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Hypertension. 2007;50:181-188
Published online before print May 14, 2007, doi: 10.1161/HYPERTENSIONAHA.107.089763
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(Hypertension. 2007;50:181.)
© 2007 American Heart Association, Inc.


Sixth International Workshop on Structure and Function of the Vascular System

Prevention of Stroke and Myocardial Infarction by Amlodipine and Angiotensin Receptor Blockers

A Quantitative Overview

Ji-Guang Wang; Yan Li; Stanley S. Franklin; Michel Safar

From the Centre for Epidemiological Studies and Clinical Trials (J.G.W., Y.L.), Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Preventive Cardiology Program (S.S.F.), University of California, Irvine; and the Diagnosis Center (M.S.), Hopital Hotel-Dieu, Paris, France.

Correspondence to Ji-Guang Wang, Shanghai Institute of Hypertension, Ruijin 2nd Rd 197, Shanghai 200025, China. E-mail jiguangwang{at}netscape.net


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowAppendix
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In the present quantitative overview of outcome trials, we investigated the efficacy of amlodipine or angiotensin receptor blockers in the prevention of stroke and myocardial infarction in patients with hypertension, coronary artery disease, or diabetic nephropathy. The analysis included 12 trials of 94 338 patients. The analysis of trials involving an amlodipine group showed that amlodipine provided more protection against stroke and myocardial infarction than other antihypertensive drugs, including angiotensin receptor blockers (–19%, P<0.0001 and –7%, P=0.03) and placebo (–37%, P=0.06 and –29%, P=0.04). The analysis of trials involving an angiotensin receptor blocker group showed contrasting results between trials versus amlodipine and trials versus other antihypertensive drugs for stroke (+19% versus –25%; P<0.0001) and myocardial infarction (+21% versus +1%; P=0.03). The results of 3 trials comparing an angiotensin receptor blocker with placebo were neutral (P≥0.14). The within-trial between-group difference in achieved systolic pressure ranged from –1.1 to +4.7 mm Hg for trials involving an amlodipine group and from –2.8 to +4.0 mm Hg for trials involving an angiotensin receptor blocker group. The metaregression analysis correlating odds ratios with blood pressure differences showed a negative relationship (regression coefficients: –3% to –8%), which reached statistical significance (regression coefficient: –6%; P=0.01) for stroke in trials involving an amlodipine group. In conclusion, blood pressure differences largely accounted for cardiovascular outcome.


Key Words: blood pressure • clinical trial • calcium channel blocker • angiotensin receptor blocker • stroke • myocardial infarction


*    Introduction
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up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowAppendix
down arrowReferences
 
In a series of previous meta-analyses,1–5 we and others have found that achieved differences in systolic blood pressure may explain most odds ratios in controlled trials of blood pressure–lowering agents in patients with hypertension or other cardiovascular disorders. These analyses included few trials involving angiotensin receptor blockers (ARBs), a relatively new and increasingly used class of antihypertensive agents. In the last few years, several trials investigated ARBs in patients with a broad range of cardiovascular or renal diseases.6–13A recent meta-analysis challenged the use of ARBs, because these drugs might provide less protection against myocardial infarction than other classes of blood pressure–lowering drugs.14 This finding raised a controversial issue but was not supported by subsequent meta-analyses with similar studies included.15,16 In a recent editorial,17 a combined analysis of 2 trials6,10 comparing ARBs with a calcium channel blocker amlodipine suggested that amlodipine provided more protection against stroke and myocardial infarction than ARBs. In addition, in keeping with previous meta-analyses,1–5 calcium channel blockade by amlodipine also prevented more stroke than angiotensin-converting enzyme (ACE) inhibitors and old drug classes (diuretics and ß-blockers).17 However, in these trials, there were significant though small differences in blood pressure between randomized groups.

