Conventional Therapy and Newer Drug Classes for Cardiovascular Protection in Hypertension
Ji-Guang Wang and
Jan A. Staessen
Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium.
Correspondence to Dr. Ji-Guang Wang, Studiecoördinatiecentrum, Laboratorium Hypertensie, Campus Gasthuisberg, Gebouw Onderwijs en Navorsing, Herestraat 49, B-3000 Leuven, Belgium. Phone: 32-16-34-7104; Fax: 32-16-34-7106;
ABSTRACT. Recently published actively controlled outcome trialsin hypertension compared conventional therapy (diuretics and-blockers) with newer antihypertensive drug classes, includingangiotensin-converting enzyme inhibitors, calcium channel blockers,-blockers, and angiotensin II antagonists. In a quantitativeoverview of nine trials including 62,605 randomized patients,it was found that conventional therapy and newer drug classeshad similar long-term efficacy in preventing cardiovascularcomplications of hypertension. BP lowering largely accountedfor most, if not all, of the observed benefits in cardiovascularoutcome. These findings emphasize the desirability of loweringBP as much as possible to maximize the reduction in cardiovascularcomplications. Furthermore, several clinical trials have beenspecifically designed to highlight specific mechanisms of actionof the newer drugs by measuring intermediate end points, suchas carotid intima-media thickening or renal dysfunction, orby studying subgroups of patients with specific disorders, suchas diabetes mellitus. In these trials, calcium channel blockerswere more effective than conventional therapy in preventingcarotid intima-media thickening and mild renal dysfunction,whereas use of calcium channel blockers or angiotensin-convertingenzyme inhibitors was associated with a lower incidence of diabetesmellitus in some studies. However, whether or not these specificeffects of the newer drugs on intermediary and/or metabolicend points in the long run also lead to fewer cardiovascularcomplications remains to be proved. E-mail: jiguang.wang@med.kuleuven.ac.be
The lifetime risk of hypertension is approximately 20%. By loweringBP, antihypertensive drugs diminish cardiovascular risk in hypertensivepatients (1,2). Among the currently recommended antihypertensiveagents, diuretics and -blockers are considered as conventionaltherapy, whereas angiotensin-converting enzyme (ACE) inhibitors,calcium channel blockers, -blockers, and angiotensin II type1 receptor antagonists are viewed as newer drug classes (3,4).There is clear evidence that diuretics and -blockers may notonly lower BP but also prevent cardiovascular complicationsof hypertension, such as stroke and myocardial infarction (1).To provide similar evidence for the newer drug classes, 11 activelycontrolled outcome trials have been reported before the endof 2001 in which conventional therapy was used as the referencetreatment (5–15). Three meta-analyses have been publishedon the basis of these trials (16–18).
The present review is mainly based on our previous meta-analysis(18) of nine actively controlled trials in hypertension, whichspecifically compared newer drug classes with conventional therapy.In addition, we also summarize the recently published LIFE (LosartanIntervention For Endpoint reduction in hypertension) study (19,20).
The characteristics of the nine trials (ALLHAT [Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart Attack Trial](13), CAPPP [Captopril Prevention Project] (8), INSIGHT [InternationalNifedipine GITS Study–Intervention as a Goal for HypertensionTreatment] (11), MIDAS [Multicenter Isradipine Diuretic AtherosclerosisStudy] (7), NICS [National Intervention Cooperative Study inElderly Hypertensives] (9), NORDIL [Nordic Diltiazem Study](12), STOP2 [Swedish Trial in Old Patients with hypertension] (10), UKPDS [UKPDS Hypertension in Diabetes Study] (15), andVHAS [Verapamil in Hypertension and Atherosclerosis Study] (14))included in our meta-analysis (18) are presented in Table 1.These trials included 33,325 patients randomized to conventionaltherapy and 29,280 patients assigned initial antihypertensivetreatment with new drugs.
