Outcome beyond blood pressure control?
Jan A Staessena,*,
Ji-Guang Wanga and
Willem H Birkenhägerb
a Study Coordinating Centre, Laboratory of Hypertension, Department of Molecular and Cardiovascular Research, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
b Erasmus University, Rotterdam, The Netherlands
* Corresponding author. Tel.: +32-16-34-7104; fax: +32-16-34-7106
E-mail address: jan.staessen{at}med.kuleuven.ac.be
Received 22 October 2002;
accepted 23 October 2002
Key Words: Cardiovascular complications Coronary heart disease Hypertension Stroke
1. Introduction
The last two decades witnessed the publication of a large number of clinical outcome trials of blood pressure lowering agents in hypertensive patients or normotensive subjects with a high cardiovascular risk profile. Placebo-controlled trials of antihypertensive drug treatment in middle-aged or older hypertensive patients predominantly with diastolic hypertension1 proved that a 56mmHg decline in diastolic pressure maintained over 5 years diminished the incidence of stroke by nearly 40% and that of coronary endpoints by 15%. Similarly, in older patients with isolated systolic hypertension, pharmacological intervention during 4 years reduced systolic pressure on average by 10mmHg and decreased cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30%, and coronary events by 23%.2
Until recently, the consensual interpretation of the evidence produced by the outcome trials in hypertensive patients339 was that blood pressure is a risk factor amenable to intervention, lower levels leading to fewer complications. However, the HOPE trial40,41 gave rise to the hypothesis that angiotensin-converting enzyme inhibitors (ACEIs) might reduce cardiovascular complications beyond blood pressure control. Subsequently published trials of angiotensin II receptor blockers (ARBs) in hypertensive patients with renal failure4244 or left ventricular hypertrophy45,46 turned this concept into a major argument for drug marketing. The objectives of this editorial are to highlight the contribution of blood pressure lowering in the prevention of cardiovascular complications and to propose from a scientific perspective new research priorities for clinical trials in hypertension.
2. Older vs newer antihypertensive drugs
We recently reviewed nine outcome trials in 62,605 hypertensive patients, who had been randomized to conventional therapy with diuretics or ß-blockers or to initial treatment with newer classes of antihypertensive drugs, such as calcium-channel blockers (CCBs), ACEIs, or
-blockers.47 Compared with conventional therapy, CCBs and ACEIs offered similar overall cardiovascular protection, but CCBs provided more reduction in the risk of stroke (13.5%; 95% CI 1.3 to 24.2%;
) and less reduction in the risk of myocardial infarction (19.2%; 95% CI 3.537.3%;
).47 These cause-specific outcome results confirmed the findings of the Blood Pressure Lowering Treatment Trialists Collaboration.48 However, the wide confidence intervals demanded a cautious interpretation.47,48 A recent update of our meta-analysis (Fig. 1) also included 16,161 patients randomized to verapamil or conventional therapy in the CONVINCE trial.23,38 The number of patients allocated CCBs or conventional treatment thereby rose from 24,322 to 40,798. The relative risk reductions achieved by CCBs compared with older drugs averaged 8.1% (95% CI 3.2 to 18.3%;
) for stroke and 7.5% (95% CI 4.7 to 21.2%;
) for myocardialinfarction (Fig. 1).

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Fig. 1 Effects of antihypertensive treatment on fatal and non-fatal stroke and myocardial infarction in trials comparing conventional therapy initiated with diuretics or ß-blockers with therapy based on new drug classes. With the exception of the LIFE trial, fatal and non-fatal myocardial infarction includes sudden death. Solid squares represent the experimental-to-control odds ratios in trials and have sizes proportional to the number of events. The 95% CIs for individual trials are denoted by lines and those for pooled odds ratios by diamonds. Acronyms and references of trials are given in Appendix A.
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Among the actively controlled trials,47 we found significant heterogeneity in the outcomes of old and new drugs (Fig. 1). This was partly due to the higher risk of cardiovascular endpoints (odds ratio 1.25), stroke (1.19), and heart failure (2.04) on treatment with doxazosin compared with chlorthalidone in the ALLHAT trial33 as well as to the higher risk of stroke (1.25) on captopril than on conventional therapy in the CAPPP study27(Fig. 1).