The CASE-J Trial18 was presented recently at the 21st Scientific Meeting of the International Society of Hypertension (October 2006, Fukuoka, Japan) and did not show any significant difference in stroke or coronary events between amlodipine- and candesartan-based antihypertensive regimens in Japanese patients with hypertension. In the present quantitative overview, we investigated the efficacy of amlodipine or ARBs in the prevention of stroke and myocardial infarction in patients with hypertension, coronary artery disease, or diabetic nephropathy and explored by meta-regression analysis whether there was any benefit or harm beyond blood pressure control for these 2 classes of antihypertensive drugs.


*    Methods
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up arrowAbstract
up arrowIntroduction
*Methods
down arrowResults
down arrowDiscussion
down arrowAppendix
down arrowReferences
 
Acquisition and Selection of Trials
We searched for outcome trials, which involved amlodipine, an ARB, or both in hypertensive patients or in patients with coronary artery disease or diabetic nephropathy. The other criteria for the studies to be included were as follows: a randomized, controlled design; publication in a peer-reviewed journal; assessment of blood pressure and cardiovascular events; follow-up for ≥2 years; and sample size of ≥100. We also accepted large-scale trials, of which the main results had been presented at international meetings with confirmatory information published on the internet.18

We first compared outcomes among patients randomly assigned to initial treatment with amlodipine or ARBs and placebo or other antihypertensive drugs, such as diuretics, ß-blockers, ACE inhibitors, or short-acting calcium channel blockers. In analyses for both amlodipine and ARBs, we incorporated trials of head-to-head comparisons between amlodipine and ARBs. For this part of our analysis, we identified 14 trials including 4 (ALLHAT,19,20 ASCOT,21,22 CAMELOT,12 and PREVENT23), 7 (ACCESS,24 DETAIL,11 IRMA2,25 LIFE,8 MOSES,13 RENAAL,7 and SCOPE9), and 3 studies (CASE-J,18 IDNT,6 and VALUE10) involving an amlodipine group, an ARB group, or both groups, respectively. However, we excluded the ACCESS Trial, because the subjects of this study were patients with hypertension within 24 hours of an acute stroke,24and the IRMA2 Trial, because the number of cardiovascular events was not reported.25 Of the 12 trials in the analysis, the ALLHAT,19 CAMELOT,12 and IDNT6 Trials included 3 randomly assigned groups. Definitions of all trial acronyms are provided in the Appendix.

We then performed meta-regression analyses separately for trials involving amlodipine or ARBs. For trials involving an amlodipine group, we included odds ratios for amlodipine versus a diuretic (ALLHAT/Chlorthalidone),19 a ß-blocker (ASCOT/Atenolol),21 ACE inhibitors (ALLHAT/Lisinopril20 and CAMELOT/Enalapril12), ARBs (CASE-J/Candesartan,18 IDNT/Irbesartan,6 and VALUE/Valsartan10), or placebo (IDNT,6 CAMELOT,12 and PREVENT23). For trials involving an ARB group, we included odds ratios for ARBs versus a ß-blocker (LIFE/Atenolol),8 an ACE inhibitor (DETAIL/Enalapril),11 a short-acting calcium channel blocker (MOSES/ Nitrendipine13), amlodipine (CASE-J,18 IDNT,6 and VALUE10), or placebo (SCOPE,9 IDNT,6 and RENAAL7).

Outcomes
We based our analysis on the summary statistics reported in the literature6–13,19–21,23 or at meetings and available in the internet.18 In all of the trials, outcome results were reported on the basis of an intention-to-treat principle. However, in 7 (ASCOT, CAMELOT, CASE-J, LIFE, MOSES, SCOPE, and VALUE) of the 12 trials, from 6 (0.3%)12 to 85 (0.4%)21 or from 0.3%8,12 to 3.8% (n=53)13of patients were excluded from the intention-to-treat analysis because of good clinical practice deficiencies,10,18 blood pressure measurement,21 or other unspecified8 irregularities; withdrawal of consent12,24; or data quality concerns or nondispense of study drugs.9 We extracted from the source documents fatal and nonfatal strokes (excluding transient ischemic attacks) and fatal and nonfatal myocardial infarctions (excluding silent). Starting from published reports, we had no other option than to accept the definitions of events as given by the investigators. For the ALLHAT and ASCOT trials, myocardial infarctions also included coronary deaths.19,21 For the CAMELOT Trial, strokes included transient ischemic attacks, and myocardial infarctions included cardiovascular deaths.12