Table 1. Characteristics of trials in hypertension comparing different active treatmentsa
Among the individual trials with information on one or moreof the fatal outcomes (7–12,14,15), there were no differencesin cause-specific mortality between the newer and older drugswith the exception of the 3.22 (95% CI, 1.12 to 11.2; P = 0.03)increase in fatal myocardial infarction on treatment with nifedipineGITS (gastro-intestinal transfer system) in the INSIGHT trial(11). For none of the pooled results, Zelen’s test indicatedsignificant heterogeneity (Table 2). The new drugs were equallyeffective as the old ones in preventing cardiovascular mortalityor deaths from stroke or myocardial infarction with or withoutsudden death (18).
Table 2. Estimates of benefit of newer over older antihypertensive drugs for cardiovascular mortalitya
With regard to fatal combined with nonfatal outcomes, therewas significant heterogeneity among the trials, which was largelydriven by the higher risk of cardiovascular complications (Table 3),stroke, and congestive heart failure on treatment with doxazosincompared with chlorthalidone in the ALLHAT trial (13,18). Afterexclusion of ALLHAT (13), there was still slight heterogeneityin the overall risk of cardiovascular complications on treatmentwith ACE inhibitors compared with conventional therapy (Table 3;P 0.03). This was due to the higher risk of stroke in theCAPPP patients randomized to captopril (18). The odds ratiowas 1.25 (95% CI, 1.01 to 1.55; P = 0.04) (8). Among the individualtrials, NORDIL patients allocated diltiazem had a lower riskof stroke than their counterparts randomized to the older drugclasses (diuretics and/or -blockers). The odds ratio was 0.80(95% CI, 0.65 to 0.99; P = 0.04) (12), but did not lead to significantheterogeneity among the trials involving calcium channel blockers.
Table 3. Estimates of benefit of newer over older antihypertensive drugs for all cardiovascular events
After exclusion of ALLHAT (13), there were no differences inoverall cardiovascular risk between the patients randomizedto diuretics or -blockers compared with those allocated initialtreatment with calcium channel blockers or ACE inhibitors (Table 3).However, in the patients randomized to calcium channel blockerscompared with those in whom treatment had been started witholder drugs, there was a greater reduction in the risk of stroke(13.5%; 95% CI, 1.3 to 24.2%; P = 0.03) and a smaller decreasein the risk of myocardial infarction (19.2%; 95% CI, 3.5 to37.3%; P = 0.01). In contrast, ACE inhibitors conferred benefitsin the prevention of stroke and myocardial infarction that weresimilar to those of the old drug classes (18).
Among the trials leading to significant heterogeneity (8,13)and those with significant differences between the treatmentgroups in the overall risk of cardiovascular events (13) orcause-specific cardiovascular complications (8,12,13), all threereported differences in the achieved systolic pressure of 2mmHg or more (Table 1). Therefore, in a further analysis weinvestigated the relationship between the odds ratios expressingbenefit and the achieved differences in systolic BP betweenthe treatment groups. In this meta-regression analysis, we includednine actively controlled trials (Table 1) (7–15) and 21previous drug trials in hypertension (for acronyms and originalpublications, see reference 18) or in patients at high cardiovascular(21–23), cerebrovascular (24,25), or renal risk (26).The meta-regression line between the odds of an event and thedifferences in systolic pressure between the study groups waslinear for cardiovascular mortality (18) and curvilinear forall cardiovascular events (Figure 1), fatal and nonfatal stroke(18), and fatal and nonfatal myocardial infarction, includingsudden death (18). The differences between the observed oddsratios and those predicted by the meta-regression lines (Figure 1)did not reach statistical significance except for the NORDIL(12) and PROGRESS (Perindopril Protection Against RecurrentStroke Study) (25) trials. In NORDIL, the risk of stroke waslower on diltiazem than on the older drug classes despite a3.1-mmHg higher systolic pressure on the calcium channel blocker.In the perindopril-only subgroup of the PROGRESS trial (25),systolic pressure was reduced by 5 mmHg, but monotherapy withthe ACE inhibitor did not affect the risk of all cardiovascularevents (Figure 2) or stroke recurrence (Figure 3)
Figure 1. Relationships between the odds ratios for all cardiovascular events and the corresponding differences in systolic BP. Odds ratios were calculated for experimental versus reference treatment and BP differences by subtracting the achieved level in the experimental group from that in the reference group. The regression lines were plotted with 95% confidence interval (CI) and were weighted for the inverse of the variance of individual odds ratios. Adapted with permission from Staessen et al. (18).