3. Secondary prevention trials in high-risk patients
Several recently published trials35,36,3941,44 tested the hypothesis that agents that inhibit the reninangiotensin system are more effective than placebo in the secondary prevention of the cardiovascularrenal complications of hypertension. These agents reduced the incidence of cardiovascular events40,41 and stroke recurrence39 as well as the risk of overt nephropathy in diabetic patients with normoalbuminuria41 or microalbuminuria,44 but they did not reduce the rate of progression of coronary36 or carotid35 atherosclerosis. Furthermore, in patients with overt nephropathy due to diabetes42,43 orhypertension,49 ACEIs49 or ARBs42,43 were more effective than conventional therapy43 or amlodipine42,49 in postponing a doubling of the serum creatinine concentration or preventing end-stage renal disease. In keeping with Fleckenstein's animal experiments,50 two placebo-controlled trials51,52 and three trials with diuretics as reference treatment16,53,54 showed that CCBs are able to slow the progression of atherosclerosis. In older hypertensive patients with diabetes mellitus but normal renal function, therapy starting with a long-acting dihydropyridine, reduced the incidence of proteinuria by 68%
.55
4. A meta-regression analysis
In middle-aged and older patients, systolic pressure is the prevailing blood pressure component with regard to cardiovascular prognosis.56,57 Significant differences in systolic pressure of 23mmHg subsisted between the groups randomized in four trials comparing conventional therapy with the newer classes of antihypertensive drugs.16,27,32,33 As reported earlier, two of these trials27,33 caused significant heterogeneity in the overall outcome results of actively controlled trials.47 Obviously, the differences in achieved systolic pressurebetween patients allocated active treatment and placebo were significant in primary as well as secondary prevention trials. The systolic/diastolic differences were 2/0mmHg in RENAAL,43 3.3/1.0mmHg in HOPE,40 5/2mmHg in PATS,14 5/2mmHg in PROGRESS patients on monotherapy with perindopril,39 12/5mmHg in PROGRESS patients on combined treatment with perindopril and indapamide39 and 4.6/3.1mmHg in PART2 and SCAT taken together, being two smaller secondary prevention trials of ACEIs vs placebo with similar design.
A recently published47 and subsequentlyupdated58 meta-regression analysis (Fig. 2) included 149,407 patients randomized in 30 trials. Net treatment effects on systolic pressure were determined by subtracting the mean change in the experimental group (follow-up minus baseline) from the corresponding mean change in the reference group. Experimental groups were those assigned to the therapy to be tested (active vs placebo, new vs old drugs or tight vs less tight blood pressure control). We correlated odds ratios of experimental vs reference treatment with the corresponding differences in systolic pressure. For these calculations, odds ratios were logarithmically transformed. The regression lines were weighted by the inverse of the variance of the individual odds ratios. The differences between the observed odds ratios and those predicted by the meta-regression lines did not reach statistical significance for cardiovascular mortality, collective cardiovascular events, stroke, and myocardial infarction (including sudden death),47,58 except for stroke in the NORDIL,32 and PROGRESS39 trials. In NORDIL,32 the risk of stroke was lower on diltiazem (odds ratio 0.81; 95% CI 0.651.01) than on conventional drugs despite a 3.1mmHg higher systolic pressure. In the perindopril-only subgroup of the PROGRESS trial,39 systolic pressure was reduced by 5mmHg, but monotherapy with the ACE inhibitor did not affect the risk of all cardiovascular events (odds ratio 0.96; 0.801.15) or stroke recurrence (odds ratio 0.95; 95% CI 0.771.19). Thus, for the endpoints reviewed in our meta-regression analysis (Fig. 2), the benefit of antihypertensive treatment could be explained by blood pressure lowering.

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Fig. 2 Published odds ratios for cardiovascular events were regressed on baseline-adjusted net differences between randomized groups across 30 trials. The regression line was plotted with 95% CI, was adjusted for the mean systolic pressure at entry, and was weighted for the inverse of the variance of individual odds ratios. Filled symbols denote trials that compared new with old drugs. Acronyms of trials are given in Appendix A. The data have been reproduced with permission.47
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5. Benefit beyond blood pressure lowering?
