almost 90% of patients received multiple medicationsin an attempt to achieve goal blood pressure. Evenusing multiple agent therapy, blood pressure wasreduced to the goal of <140/<90 mm Hg in only 48%of the L and 45% of the A patients.

A n a l y s i s o f R e c e n t P a p e r s i n H y p e r t e n s i o nJ a n B a s i l e , M D , S e c t i o n E d i t o r

Jan Basile, MD

From the Ralph H. Johnson VA Medical Center, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SCAddress for correspondence:Jan Basile, MD, Ralph H. Johnson VA Medical Center,1090 Bee Street, Charleston, SC 29403

THE JOURNAL OF CLINICAL HYPERTENSION VOL. IV NO. IV JULY/AUGUST 2002296

The study was stopped after 1040 patients hadexperienced a primary composite end point, occur-ring after a mean follow-up of 4.8 years. By anintention-to-treat analysis, after adjusting for dif-ferences in achieved blood pressure levels, Lreduced the primary composite end point of firststroke, MI, or cardiovascular death by 13%. Mostof the benefit was driven by a 25% reduction inthe risk of fatal and nonfatal stroke, with no ben-efit seen for fatal and nonfatal MI or cardiovascu-lar death. Of the secondary end points, new onsetdiabetes was reduced 25% with L. In addition, Lwas more effective in regressing ECG-LVH than A.According to the authors, only part of the benefiton study outcome was explained after adjustingfor differences in both the achieved blood pressureand degree of ECG-LVH regression.

Tolerability was slightly better with L than withA. At the end of the trial, 23% of the participantswere off L and 27% were off A. More A subjectsdiscontinued therapy because of adverse, or drug-related events including bradycardia, cold extrem-ities, and sexual dysfunction. There was no differ-ence between the two groups in either the risk ofcough or angioedema.

The authors conclude that in patients withessential hypertension and ECG-LVH, treatmentbased on L, as compared to a treatment regimenbased on A, was associated with less overall car-diovascular morbidity and mortality, stroke, andnew onset of diabetes although no difference wasnoted between groups in the occurrence of MI orcardiovascular death. In addition, L was better tol-erated and caused greater regression of ECG-LVHfor a similar amount of blood pressure reduction.L appears to confer benefits beyond blood pressurereduction in older patients with hypertension andECG-LVH.—Dahlof B, Kjeldsen SE, DevereuxRB, et al. Cardiovascular morbidity and mortalityin the Losartan Intervention For Endpoint reduc-tion in hypertension study (LIFE): a randomisedtrial against atenolol. Lancet. 2002;359:995–1003.

CommentUp to now, there have been only a few comparativetrials that have examined the effects of specificblood pressure lowering agents on reducing car-diovascular morbidity and mortality. The LIFEstudy found that initial treatment with the ARB Lwas more effective in reversing ECG-LVH andreducing the risk of the combined end point of car-diovascular death, MI, and stroke compared to theinitial use of a β blocker-based regimen using A.This 13% difference occurred, however, mainly

because of a 25% reduction in the risk of fatal andnonfatal stroke in those on L with no differencenoted between groups in either cardiovascular oroverall mortality. The risk of MI, although not sig-nificantly different, was 7% more likely to haveoccurred in the L group (198 events with L com-pared to 188 with A), a trend that remains unex-plained. Even though the systolic blood pressurewas reduced 1 mm Hg more in the L group, theauthors state that there was no appreciable changein the outcome after adjusting for this difference.

What are the clinical implications of this trial?

1. Although an echocardiogram is more sensi-tive in detecting the presence of LVH, the stud-ies’ clinical utility is strengthened by the use ofa screening ECG. This is a recommended screen-ing test for all hypertensives as stated in theSixth Report of the Joint National Committeeon Prevention, Detection, Evaluation, andTreatment of High Blood Pressure (JNC VI).

2. Only 11% of patients at the end of the studyremained on single-agent therapy with only 2%on 100 mg of L or A as monotherapy. As thedistribution of additional drugs is said not todiffer between the L and A groups, almost allpatients required additional therapy with a thi-azide diuretic. As “other drugs,” a calciumantagonist (not specifically mentioned in thepaper), was probably also required in about onehalf of the patients. In a treatment program thatincludes an ARB, L appears more effective thana regimen based on A, to reduce the risk ofstroke and regress LVH. The practice of usingan ARB with a thiazide diuretic appears toimprove outcome.