Figure 2. Observed and predicted odds ratios for all cardiovascular events. Observed odds ratios were reported in the published articles. Predicted odds ratios were derived from the regression model. Odds ratios were represented by the point estimate and 95% CI.
The benefits of conventional therapy and the newer antihypertensivedrug classes in preventing cardiovascular complications aresimilar and to a large extent depend on BP reduction (18). However,antihypertensive drugs have different mechanisms of action.Several clinical trials have been specifically designed to highlightthese differences by measuring intermediate end points, suchas carotid intima-media thickening (7,27–29) or mild renaldysfunction (9,11), or by studying subgroups of patients withspecific disorders, such as diabetes mellitus (8,20).
Renal Dysfunction
In the INSIGHT trial, the patients started on long-acting nifedipinehad significantly (P < 0.0001) lower incidence rates of mildlyimpaired renal function and hyperuricemia than those assignedconventional therapy with co-amilozide (11). The numbers ofincident cases of renal failure were 8 and 13 in patients treatedwith nifedipine and co-amilozide, respectively (11). In theNICS trial in 414 elderly hypertensive Japanese subjects (9),serum uric acid at the end of follow-up was 27.3 µmol/Llower in subjects treated with sustained-release nicardipinethan in those on trichlormethiazide (P < 0.0001). Blood ureanitrogen also tended to be lower in nicardipine-treated subjects(P = 0.07).
Intima-Media Thickening
Intima-media thickening was the primary outcome measure in theMIDAS (7) and VHAS (27) trials and in a substudy to the INSIGHTtrial (28). In the MIDAS trial, mean intima-media thickeningover 3 yr of follow-up was smaller in patients on the dihydropyridinecalcium channel blocker isradipine than in those randomizedto hydrochlorothiazide (7). In the VHAS trial, although theresults of intima-media thickness favored verapamil, the differencebetween this non-dihydropyridine calcium channel blocker verapamiland chlorthalidone did not reach significance (27).
In a substudy to the INSIGHT trial (11), common carotid intima-mediathickness progression was compared between long-acting nifedipineand co-amilozide in 439 enrolled patients (28). With similarBP reduction, the progression rate of intima-media thickness(slope of intima-media thickness regression over time) in thenifedipine group compared with co-amilozide tended to be slowerin 324 patients who were followed for at least 1 yr (P = 0.09)and was significantly smaller in the 242 patients who had completedfollow-up (-0.7 versus +7.7 µm/yr; P = 0.002). In linewith these results of carotid intima-media thickness (28), anotherINSIGHT project that involved annual double-helix computerizedtomography of the heart, showed that, compared with diuretics,long-acting nifedipine decreased the progression of coronaryartery calcification during 3 yr of follow-up in 201 hypertensivepatients (29).
The carotid arterial results of the three trials comparing acalcium channel blocker with diuretics (7,27,28) suggest thatthe anti-atherosclerotic effect of calcium channel blockade,which have been shown in previous placebo-controlled trials(30,31), might be independent of BP reduction.
Diabetes Mellitus
Several recent trials reported the incidence of diabetes mellitusin patients on treatment with different antihypertensive drugs(8–12,20). The INSIGHT trial demonstrated that, comparedwith co-amilozide, calcium channel blockade (nifedipine) significantlyreduced the incidence of diabetes mellitus by 30% (P = 0.01)(11). A similar tendency was also observed in NORDIL (-13%;P = 0.14) (12) and NICS (4 versus 0 cases; P = 0.12) (9), butnot in the STOP2 study (P = 0.83) (10). The CAPPP trial founda 14% (P = 0.04) reduction in diabetes mellitus in patientson captopril as compared with those on diuretics and -blockers(8). However, the latter observation was not confirmed in theSTOP2 trial (10). The conflicting findings in the STOP2 trialmay be due to the high crossover of study medications betweenthe study groups to be compared (10). More recently, the LIFEstudy found a 25% reduction in the incidence of diabetes mellitusin patients treated with losartan as compared with atenolol(20). Because the old drugs do have metabolic adverse effectsand all three classes of new drugs showed similar benefits inthis regard, one may postulate that the difference in the riskof diabetes between old and new drugs classes may be due toan impairment of glucose metabolism on conventional therapyin particular diuretics.