LIFE was a double-blind parallel-group trial involving 9193 patients randomized to first-line treatment with losartan or atenolol to test the hypothesis whether selective blockade of type-1 angiotensin II receptors might reduce the incidence of cardiovascular morbidity and death beyond blood pressure control.12 In all patients combined,46 blood pressure fell by 30.2/16.6mmHg in the losartan group and by 29.1/16.8mmHg in patients allocated atenolol. In 1195 diabetic patients,46 these decreases amounted to 31/17 and 28/17mmHg, respectively. The primary endpoint consisted of non-fatal myocardial infarction, non-fatal stroke, and mortality due to myocardial infarction, stroke, sudden death, heart failure, or other cardiovascular causes. In the losartan compared with the atenolol group, relative risk decreased by 13% (95% CI 232%;
) in all patients46 and by 24% (95% CI 232%;
) in the diabetic subgroup.45 From the publishedreports,45,46 we calculated the outcome results in the 7998 non-diabetic patients and compared non-cardiovascular mortality according to randomization in diabetic as well as in non-diabetic patients (Fig. 3). The researchers of the LIFE study45,46 reported that adjustment for on-treatment blood pressure had little effect on endpoints. Their conclusion was that first-line treatment with losartan, compared with atenolol, improved outcome over and beyond blood pressure control.45,46 They did not consider the alternative hypothesis that atenolol might have fallen short of the expectation based on the decline in blood pressure.59

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Fig. 3 Outcome results in diabetic and non-diabetic patients randomized in the LIFE trial. Results for non-cardiovascular mortality and those for non-diabetic patients were calculated from unadjusted outcome data.45,46
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The LIFE investigators measured achieved blood pressure at the end of follow-up (mean 4.8 years) or just before an event.45,46 This definition did not account for the differences in systolic pressure (higher on atenolol), diastolic pressure (lower on atenolol), or pulse pressure (higher on atenolol), which occurred during the first years of follow-up. In the ß-blocker compared with the losartan group, more patients withdrew from double-blind medication (27.1 vs 22.6%;
), whereas fewer proceeded to combination therapy (61.7 vs 65.9%;
). The LIFE consortium did not publish the parameters of fully adjusted Cox models, including an appropriate component of the on-treatment blood pressure (systolic pressure or pulse pressure) as well as the interaction between randomization group and achieved blood pressure. This interaction term tests whether for the same on-treatment blood pressure, outcome significantly different according to randomization. The decrease of non-cardiovascular mortality by 42% (95% CI 565%;
) in the diabetic LIFE patients (Fig. 3), which we noticed in our calculations from the published outcome data,45,46 remains unaccounted for. There is consensus that ß-blockade reduces the incidence of sudden death, especially among patients with left ventricular dysfunction.60 Nonetheless, suddendeath was not included in the definition of myocardial infarction nor analysed as a separate endpoint. Stroke is the hypertensive complication, which is most amenable to prevention even by a few millimetres mercury reduction in bloodpressure.1,47 The beneficial outcome in the losartan group46 was mainly driven by a reduction of the stroke rate (Fig. 3). In our view (Table 1), the LIFE trial results as well as those of two other trials in patients with left ventricular dysfunction61,62 did not deviate from what one might expect based on the differences in achieved systolic pressure, which averaged 1mmHg in all LIFE patients,46 3mmHg in the diabetic subgroup of the LIFE trial,45 and 6mmHg in two other trials.61,62 We believe that by taking the blood pressure at the end of follow-up the systolic blood pressure gradient between the groups randomized in the LIFE trial was underestimated by 23mmHg. Accounting for anunbiased on-treatment systolic pressure might even move the LIFE data points to the right closer to the regression line than suggested by our plot (Fig. 4).

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Fig. 4 Odds ratios for cardiovascular events in all LIFE patients (LIFE/ALL),46 in diabetic LIFE patients (LIFE/DM),45 and in two trials of ACEIs vs placebo in patients with left ventriculardysfunction.61,62 The published odds ratio were plotted as a function of the observed differences in systolic pressure between randomized groups and were superimposed on the meta-regression model given in Fig. 3.