3. A was given once a day, a practice oftenduplicated outside of clinical trials. Although itreduced heart rate more than L, it needed to begiven twice a day in these high-risk patients tomore effectively block angiotensin II and reduceLVH. Furthermore, LVH regression may occurless frequently with β blocker therapy than withARB therapy, even when adjusted for bloodpressure reduction.

4. In the 87% of patients without diabetes at ran-domization, diabetes developed in 6% of the Lpatients and 8% of those on A. Although thiswould appear to be a high rate overall for the devel-opment of diabetes, hypertension is an insulin-resist-ant state and most patients with hypertension havesome degree of insulin resistance. As some but not

all studies have noted β blocker therapy to be moreoften associated with the development of new-onsetdiabetes, we are left wondering if the findings in thistrial are due to the beneficial effect of L or the dele-terious effect of A on insulin resistance. That beingsaid, this trial demonstrates the benefit of an ARBon the prevention of diabetes; this is consistent withtwo previous studies noting similar observationswith ACE inhibitor therapy. It is of interest to notethat the United Kingdom study in more than 1100type 2 diabetic patients over an 8+ year period failedto demonstrate a difference in cardiovascular out-come where an ACE inhibitor group of subjects wascompared to a group of patients on a β blocker (A)based regimen.

5. L was better tolerated than A. Clinicians,based on similar observations in their own prac-tice, often consider ARB therapy before they usea β blocker.

6. The significant 25% reduction in stroke isimpressive and needs comment. Stroke was themost likely primary end point to occur among thethree composite end points and continues to be themost devastating consequence of hypertension.LVH remains a blood-pressure-independent pre-dictor for stroke. That L was more effective inregressing LVH and reducing stroke than A com-plements the Heart Outcomes Prevention Eval-uation (HOPE) study, which also found a protec-tive effect on stroke when a group of patients onantihypertensive drugs that included the ACEinhibitor ramipril was compared to subjects notreceiving an ACE inhibitor. Although blood pres-sure reduction is essential for reducing the rate ofstroke, blockade of the renin-angiotensin systemseems to have importance as well.

7. As only 6% of the participants were black, itis unclear if the results can be generalized to allethnic populations.

With these comments noted, the results of thistrial remain directly applicable to clinical practice.Although we continue to debate if the manner inwhich we reduce blood pressure is important forreducing cardiovascular disease in those withhypertension, it appears that in hypertensivepatients with ECG-LVH it does. The selection of theARB L may be a better choice than the β blocker Aas part of a treatment regimen. Multiple agents are,however, needed to control blood pressure. Weremain unclear regarding the implications of thistrial for the entire ARB class. Accordingly, head-to-

head ARB and ARB vs. ACE-inhibitor-based trials,need to be conducted. Until those trials are com-pleted, an ARB-diuretic combination should beconsidered to achieve blood pressure control whenthere is evidence of ECG-LVH.

EFFECTS OF AN ARB-BASED REGIMEN COMPARED TO A ββ BLOCKER-BASED PROGRAM IN DIABETICS WITH LVH The Losartan Intervention for Endpoint Reductionin Hypertension (LIFE) study (see above) foundthat losartan (L) reduced cardiovascular morbidityand mortality (mainly stroke) better than atenolol(A) in hypertensive patients with evidence of leftventricular hypertrophy (LVH) on ECG (ECG-LVH). Whether this same benefit was seen in the13% of the participants who were diabetics onentry into the trial was evaluated in this separateanalysis of the overall LIFE cohort.

Utilizing World Health Organization criteria forthe diagnosis of diabetes, patients randomized toeither A (n=609) or L (n=586) were evaluated in asimilar fashion as performed in the overall trial.There was a significantly greater number ofpatients with atrial fibrillation in the A group com-pared to the L cohort. This substudy found thatthose with diabetes randomized to L experienced a24% reduction in the primary composite end point(more favorable than the 13% reduction seen inthe overall trial). Although there was no benefit onthe specific end point of cardiovascular mortalityin the entire study, L reduced the risk of cardiovas-cular death by 37% and the secondary end point oftotal mortality by 39% as well as hospitalizationfor heart failure by 41%. As in the overall trial,there was no difference in the risk of myocardialinfarction between the two groups.