Statistical Methods
We determined the relative difference from the odds ratios in stratified 2x2 contingency tables.26 We used StatXact for Windows (CYTEL Software Corporation), version 4.0, to check the homogeneity of the odds ratios by Zelen’s test and to compute exact 95% CIs.27 In the presence of significant heterogeneity, we applied a random-effects model to compute pooled estimates.28 To permit comparisons with other overviews,1–3 we also derived the SDs of the pooled odds ratios by analogy with the asymptotic approach by dividing the logarithmically transformed 95% CI by 2x1.96. All reported P values are for 2-sided hypotheses.

We performed separate metaregression analyses for trials involving amlodipine or ARBs and pooled trials with reference treatment of the same class. We used the SAS statistical software (SAS Institute), version 9.1, to correlate odds ratios of amlodipine or an ARB versus reference treatment with the corresponding baseline-adjusted differences in systolic blood pressure between randomized groups. For these calculations, odds ratios were logarithmically transformed. The regression lines were weighted by the inverse of the variance of the individual odds ratios.29 Net treatment effects on blood pressure were determined by subtracting the mean change in the amlodipine or ARB group from the corresponding mean change in the reference group. When a group of trials were pooled, the blood pressure difference was calculated by averaging the between-group blood pressure difference within each trial with the number of randomly assigned patients as a weighting factor. To standardize estimates of relative risk across trials, whenever possible, we computed observed odds ratios with exact 95% CI from 2x2 contingency tables.


*    Results
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up arrowMethods
*Results
down arrowDiscussion
down arrowAppendix
down arrowReferences
 
Amlodipine Versus Placebo or Other Antihypertensive Drugs
Seven trials with 78 323 randomly assigned patients compared amlodipine with a diuretic (n=24 303),19 a ß-blocker (n=19 257),21 ACE inhibitors (n=19 438),12,20 ARBs (n=21 094),6,10,18 or placebo (n=3279).6,12,23 Tables 1 and 2Down show the characteristics of these trials and randomly assigned patients, respectively. For the pooled analyses, including stroke and myocardial infarction, the P values for heterogeneity did not reach statistical significance (0.12≤P≤0.99; Figure 1).


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TABLE 1. Characteristics of Trials


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TABLE 2. Characteristics of Patients


Figure 1
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Figure 1. Effects of antihypertensive treatment on stroke (left) and myocardial infarction (right) in trials comparing amlodipine with placebo or other classes of antihypertensive drugs, including ARBs. {blacksquare}, Odds ratios in trials, with a size proportional to the number of events. 95% CIs for individual trials are denoted by lines and those for the pooled odds ratios by diamonds. Where appropriate, the comparator drug is given after the acronym of each trial. Acronyms of trials are explained in a separate section of this article.

For actively controlled trials, overall, the pooled analyses showed that amlodipine provided significantly more protection against stroke and myocardial infarction than other classes of antihypertensive drugs. For the 6 trials combined,6,10,12,18–21 the odds ratio was 0.81 (95% CI: 0.75 to 0.87; P<0.0001) for stroke and 0.93 (95% CI: 0.87 to 0.99; P=0.03) for myocardial infarction. However, the benefit of amlodipine was more consistent and prominent for stroke than for myocardial infarction. For stroke, the odds ratio was statistically significant regardless of trials versus ARBs (odds ratio: 0.84; 95% CI: 0.73 to 0.97; P=0.02) or trials versus other antihypertensive drugs (odds ratio: 0.79; 95% CI: 0.72 to 0.87; P<0.0001). For myocardial infarction, the odds ratio was only significant in trials versus ARBs (odds ratio: 0.83; 95% CI: 0.72 to 0.96; P=0.01) but not in trials versus other drugs (P=0.29).