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6. Economic implications of trial results
Statistics over 12 months to March 2000 showed that hypertension was the leading diagnosis for drug prescriptions to patients older than 50 years both in Europe and in North America.63 In both markets, around one in four prescriptions for hypertension was for ACEIs (plain or in combination), while a further one in five was for calcium-channel blockers (plain). Diuretics were the third most common treatment and together with ß-blockers accounted for almost 30% of all prescriptions written for hypertension. ARBs are the fastest-growing class of antihypertensive agents with a 510% market share. Sales of cardiovascular drugs at retail pharmacies in the main markets of Europe, the Americas, and Japan totalled approximately 52,000 million.64
In an era of strong reliance on evidence-based treatment guidelines,65,66 clinical outcome trials are increasingly becoming a marketing tool for antihypertensive drugs. The silent infiltration of commercial incentives into the scientific objectives of clinical trials increases the probability of selective presentation or a one-sided interpretation of the results. The saying that one sees only what one looks for is bearing upon the matter. Patient characteristics and reference drugs may be chosen to maximize the probability of success. Although selection substantially narrows the external validity of trials, results may nevertheless be presented as being applicable to unselected patients with or without hypertension. Furthermore, sponsors may decide to close clinical trials prematurely, if business interests will not be met or change over time. Blinded validation of disease outcomes in open trials67 saves costs. However, this design does not rule out the possibility that prior knowledge of treatment allocation results in selective over-reporting or under-reporting of events. Rates of adverse effects, such as for instance ankle oedema on CCBs or cough on ACEIs, are on average twice as high in open trials as in double-blind studies.
7. Perspective on future trials in hypertension
Benefit beyond blood pressure control has been a leading theme in comparative trials in hypertensive patients,45,46 in placebo-controlled studies in high-risk normotensive and hypertensive patients,3941 and in recently published trials in patients with diabetic nephropathy.4244 Notwithstanding, the publicity on which drug is the better choice to initiate antihypertensive treatment, this is largely an obsolete question. The reductionist idea that interference with a single pathophysiological mechanism40,41,45,46 provides a leading edge in the treatment of hypertension is an oversimplification that ignores the heterogeneous nature of this disorder. The overwhelming majority of hypertensive patients have to proceed to combination therapy to achieve blood pressure control.22 A host of other research themes with far larger clinical relevance must be addressed. A few examples are given below.
Regulators continue to approve drugs for antihypertensive treatment based on their potential to lower blood pressure, an intermediate endpoint. In spite of the overwhelming evidence highlighting the risk of systolic hypertension in the elderly2 and the risk possibly associated with a forced reduction of a normal diastolic pressure,68 regulators still insist that both systolic and diastolic blood pressures must be lowered for a new drug to be approved. The hypothesis that in older patients selective lowering of systolic pressure, for instance by long-acting nitrates,69 might improve prognosis more than the indiscriminate reduction of both systolic and diastolic pressures, remains to be tested. A further and more compelling issue is whether blood pressure lowering can prevent vascular and neurodegenerative dementia. In placebo-controlled trials, treatment based on thiazides,8,70 ß-blockers,8,70 the ACEI perindopril given inmonotherapy39,
or the ARB candesartan71,
failed to protect against cognitive impairment and dementia.2,3 In contrast, therapy initiated with nitrendipine reduced the incidence of dementia by half.72,73 Dihydropyridine CCBs cross the bloodbrain barrier74,75 and reduce the turnover of monoamine neurotransmitters,74 of which many are deficient in degenerative dementias.76 In view of the pandemic of mainly neurodegenerativedementia,77 the question whether dihydropyridines specifically protect against cognitiveimpairment72,73 must be addressed.
Placebo-controlled trials with double-blind design should be mounted to establish the benefit to risk ratio and cost effectiveness of treating mild isolated systolic hypertension in patients without cardiovascular complications78 and to determine the optimal level to which systolic pressure and pulse pressure79 must be lowered. In contrast to recent suggestions,80 there is no evidence that a high-normal blood pressure should be lowered in subjects with average cardiovascular risk. The question to what extent race,81,82 gender,83 and genetic predisposition8486 should be accounted for in prescriptions for individual patients increasingly merits attention. Indeed, the number of hypertensive patients seeking treatment will continuously grow, not only because people live longer and hypertension is age-related, but also because blood pressure thresholds for diagnosis and effective control of the condition may be expected to decline further in the years to come as they did in the past.78
8. Conclusions
In trials in hypertensive and high-risk patients, lower systolic blood pressure was associated with better outcome. Although we did not investigate to what extent blood pressure should be lowered, our findings indicate that blood pressure control is important. On balance, all antihypertensive drugs share similar long-term efficacy and safety. Accepting this point of view, will free resources to address new issues with far greater clinical relevance than the question which drug is better.