Interestingly, at the conclusion of the trial,although systolic blood pressure was reduced 2mm Hg more in the L (146/79 mm Hg) than in theA group (148/79 mm Hg), there was no differencein the risk of stroke, which accounted for themajority of benefit in the overall analysis.

L was more effective than A in reversing LVH.Interestingly, serum glucose did not differ betweenthe two groups throughout the study. Although thepercent of patients with clinical nephropathy (atleast 300 mg of protein/g creatinine/day) was simi-lar in the two groups at study entry, fewer patientsin the L group still had evidence of nephropathy atthe study’s conclusion.

L was more effective than A in reducing cardio-vascular and all-cause mortality in patients withhypertension, diabetes, and LVH. The observation


in this substudy that there was no difference in therisk of stroke as noted in the overall trial remainsunexplained. —Lindholm L, Ibsen H, Dahlof B, etal. Cardiovascular morbidity and mortality inpatients with diabetes in the Losartan InterventionFor Endpoint reduction in hypertension study(LIFE): a randomised trial against atenolol.Lancet. 2002;359:1004–1010.

CommentThis substudy seems to raise some interestingobservations.

1. Few patients remained only on the blindedmedicine (9%) as almost all participants endedup on two or more medicines and still fell shortof the blood pressure goal recommended forthose with diabetes (<130/80 mm Hg).

2. Although the authors adjusted for the 2 mmHg greater reduction in systolic blood pressureseen in those on L, this should have accountedfor a further reduction in stroke as seen in theoverall trial but not in the diabetic cohort.

3. As the diabetic cohort usually accounts forthe greatest clinical benefit seen within a trial,the discordant findings between the overallcohort and the diabetic cohort on the primaryend points remains unexplained. Cardiovascularmortality was reduced in the diabetics on Lwhen compared to A. However, it is of interestto speculate on possible differences in thegroups at baseline in the presence of atrial fib-rillation. Did the A subjects have more cardio-vascular disease before the study started?

4. In the L group, proteinuria was present in11% of patients at study entry and was reducedto 8%, whereas A was associated with a12%–11% reduction at the study’s conclusionsuggesting that an angiotensin receptor blockermay be more effective in reducing clinicalnephropathy than a β blocker.

5. While L decreased the risk of new-onset diabetesby 25% in the overall trial, once diabetes occurred,there was no difference between the groups in serumglucose levels over a mean 4.7 years.

The LIFE trial suggests that LVH reversal leadsto an improvement in outcome in the diabetic.Many questions still remain. Until more informa-tion is forthcoming, multiple agents continue to benecessary to achieve the goal blood pressure of

<130/80 mm Hg recommended for the diabeticpatient. The initial use of the angiotensin receptorblocker as a component of therapy appears morebeneficial than the initial use of the β blocker inthose with hypertension, diabetes, and ECG-LVH.

STROKE INCIDENCE REDUCED IN HIGH-RISK PATIENTS WITH THE ACE INHIBITOR RAMIPRILStroke remains the third leading cause of death in theUnited States. The Sixth Report of the Joint NationalCommittee on the Prevention, Detection, Evaluation,and Treatment of High Blood Pressure (JNC VI) rec-ommends diuretics and β blockers to prevent theoccurrence of initial stroke in those with uncomplicat-ed hypertension. Although antiplatelet agents can pre-vent stroke in those at high risk, antihypertensive ther-apy has not previously been evaluated to prevent aninitial stroke in high-risk individuals with diabetes,underlying cardiovascular or peripheral vascular dis-ease, or in those without hypertension. Prevention of arecurrent stroke in those with a history of previousstroke has recently been reported with the use ofangiotensin-converting enzyme (ACE) inhibitor/diuretic combination therapy.

As previously shown in the Heart OutcomesPrevention Evaluation (HOPE) study, participants55 years of age and over had a reduction in the riskof myocardial infarction, stroke, cardiovasculardeath, as well as total mortality, when the ACEinhibitor ramipril was added to the patients’ estab-lished therapy compared to a group of subjects onother agents that did not include an ACE inhibitor.Now, in a subanalysis of the 9297 patients whoparticipated in the original HOPE trial, the sec-ondary prevention of stroke, transient ischemicattack (TIA), and cognitive function was evaluat-ed. Stroke was confirmed by computed tomogra-phy, magnetic resonance imaging, or autopsy in84% of the cases. Blood pressure was recorded atstudy entry, after 2 years, and at the study’s fourand one-half year conclusion with the lower of thetwo values at each visit recorded.