For the placebo-controlled trials, the pooled odds ratios had a size consistent with estimations of previous meta-analyses, but probably because of the relatively small number of events (74 strokes and 159 myocardial infarctions) only reached borderline statistical significance for stroke (odds ratio: 0.63; 95% CI: 0.38 to 1.04; P=0.06) and myocardial infarction (odds ratio: 0.71; 95% CI: 0.51 to 0.99; P=0.04).

ARBs Versus Placebo and Other Antihypertensive Drugs
Eight trials with 39 487 randomly assigned patients compared ARBs with a ß-blocker (n=9193),8 an ACE inhibitor (n=250),11 a short-acting calcium channel blocker (n=1352),13 amlodipine (n=21 094),6,10,18 or placebo (n=7598).6,7,9 Tables 1 and 2Up show the characteristics of these trials and randomly assigned patients, respectively. Of these 8 trials, 3 head-to-head comparison trials of ARBs versus amlodipine6,10,18 had been included in the analysis of amlodipine versus other antihypertensive drugs. For none of the pooled analyses except that of all actively controlled trials (P=0.0007) did the P values for heterogeneity reach statistical significance (0.26≤P≤0.68; Figure 2).


Figure 2
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Figure 2. Effects of antihypertensive treatment on stroke (left) and myocardial infarction (right) in trials comparing ARBs with placebo or other classes of antihypertensive drugs, including amlodipine. *A random-effects model was used. For further explanation, see Figure 1.

For stroke, because of significant heterogeneity, we contrasted the pooled odds ratios of 3 head-to-head comparison trials of ARBs versus amlodipine and 3 trials versus other antihypertensive drugs (odds ratio: 1.19; 95% CI: 1.03 to 1.38 versus odds ratio: 0.75; 95% CI: 0.64 to 0.89; P<0.0001). For myocardial infarction, in spite of insignificant heterogeneity (P=0.26), the pooled odds ratios were also significantly different among 3 head-to-head comparison trials of ARBs versus amlodipine and 3 trials versus other antihypertensive drugs (odds ratio: 1.21; 95% CI: 1.04 to 1.40 versus odds ratio: 1.01; 95% CI: 0.84 to 1.22; P=0.03). The combined result of the 3 placebo-controlled trials was neutral for stroke (P=0.14) and for myocardial infarction (P=0.46).

Metaregression Analysis
We plotted odds ratios for both amlodipine and ARB trials in the same figure but performed metaregression analyses separately for trials involving an amlodipine group and those involving an ARB group (Figure 3). The within-trial, between-group difference in systolic blood pressure ranged from –1.1 mm Hg19 to 4.7 mm Hg6,12,13 for trials involving an amlodipine group and from –2.8 mm Hg13 to 4.0 mm Hg11 for trials involving an ARB group (Table 2 and Figure 3).


Figure 3
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Figure 3. Odds ratios for fatal and nonfatal stroke (left) and fatal and nonfatal myocardial infarction (right) in relation to corresponding differences in systolic blood pressure. Odds ratios were calculated for the amlodipine group vs placebo or other classes of antihypertensive drugs including ARBs (dots) or for the angiotensin receptor group vs placebo or other classes of antihypertensive drugs including amlodipine (squares). Blood pressure differences were obtained by subtracting the mean change in the amlodipine or ARB group from the corresponding mean change in the reference group. When a group of trials was pooled, the blood pressure difference was calculated by averaging the between-group blood pressure difference within each trial with the number of randomly assigned patients as weighting factor. Positive values indicate tighter blood pressure control in the experimental group. The regression line was drawn for trials involving an amlodipine group and weighted by the inverse of the variance of the individual odds ratios. For further explanation, see the Statistical Methods section.