Appendix AAcronyms of trials
ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial33); ATMH (Australian Trial in Mild Hypertension13); CAPPP (Captopril Prevention Project27); CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular Endpoints Trial23,38); EWPHE (trial conducted by the European Working Party on High Blood Pressure in the Elderly3); HEP (trial of Hypertension in Elderly Patients in primary care4); HOPE (Heart Outcomes Prevention Evaluation Study40,41); HOT (Hypertension Optimal Treatment trial22); HOT M vs H (Hypertension Optimal Treatment trial2285 vs 90mmHg as target diastolic pressure); HOT L vs H (Hypertension Optimal Treatment trial2280 vs 90mmHg as target diastolic pressure); HSCS (HypertensionStroke Cooperative Study17); IDNT2 (Irbesartan Diabetic Nephropathy Trial in patients with type-2 diabetes mellitus42); INSIGHT (International Nifedipine GITS StudyIntervention as a Goal for Hypertension Therapy31); IRMA2 (Irbesartan in patients with type-2 diabetes and MicroAlbuminuria study44); LIFE (Losartan Intervention For Endpoint Reduction in hypertension study12,45,46); MIDAS (Multicenter Isradipine Diuretic Atherosclerosis Study16); MIDAS/NICS/VHAS (combined results of MIDAS,16 NICS,28 and VHAS34); MRC1 (Medical Research Council trial of treatment of mild hypertension7); MRC2 (Medical Research Council trial of treatment of hypertension in older adults6); NICS (National Intervention Cooperative Study in Elderly Hypertensives28); NORDIL (Nordic Diltiazem Study32); OSLO (Oslo Study on the Treatment of Mild Hypertension15); PART2 (Prevention of Atherosclerosis with Ramipril Trial35); PART2/SCAT (combined results of PART235 and SCAT36); PATS (Post-stroke Anti-hypertensive Treatment Study14); PROGRESS (Perindopril Protection Against Recurrent Stroke Study30,39); PROGRESS/Com (Perindopril PrOtection Against Recurrent Stroke Study30,39group on combined therapy); PROGRESS/Per (Perindopril PrOtection Against Recurrent Stroke Study30,39group on single-drug treatment); RCT70-80 (combined results of four smaller trials published from 1970 through 1980, including HSCS,17 OSLO,15 USPHS,18 and VACS19); RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II AntagonistLosartan43); SCAT (Simvastatin/Enalapril Coronary Atherosclerosis Trial36); SHEP (Systolic Hypertension in the Elderly Program8,10); STONE (Shanghai Trial of Nifedipine in the Elderly9); STOP1 (Swedish Trial in Old Patients with hypertension5); STOP2(Swedish Trial in Old Patients with hypertension-229);STOP2/ACEIs (Angiotensin-Converting Enzyme Inhibitor arm of STOP229); STOP2/CCBs (Calcium-Channel Blocker arm of STOP229); Syst-China (Systolic Hypertension in China trial20,25); Syst-Eur (Systolic Hypertension in Europe trial11,21,24); UKPDS (UKPDS Hypertension in Diabetes Study26,37); UKPDS C vs A (UKPDS Hypertension in Diabetes Studycaptopril vs atenolol37); UKPDS L vs H (UKPDS Hypertension in Diabetes Studylow vs high on-treatment blood pressure26); USPHS (United States Public Health Service Hospitals Cooperative Study18); VACS (Veterans Administration Cooperative Study in patients with diastolic blood pressure averaging 90114mmHg19); VHAS (Verapamil in Hypertension and Atherosclerosis Study34).
Footnotes
Dr H. Black (RUSH-Presbyterian-St Luke's Medical Center, Chicago, IL, USA) presented the results of the CONVINCE trial on 18 May 2002 at the 17th Annual Scientific Meeting of the American Society of Hypertension (New York). The number of endpoints are available on-line at http://www.gik.gr.jp/
skj/mega_ht/convince.php3 (accessed 1 October 2002). 