In those who received an ACE inhibitor plusother drugs, compared to a regimen that did notinclude an ACE inhibitor, the risk of overall strokewas decreased by 32% while the risk of fatal strokewas reduced by 61%. Mean baseline blood pressurein those who experienced a stroke was 143/79 mmHg compared to 139/79 mm Hg in those who didnot develop a stroke. After adjusting for differencesin baseline blood pressure as well as changes inblood pressure in those who received ramipril, therewas still a 28% reduction in the risk of stroke in this


group. These benefits were seen across all subgroupsincluding patients with (11%) and without previousstroke, underlying coronary artery disease (80%),peripheral arterial disease (43%), or diabetes (38%).In addition, the benefit was seen at all levels of bloodpressure including those hypertensive and those withan initial blood pressure <120/70 mm Hg. Cognitivedecline or functional impairment also occurred lessoften on ramipril.

The authors of this subanalysis conclude thatpatients at high risk for stroke should continue toreceive aspirin and, in addition to other blood pres-sure lowering agents required to achieve bloodpressure control, an ACE inhibitor. They believethe widespread use of an ACE inhibitor, such asramipril, in those at high risk for stroke, may havea major impact on public health.—Bosch J, YusufS, Pogue J, et al., on behalf of the HOPE investi-gators. Use of ramipril in preventing stroke: doubleblind randomized trial. BMJ. 2002;324:699–702.

CommentThe HOPE study, in which 11% of the patientsenrolled had a history of a stroke or TIA, foundthat treatment with an ACE inhibitor (plus othermedications) reduced the risk of fatal and nonfatalstroke and TIA at all levels of entry blood pressure.The benefit was seen in all subtypes of stroke and,according to the authors, was independent of themodest reduction in blood pressure that occurredwith ramipril (3/2 mm Hg), compared to otheragents. In the HOPE study, blood pressure wasonly measured several times throughout the study.

These results are consistent with another ACEinhibitor trial, the Perindopril Protection AgainstStroke Study (PROGRESS) (Lancet 2001;358:1033–1041), in which 100% of the 6105 patients hada previous stroke or TIA. Patients were randomized toplacebo or 4 mg of perindopril, with the addition of2.5 mg of indapamide left to the discretion of the cli-nician. Overall, the risk of recurrent stroke wasreduced by 28% with an average blood pressurereduction of 9/4 mm Hg. In the 58% of patients oncombination therapy who experienced a blood pres-sure reduction of 12/5 mm Hg, the reduction in strokerisk was 43% whereas in the 42% of patients treatedonly with perindopril, in whom blood pressure wasreduced by only 5/3 mm Hg, there was no reductionin stroke. In this trial, as opposed to the HOPE study,blood pressure was measured five times during thefirst year and twice a year during the second and sub-sequent 4 years of the trial. The benefit of combina-tion therapy over single-drug therapy occurred inthose both with and without hypertension, as most

patients were on antiplatelet therapy and almost onehalf of the patients were on concomitant antihyper-tensive therapy.

The PROGRESS trial emphasizes that the degreeof blood pressure reduction achieved with an ACEinhibitor/diuretic based combination appears moreimportant than less effective blood pressure reduc-tion with ACE inhibitor monotherapy. It should benoted that most of the patients included in theHOPE study were on diuretic therapy at entry.Therefore, blood pressure reduction with treat-ment with an ACE inhibitor/diuretic combinationappears beneficial in reducing the risk of first andrecurrent stroke in high-risk patients with andwithout hypertension. These two agents can be rec-ommended for patients with a history of stroke orTIA, regardless of their initial blood pressure.Benefit is greater in patients with hypertension—itshould be noted that stroke reduction in both theyoung and elderly has also been noted with otherantihypertensive agents when given with a diuretic.