The metaregression analysis correlating the odds ratios with the corresponding within-trial differences in systolic blood pressure showed negative relationship (regression coefficients: –3% to –8%). For the trials involving an amlodipine group, the metaregression line was significant and linear for stroke (regression coefficient±SE: –6±2%; P=0.01) but not statistically significant for myocardial infarction (regression coefficient±SE: –3±2%, P=0.18). For stroke, blood pressure differences accounted for 90% of the variance of individual odds ratios, and the intercept of the metaregression line also reached statistical significance (intercept±SE: 89±33%; P=0.007), indicating an 11% benefit in outcome beyond systolic pressure differences between randomized groups. For the trials involving ARBs, the metaregression line was not significant for either stroke or myocardial infarction (P>0.22 for the 2 intercepts and P>0.20 for the 2 regression coefficients).


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowAppendix
down arrowReferences
 
The main finding of our overview was that calcium channel blockade by the use of amlodipine substantially reduced the risk of stroke and myocardial infarction. The benefit of initial treatment with this drug versus other antihypertensive drugs could be largely, though not entirely, explained by blood pressure differences between randomized groups of trials. The performance of ARBs seemed to some extent dependent on the comparator drug. When compared with an ACE inhibitor or particularly with a ß-blocker or a short-acting calcium channel blocker, ARBs showed superiority for stroke prevention and similarly for coronary prevention. When contrasted with a long-acting calcium channel blocker, amlodipine, ARBs were less effective in lowering blood pressure and also demonstrated inferiority for the prevention of stroke and myocardial infarction.

Our overview has to be interpreted within the context of its limitations. As in all meta-analyses that start from published summary statistics, we achieved less standardization than is attainable in quantitative overviews based on individual patient data.30 Thus, the participants’ characteristics may have influenced our estimates of benefits or risks, as well as the definition and validation of end points in individual trials. Indeed, the trial with an open design tended to produce results in favor of the tested drug.13 Blinded end point evaluation cannot avoid overreporting or underreporting of events by investigators. Second, there is limited trial evidence for ARBs in hypertension, especially for the comparison with ACE inhibitors, which might decrease the validity of the meta-analysis in general and metaregression analysis in particular. The ongoing ONTARGET Trial might provide some additional evidence.31 More studies are definitely required, considering the huge number of patients with hypertension who are currently exposed to various ARBs. Third, this analysis was restricted to trials in patients with hypertension or in patients with coronary artery disease or diabetic nephropathy, of whom the majority also had high blood pressure. Thus, the findings of this analysis cannot be directly extrapolated to other patient populations, such as those with acute myocardial infarction or congestive heart failure. Fourth, a few trials, such as ALLHAT,19,20 ASCOT,21 and VALUE,10 are much larger than the other studies included in our analysis and, hence, in pooled analyses may overwhelm the small trials. However, the results of the small trials appear qualitatively similar to those of the large trials so that the inequality of sample size probably does not greatly affect the overall results. In addition, we did not include in our analysis heart failure as an outcome, mainly because the diagnostic procedure for heart failure is inconsistent across trials, and because heart failure is not always precisely reported.

Our findings on amlodipine versus diuretics, ß-blockers, or ACE inhibitors are in keeping with the results of previous meta-analyses,1–5 which showed that calcium channel blockade in general provides more protection against stroke2–5 and that amlodipine in particular provides similar protection against myocardial infarction.1 For the comparison between amlodipine and ARBs, the pooled results remained virtually unaltered from the combined results of 2 trials17 after adding on data of the CASE-J Trial.18 Amlodipine provided 16% and 17% more protection against stroke and myocardial infarction than ARBs, in the presence of {approx}1.5 mm Hg of systolic pressure difference favoring amlodipine. The 1.5 mm Hg of difference in systolic blood pressure may account for most if not all of the difference in stroke and probably also in myocardial infarction.