Dr J. Chalmers (University of Sydney, Australia) presented the PROGRESS results on dementia and cognitive function on 17 May 2002 at the 17th Annual Scientific Meeting of the American Society of Hypertension (New York). 
Dr H. Lithell (University of Uppsala, Sweden) presented the SCOPE results on dementia on 27 June 2002 at the joint 19th/12th Scientific Meeting of the International/European Society of Hypertension. 
References
- Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272298.[Abstract]
- Staessen JA, Gasowski J, Wang JG et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355:865872.[CrossRef][Medline]
- Amery A, Birkenhäger W, Brixko P et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet. 1985;i:13491354.
- Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J. 1986;293:11451151.[Medline]
- Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991;338:12811285.[Medline]
- MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J. 1992;304:405412.[Medline]
- Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J. 1985;291:97104.[Medline]
- SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:32553264.[Abstract]
- Gong L, Zhang W, Zhu Y et al. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens. 1996;14:12371245.[Medline]
- Curb JD, Pressel SL, Cutler JA et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA. 1996;276:18861892.[Abstract]
- Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757764.[CrossRef][Medline]
- Dahlöf B, Devereux R, de Faire U et al. The Losartan Intervention For Endpoint Reduction (LIFE) in hypertension study: rationale, design and methods. Am J Hypertens. 1997;10:705713.[CrossRef][Medline]
- Management Committee. The Australian Therapeutic Trial in Mild Hypertension. Lancet. 1980;i:12611267.
- PATS Collaborative Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J. 1995;108:710717.[Medline]
- Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. Am J Med. 1980;69:725732.[Medline]
- Borhani NO, Mercuri M, Borhani PA et al. Final outcome results of the multicenter isradipine diuretic atherosclerosis study (MIDAS). A randomized controlled trial. JAMA. 1996;276:785791.[Abstract]
- Hypertension-Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. JAMA. 1974;229:409418.[CrossRef][Medline]
- US Public Health Service Hospitals Cooperative Study Group (McFate Smith WM). Treatment of mild hypertension:results of a ten-year intervention trial. Circ Res. 1977;40:98105.[Abstract]
- Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115129 mm Hg. JAMA. 1967;202:116122.[CrossRef][Medline]
- Liu L, Wang JG, Gong L, Liu G, Staessen JAfor the Systolic Hypertension in China (Syst-China) Collaborative Group. Comparison of active treatment and placebo in older patients with isolated systolic hypertension. J Hypertens. 1998;16:18231829.[CrossRef][Medline]
- Tuomilehto J, Rastenyte D, Birkenhäger WH et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med. 1999;340:677684.[Abstract/Free Full Text]
- Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:17551762.[CrossRef][Medline]
- Black HR, Elliott WJ, Neaton JD et al. Rationale and design for the controlled onset verapamil investigation of cardiovascular endpoints (CONVINCE) trial. Control Clin Trials. 1998;19:370390.[CrossRef][Medline]
- Staessen JA, Thijs L, Birkenhäger WH, Bulpitt CJ, Fagard Ron behalf of the Syst-Eur Investigators. Update on the Systolic Hypertension in Europe (Syst-Eur) Trial. Hypertension. 1999;33:14761477.[Free Full Text]
- Wang JG, Staessen JA, Gong L, Liu Lfor the Systolic Hypertension in China (Syst-China) Collaborative Group. Chinese trial on isolated systolic hypertension in the elderly. Arch Intern Med. 2000;160:211220.[Abstract/Free Full Text]
- UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J. 1998;317:703713.[Abstract/Free Full Text]
- Hansson L, Lindholm LH, Niskanen L et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611616.[CrossRef][Medline]
- National Intervention Cooperative Study in Elderly Hypertensives Study Group. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. Hypertension. 1999;34:11291133.[Abstract/Free Full Text]
- Hansson L, Lindholm LH, Ekbom T et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354:17511756.[CrossRef][Medline]
- PROGRESS Management Committee. PROGRESSPerindopril Protection Against Recurrent Stroke Study: characteristics of the study population at baseline. J Hypertens. 1999;17:16471655.[CrossRef][Medline]
- Brown MJ, Palmer CR, Castaigne A et al. Morbidity and mortality in patients randomised to double-blind treatment with long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertensive Treatment (INSIGHT). Lancet. 2000;356:366372.[CrossRef][Medline]
- Hansson L, Hedner T, Lund-Johansen P et al. Randomised trial of effects of calcium antagonists compared with diuretics and ß-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000;356:359365.[CrossRef][Medline]
- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs. chlorthalidone. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283:19671975.[Abstract/Free Full Text]
- Agabiti Rosei E, Dal Palú C, Leonetti G et al. Clinical results of the Verapamil in Hypertension and Atherosclerosis Study. J Hypertens. 1997;15:13371344.[CrossRef][Medline]
- MacMahon S, Sharpe N, Gamble G et al. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. J Am Coll Cardiol. 2000;36:438443.[CrossRef][Medline]
- Teo KK, Burton JR, Buller CE et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis. The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation. 2000;102:17481754.[Abstract/Free Full Text]
- UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J. 2000;317:713720.