The UKPDS trial (15) and subgroup analyses of other comparativetrials (8,12,20,32) focused on the cardiovascular outcome ofhypertensive patients with diabetes mellitus. In STOP2 (32)and NORDIL (12), calcium channel blockers provided similar cardiovascularbenefit as conventional therapy in the diabetic subgroup. TheCAPPP trial showed in 572 diabetic patients that captopril wasbetter than conventional therapy in preventing fatal and nonfatalmyocardial infarction (8). However, this finding was not confirmedby the STOP2 (32) and UKPDS (15) trials, which respectivelyincluded 488 and 758 diabetic patients.
In 1195 hypertensive diabetic patients with electrocardiographicleft ventricular hypertrophy, the LIFE trial demonstrated thatcompared with atenolol losartan significantly reduced totalmortality by 39% (20). However, similar reductions were observedfor cardiovascular (-38%) and noncardiovascular (-42%) mortality.Moreover, on randomized treatment, systolic pressure was 3 mmHglower in the losartan group as compared with the patients randomizedto atenolol (20).
The actively controlled trials demonstrated that on averageconventional therapy and the newer antihypertensive drugs havesimilar long-term efficacy and safety. Compared with the olderdrug classes, calcium channel blockers and converting enzymeinhibitors provided the same overall protection against cardiovascularcomplications. In the trials in hypertensive and/or high-riskpatients, BP lowering largely accounted for most, if not all,of the observed benefits in cardiovascular outcome. These findingsemphasize the desirability of lowering BP as much as possibleto maximize the reduction in cardiovascular complications. Whetheror not the specific effects of the newer drugs on intermediaryor metabolic end points in the long-run also lead to fewer cardiovascularcomplications remains to be proved.
Acknowledgments
Dr Wang was supported by the bilateral scientific and technicalcollaboration between the People’s Republic of China andFlanders (contract number BIL98/15).
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Abstract
Introduction
-blockers) with newer antihypertensive drug classes, including angiotensin-converting enzyme inhibitors, calcium channel blockers, 
-blockers, and angiotensin II antagonists. In a quantitative overview of nine trials including 62,605 randomized patients, it was found that conventional therapy and newer drug classes had similar long-term efficacy in preventing cardiovascular complications of hypertension. BP lowering largely accounted for most, if not all, of the observed benefits in cardiovascular outcome. These findings emphasize the desirability of lowering BP as much as possible to maximize the reduction in cardiovascular complications. Furthermore, several clinical trials have been specifically designed to highlight specific mechanisms of action of the newer drugs by measuring intermediate end points, such as carotid intima-media thickening or renal dysfunction, or by studying subgroups of patients with specific disorders, such as diabetes mellitus. In these trials, calcium channel blockers were more effective than conventional therapy in preventing carotid intima-media thickening and mild renal dysfunction, whereas use of calcium channel blockers or angiotensin-converting enzyme inhibitors was associated with a lower incidence of diabetes mellitus in some studies. However, whether or not these specific effects of the newer drugs on intermediary and/or metabolic end points in the long run also lead to fewer cardiovascular complications remains to be proved. E-mail: jiguang.wang@med.kuleuven.ac.be 
0.03). This was due to the higher risk of stroke in the CAPPP patients randomized to captopril (18). The odds ratio was 1.25 (95% CI, 1.01 to 1.55; P = 0.04) (8). Among the individual trials, NORDIL patients allocated diltiazem had a lower risk of stroke than their counterparts randomized to the older drug classes (diuretics and/or 