Calcium channel blockade prevents intima-media thickening.32 This might contribute to the observed 11% of blood pressure–independent benefit of amlodipine on stroke. However, it is also possible that the benefit is only independent of blood pressure measured in the clinic, in the daytime, or at the brachial artery, but not necessarily independent of blood pressure obtained at home, for 24 hours, especially at night or at the aorta. There is some evidence that the latter pressures might be more predictive of cardiovascular outcome than the former pressure parameters.33 The ASCOT Conduit Artery Function Evaluation substudy showed that amlodipine-based regimen, compared with atenolol-based treatment, reduced central systolic pressure by 4.3 mm Hg, despite similar influence on brachial pressure.34 The ambulatory blood pressure–monitoring substudy of the ASCOT Trial reported recently in meetings that amlodipine-based regimen, compared with atenolol-based treatment, significantly reduced nighttime pressure. However, whether the difference in nighttime pressure or in central pressure estimated by a transfer function could account for outcome remains to be elucidated.

Our analysis on ARBs focused on trials in hypertension in the presence or absence of cardiovascular disease or diabetic nephropathy, and, hence, differed slightly from previous analyses on this issue.15,16 In general, ARBs provided average protection against stroke but inferior protection against myocardial infarction. The contrasting results between trials versus amlodipine and trials versus other drugs suggest that the outcome effect of ARBs depended on the comparator drug. This dependency, however, can still be attributable to blood pressure differences (–1.1 versus +0.7 mm Hg; {Delta}=1.8 mm Hg), despite insignificant results in the metaregression analysis. Ancillary pharmacological properties of certain drugs might also play a part. For instance, amlodipine prevents intima–media thickening.32

According to Fournier’s hypothesis, angiotensin type 1 receptor blockade is neuroprotective by the upregulation of the angiotensin type 2 receptor in the brain.35 However, there is insufficient evidence of randomized trials, in spite of significant findings in the MOSES13 and LIFE trials.8 The MOSES Trial had an open design, small sample size (n=1352), and high exclusion rate after randomization (3.8%).13 The LIFE Study compared losartan with atenolol, which had been repeatedly shown inferior to other classes of antihypertensive drugs, especially in stroke prevention,36,37 needless to say the significant, though small, blood pressure difference in favor of losartan.8 In addition, the estimation of the inferiority of ARBs in coronary prevention was relatively small (+13%), with a wide CI (+1 to +30%). This new class of drugs requires more randomized trials, especially in patients with hypertension.

Conclusions
The conclusions of our previous meta-analyses1–3 that blood pressure differences largely account for cardiovascular outcome remain valid, consistently and strongly emphasizing the desirability of tight blood pressure control. There is some evidence that certain drugs or classes of drugs might confer small blood pressure–independent superior or inferior influence on certain outcome measures or in certain populations. However, before we incorporate the tiny evidence into clinical guidelines, more studies are required.

Perspectives
As evidenced by ALLHAT19,20 and ASCOT,21 the 2 largest-ever trials in hypertension, amlodipine-based antihypertensive regimen, compared with other drug regimens, might confer more outcome benefit, possibly by lowering central systolic pressure34 or ambulatory pressure over 24 hours. The latter hypothesis should be tested against antihypertensive drugs, preferably long acting and other than ß-blockers, especially atenolol. Because ARBs are gaining market in most countries, there is urgent need for well-designed and well-conducted randomized, controlled trials. For instance, ARBs should be compared with ACE inhibitors to test whether the former are neuroprotective in acute stroke patients and to test whether the latter are more protective against myocardial infarction in patients with hypertension at high cardiac risk.


*    Appendix
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*Appendix
down arrowReferences
 