- Black HR, Elliott WJ, Neaton JD et al. Baseline characteristics and early blood pressure control in the CONVINCE trial. Hypertension. 2001;37:1218.[Abstract/Free Full Text]
- PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure lowering regimen among 6105 individuals with prior stroke or transient ischaemic attack. Lancet. 2001;358:10331041.[CrossRef][Medline]
- The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145153.[Abstract/Free Full Text]
- Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253259.[CrossRef][Medline]
- Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851860.[Abstract/Free Full Text]
- Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861869.[Abstract/Free Full Text]
- Parving HH, Lehnert H, Bröchner-Mortensen J et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870878.[Abstract/Free Full Text]
- Lindholm LH, Ibsen H, Dahlöf B et al. Cardiovascularmorbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:10041010.[CrossRef][Medline]
- Dahlöf B, Devereux RB, Kjeldsen SE et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:9951003.[CrossRef][Medline]
- Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a meta-analysis. [erratum published in The Lancet 2002, volume 359, January 26, p. 360]Lancet. 2001;358:13051315.[CrossRef][Medline]
- 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;355:19551964.[CrossRef][Medline]
- Agodoa LY, Appel L, Bakris GL et al. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis. JAMA. 2001;285:27192728.[Abstract/Free Full Text]
- Fleckenstein A, Frey M, Thimm F, Fleckenstein-Grün G. Excessive mural calcium overloadA predominant causal factor in the development of stenosing coronary plaques in humans. Cardiovasc Drugs Ther. 1990;4:10051014.[Medline]
- Lichtlen PR, Hugenholtz PG, Rafflenbeul W et al. Retardation of coronary artery disease in humans by the calcium-channel blocker nifedipine: results of the INTACT Study (International Trial on Antiatherosclerotic Therapy). Cardiovasc Drugs Ther. 1990;4:10471068.[Medline]
- Pitt B, Byington RP, Furberg CD et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102:15031510.[Abstract/Free Full Text]
- Zanchetti A, Agabiti Rosei E, Dal Palú C et al. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens. 1998;16:16671676.[CrossRef][Medline]
- Simon A, Gariépy J, Moyse D, Levenson J. Differentialeffects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation. 2001;103:29492954.[Abstract/Free Full Text]
- Voyaki SM, Staessen JA, Thijs L et al. Follow-up of renal function in treated and untreated older patients withisolated systolic hypertension. J Hypertens. 2001;19:511519.[CrossRef][Medline]
- Staessen J, Amery A, Fagard R. Editorial review. Isolated systolic hypertension in the elderly. J Hypertens. 1990;8:393405.[Medline]
- Franklin SS, Larson MG, Khan SA et al. Does the relation of blood pressure to coronary heart disease change with aging? The Framingham Heart Study. Circulation. 2001;103:12451249.[Abstract/Free Full Text]
- Staessen JA, Wang JG, Thijs L. Calcium-channel blockade and cardiovascular prognosis: recent evidence from clinical outcome trials. Am J Hypertens. 2002;15:85S93.[CrossRef][Medline]
- Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA. 1998;279:19031907.[Abstract/Free Full Text]
- Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;XXVII:335345.