A 90% LIFETIME RISK OF DEVELOPINGHYPERTENSION FOR MIDDLE-AGED MENAND WOMENThe lifetime risk statistic, the probability that an indi-vidual will develop a disease over their lifetime, offersthe public an easy-to-use estimate rather than the dif-ficult to explain age-specific prevalence, which con-veys nothing about an individual’s risk for a specificdisease. For example, according to the AmericanCancer Society, the lifetime risk for a woman devel-oping breast cancer remains at 1 in 9. Although life-time risk estimates are available for a number ofchronic diseases, the lifetime risk for developinghypertension has not been previously reported.

In order to estimate the residual lifetime risk forhypertension in older US adults from 1976–1998,researchers from the Framingham Heart Studyevaluated 1298 study participants (589 men and709 women) who were 55–65 years of age and freeof hypertension in 1975. To evaluate temporaltrends in that same lifetime risk for hypertension,they were compared to Framingham participantsevaluated 25 years earlier, from 1952–1975.

In both 55 and 65-year-old participants, thecumulative lifetime risk for the development ofhypertension (at or above 140/90 mm Hg regard-less of treatment) was 90%. Compared with astudy group evaluated 25 years earlier(1952–1975), men had a 60% increased risk fordeveloping hypertension in the more recent1976–1998 period whereas the risk in women dur-ing the same time periods remained unchanged.


This temporal trend was felt secondary to the age-adjusted increase in body mass index in men, which,in contrast, was slightly decreased in women.

As more patients with stage 2 or higher hyper-tension (at least 160/100 mm Hg) have been moreaggressively treated, the residual lifetime risk from1976–1998 for this degree of hypertension was35%–44%. This was a considerable decline fromthe 35%–57% seen in the study group evaluatedfrom 1952–1975, 25 years earlier.

The authors note that despite the decline in life-time risk for stage 2 or higher hypertension, theobservation that 90% of middle-aged and olderindividuals have a residual lifetime risk for thedevelopment of hypertension represents a majorpublic health challenge. These results are based ona single blood pressure measurement with all of itsinherent variability performed only once every twoyears in an almost entirely white population.Despite this limitation, the importance of advisingpatients and their children to adopt healthierlifestyles as well as to prevent weight gain remainsof concern.—Vasan RS, Beiser A, Seshadri S, et al.Residual lifetime risk for developing hypertensionin middle-aged women and men. The FraminghamHeart Study. JAMA. 2002;287:1003–1010.

CommentThe longitudinal surveillance of the same communi-ty-based cohort over a 50-year period, now estimatesthat 9 out of 10 middle-aged and older adults arelikely to develop hypertension over their lifetime. Inaddition, more than one half of that lifetime riskoccurs during the 10-year period between the ages of55–65 years of age. With 60% of individuals havinga lifetime probability of needing antihypertensivemedication, the public health implications of anaging population who may require drug therapy formore than 20 years are staggering.

The Sixth Report of the Joint National Committeeon the Prevention, Detection, Evaluation, andTreatment of High Blood Pressure (JNC VI) calls forearly lifestyle modification in those with high-normalblood pressure as well as in subjects with establishedhypertension. Weight reduction, physical activity, mod-eration of alcohol intake, reduction in sodium intake,and a diet high in potassium, calcium, and magnesiumare all recommended. In addition, eating a diet high infruits, vegetables, and grains, as well as one low in saltand saturated fats as applied in the Dietary Approachesto Stop Hypertension (DASH) trial is an evidence-based strategy that results in a significant reduction inblood pressure. It is of concern in the more recent timeperiod that men had a 60% increase in the risk ofdeveloping hypertension that was related to their beingheavier than the previous 25-year time period.Dramatic increases in the prevalence of obesity willcontinue to contribute to the epidemic of hypertensionunless societal changes occur.

Although only individuals who were free ofhypertension between the ages of 55–65 were stud-ied, a considerable proportion of individuals experi-ence the onset of hypertension before this age.Accordingly, the lifetime risk for younger individualsmay be different than those studied here. Preventionof hypertension remains the best strategy. Sodiumintakes continue to increase while leisure-time activ-ity remains at an all-time low and continues todecrease. Until local, state, and national governmen-tal agencies require the food industry to providemore healthy choices for our schoolchildren, andexercise becomes a way of life, significant changes inlifestyle will not occur. Hypertension remains animportant public health problem that needs a bettersolution than just an increase in the use of drug ther-apy. It is time to increase efforts to convince peopleto live a healthier lifestyle and, if unsuccessful, tounderstand the consequences that may occur.


analysis of recent papers in hypertension

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