Acronyms of Trials
ACCESS (Acute Candesartan CilExetil therapy in Stroke Survivors24); ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial19,20); ALLHAT/Diu (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial–Amlodipine Versus Chlorthalidone19); ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial21,22); CAMELOT (Comparison of AMlodipine versus Enalapril to Limit Occurrences of Thrombosis12); CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan18); DETAIL (Diabetics Exposed to Telmisartan And enalaprIL Study11); IDNT (Irbesartan Diabetic Nephropathy Trial in patients with type-2 diabetes mellitus6); IRMA2 (IRbesartan in patients with type-2 diabetes and MicroAlbuminuria Study25); LIFE (Losartan Intervention For Endpoint reduction in hypertension8); MOSES (MOrbidity and mortality after Stroke, Eprosartan compared with nitrendipine for Secondary prevention13); PREVENT (Prospective Randomized Evaluation of the Vascular Effects Norvasc Trial23); RENAAL (Reduction of Endpoints in Noninsulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan7); SCOPE (Study on COgnition and Prognosis in the Elderly9); and VALUE (Valsartan Antihypertensive Long-term Use Evaluation Trial10).


*    Acknowledgments
 
Sources of Funding

This study was financially supported by grants from the National Natural Science Foundation of China (30571607), the Shanghai Commission of Science and Technology (06QA14043 [the Rising Star Project]), and the Shanghai Commission of Education (the Dawn Project).

Disclosures

S.S.F. is on the speakers bureau of Boehringer Ingelheim, Bristol–Myers Squibb, and Merck and on the consultant/advisory board of Bristol–Myers Squibb, AtCor Medical, Merck, and Pfizer. All compensation is insignificant except for that of the advisory board of Bristol–Myers Squibb. The remaining authors report no conflicts.

Received February 20, 2007; first decision March 13, 2007; accepted April 12, 2007.


*    References
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up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
up arrowAppendix
*References
 
1. Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 2003–2004 secondary prevention trials. Hypertens Res. 2005; 28: 385–407.[CrossRef][Medline] [Order article via Infotrieve]

2. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a meta-analysis. Lancet. 2001; 358: 1305–1315.(Correction. 2002;359:360.)[CrossRef][Medline] [Order article via Infotrieve]

3. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until March 2003. J Hypertens. 2003; 21: 1055–1076.[CrossRef][Medline] [Order article via Infotrieve]

4. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000; 355: 1955–1964.[CrossRef][Medline] [Order article via Infotrieve]

5. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527–1535.[CrossRef][Medline] [Order article via Infotrieve]

6. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345: 851–860.[Abstract/Free Full Text]

7. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861–869.[Abstract/Free Full Text]

8. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline] [Order article via Infotrieve]

9. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomised double-blind intervention trial. J Hypertens. 2003; 21: 875–886.[CrossRef][Medline] [Order article via Infotrieve]

10. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Platt F, Schork A, Smith B, Zanchetti A; VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004; 363: 2022–2031.[CrossRef][Medline] [Order article via Infotrieve]

11. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J; Diabetes Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004; 351: 1952–1961.[Abstract/Free Full Text]

12. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H, Buebendorf E, Topol EJ; CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary heart disease and normal blood pressure. The CAMELOT study: a randomized controlled trial. JAMA. 2004; 292: 2217–2226.[Abstract/Free Full Text]

13. Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, Zidek W, Dominiak P, Diener HC; MOSES Study Group. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention. Principal results of a prospective controlled study (MOSES). Stroke. 2005; 36: 1218–1226.[Abstract/Free Full Text]

14. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. These drugs may increase myocardial infarction and patients need to be told. BMJ. 2004; 329: 1248–1249.[Free Full Text]

15. Strauss MH, Hall AS. Do angiotensin receptor blockers increase the risk of myocardial infarction? Circulation. 2006; 114: 838–854.[Free Full Text]

16. Verdecchia P, Angeli F, Gattobigio R, Reboldi GP. Do angiotensin II receptor blockers increase the risk of myocardial infarction. Eur Heart J. 2005; 26: 2381–2386.[Abstract/Free Full Text]

17. Messerli FH, Staessen JA. Amlodipine better than lisinopril? How one randomized clinical trial ended fallacies from observational studies. Hypertension. 2006; 48: 359–361.(Correction. 2006;48:e24.)[Free Full Text]