- Pfeffer MA, Braunwald E, Moyé LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992;327:669677.[Abstract]
- Yusuf S, Pepine CJ, Garces C et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992;340:11731178.[Medline]
- Intercontinental Marketing Services Health (IMS Health). The boom of the baby boomers. Accessed on 9 September 2002 athttp://www.ims-global.com//insight/news_story/ 0101/news_story_010123.htm.
- Intercontinental Marketing Services Health (IMS Health). World drug purchasesretail pharmacies. Accessed on 9 September 2002 athttp://www.ims-global.com.
- The Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:24132446.[Abstract]
- Guidelines Subcommittee. 1999 World Health OrganizationInternational Society of Hypertension guidelines for the management of hypertension. J Hypertens. 1999;17:151183.[CrossRef][Medline]
- Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Blood Press. 1992;1:113119.[Medline]
- Somes GW, Pahor M, Shorr RI, Cushman WC, Applegate WB. The role of diastolic blood pressure when treating isolated systolic hypertension. Arch Intern Med. 1999;159:20042009.[Abstract/Free Full Text]
- Duchier J, Iannascoli F, Safar M. Antihypertensive effect of sustained-release isosorbide dinitrate for isolated systolic systemic hypertension in the elderly. Am J Cardiol. 1987;60:99102.[Medline]
- Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council's treatment trial of hypertension in older adults. Br Med J. 1996;312:801805.[Abstract/Free Full Text]
- Hansson L, Lithell H, Skoog I et al. Study on COgnition and Prognosis in the Elderly (SCOPE). Blood Press. 1999;8:177183.[CrossRef][Medline]
- Forette F, Seux ML, Staessen JA et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998;352:13471351.[CrossRef][Medline]
- Forette F, Seux ML, Staessen JA et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) Study. Arch Intern Med. 2002;162:20462052.[Abstract/Free Full Text]
- Hong YL. The relationship between calcium antagonist-induced hypotension and central monoaminergic system in spontaneously hypertensive rats. Int J Clin Pharmacol Ther Toxicol. 1987;11:589597.
- Murzenok PP, Huang BS, Leenen FHH. Sympathoinhibition by central and peripheral infusion of nifedipine in spontaneously hypertensive rats. Hypertension. 2000;35:631636.[Abstract/Free Full Text]
- Parnetti L, Senin U, Mecocci P. Cognitive enhancement therapy for Alzheimer's disease. The way forward. Drugs. 1997;53:752768.[Medline]
- Fratiglioni L, De Ronchi D, Agüero-Torres H. Worldwide prevalence and incidence of dementia. Drugs Aging. 1999;15:365375.[Medline]
- Tikhonoff V, Casiglia E, Nawrot T, Staessen JA. Should high-normal blood pressure be treated? J Hypertens. 2002;20:10281030.[CrossRef]
- Blacher J, Staessen JA, Girerd X et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med. 2000;160:10851089.[Abstract/Free Full Text]
- Rowland Yeo K, Yeo WW. Should we treat high-normal blood pressure? J Hypertens. 2002;20:20572062.[CrossRef][Medline]
- Materson BJ, Reda DJ, Cushman WC et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328:914921.[Abstract/Free Full Text]
- Sareli P, Radevski IV, Valtchanova ZP et al. Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects. Results of a randomized trial in Johannesburg, South Africa. Arch Intern Med. 2001;161:965971.[Abstract/Free Full Text]
- Safar ME, Myers MG, Leenen F, Asmar R. Gender influence on the dose-ranging of a low-dose perindoprilindapamide combination in hypertension: effect on systolic and pulse pressure. J Hypertens. 2002;20:16531661.[CrossRef][Medline]
- Ferrari P, Bianchi G. Genetic mapping and tailored antihypertensive therapy. Cardiovasc Drugs Ther. 2000;14:387395.[CrossRef][Medline]
- Psaty BM, Smith NL, Hecbert SR et al. Diuretic therapy, the
-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA. 2002;287:16801690.[Abstract/Free Full Text]
- van der Kleij FGH, de Jong PE, Henning RH, de Zeeuw D, Navis G. Enhanced responses of blood pressure, renal function and aldosterone to angiotensin I in DD genotype are blunted by low sodium intake. J Am Soc Nephrol. 2002;13:10251033.[Abstract/Free Full Text]