18. Fukui T, Rahman M, Hayashi K, Takeda K, Higaki J, Sato T, Fukushima M, Sakamoto J, Morita S, Ogihara T, Fukiyama K, Fujishima M, Saruta T. Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial of cardiovascular events in high-risk hypertensive patients. Rationale, design and methods. Hypertens Res. 2003; 26: 979–990.[CrossRef][Medline] [Order article via Infotrieve]

19. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288: 2981–2997.[Abstract/Free Full Text]

20. Leenen FHH, Nwachuku CE, Black HR, Cushman WC, Davis BR, Simpson LM, Alderman MH, Atlas SA, Basile JN, Cuyjet AB, Dart R, Felicetta JV, Grimm RH, Haywood LJ, Jafri SZA, Proschan MA, Thadani U, Whelton PK, Wright JT; ALLHAT Collaborative Research Group. Clinical events in high-risk hypertensive patients randomized to calcium channel blocker vs. ACE-inhibitor in ALLHAT. Hypertension. 2006; 48: 374–384.[Abstract/Free Full Text]

21. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Östergren J; ASCOT Investigators. Prevention of cardiovascular events with an amlodipine /perindopril strategy compared with an atenolol /thiazide strategy. The Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005; 366: 895–906.[CrossRef][Medline] [Order article via Infotrieve]

22. Poulter NR, Wedel H, Dahlöf B, Sever PS, Beevers DG, Caulfield M, Kjeldsen JH, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Östergren J, Pocock S; ASCOT Investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm. Lancet. 2005; 366: 907–913.[CrossRef][Medline] [Order article via Infotrieve]

23. Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini J, Miller ME, Riley W; PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000; 102: 1503–1510.[Abstract/Free Full Text]

24. Schrader J, Lüders S, Kulschewski A, Berger J, Zidek W, Treib J, Einhäupl K, Diener HC, Dominiak P; ACCESS Study Group. The ACCESS Study. Evaluation of acute candesartan cilextil therapy in stroke survivors. Stroke. 2003; 34: 1699–1703.[Abstract/Free Full Text]

25. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001; 345: 870–878.[Abstract/Free Full Text]

26. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994; 50: 272–298.[Abstract/Free Full Text]

27. Mehta C, Patel N. Stratified 2 x 2 contingency tables. In: StatXact 4 for Windows. Statistical Software for Exact Nonparametric Inference. User Manual. Cambridge, MA: CYTEL Software Corporation; 1998: 469–496.

28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7: 177–188.[CrossRef][Medline] [Order article via Infotrieve]

29. Hedges LV, Olkin I. Statistical Methods for Meta-Analysis. San Diego, CA: Academic Press Inc; 1985.

30. Wang JG, Staessen JA, Franklin SS, Fagard R. Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension. 2005; 45: 907–913.[Abstract/Free Full Text]

31. Sleight P. Progress beyond hope and life: the ontarget trial programme. Eur Heart J. 2003; 5: F40–F47.[CrossRef]

32. Wang JG, Staessen JA, Li Y, Van Bortel LM, Nawrot T, Messerli FH, Safar M. Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized trial. Stroke. 2006; 37: 1933–1940.[Abstract/Free Full Text]

33. Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster J; Systolic Hypertension in Europe Trial Investigators. Predicting cardiovascular risk using conventional and ambulatory blood pressure in older patients with systolic hypertension. JAMA. 1999; 282: 539–546.[Abstract/Free Full Text]

34. The CAFE Investigators. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113: 1213–1225.[Abstract/Free Full Text]

35. Fournier A, Choukroun G, Modeliar SS, Godefroy O, Achard JM, Wang J, Messerli F. Does the MOSES trial establish superiority of AT1-receptor blockers over dihydropyridine/calcium antagonists in secondary stroke prevention? Stroke. 2006; 37: 336–337.[Free Full Text]

36. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA. 1998; 279: 1903–1907.[Abstract/Free Full Text]

37. Lindholm LH, Carlberg B, Samuelsson O. Should ß blockers r{epsilon}main first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005; 366: 1545–1453.[CrossRef][Medline] [Order article via Infotrieve]




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