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NDT Advance Access originally published online on December 29, 2005
Nephrology Dialysis Transplantation 2006 21(4):843-845; doi:10.1093/ndt/gfk025
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial Comment

Blood pressure lowering or selection of antihypertensive agent: which is more important?

Luis M. Ruilope and Julian Segura

Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain

Correspondence and offprint requests to: Dr Luis M. Ruilope, Hypertension Unit, Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain. Email: ruilope{at}ad-hocbox.com

Keywords: Blood pressure; antihypertensive therapy; cardiovascular risk; renal insufficiency

The relationship between an elevated blood pressure (BP) and cardiovascular (CV) and renal damage has been clearly established. It has remained a matter of debate, however, whether effects beyond BP control force the clinician to prefer certain class(es) of antihypertensive drug(s) beyond what nowadays are considered compelling indications for antihypertensive therapy.



   The ALLHAT study
Top
 The ALLHAT study
The LIFE and ASCOT...
 Renoprotection
 The evidence
 Conclusion
 References
 
After the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [1], those defending the idea that only BP control matters have argued that diuretics are the first-choice drugs and this stance has been supported by the Joint National Committee-7, in the absence of real arguments according to the definition of evidence-based medicine [2]. Among the many flaws in the ALLHAT study, we simply point out that probably two-thirds of the patients were on a diuretic before entering the trial; they were then selected as responders to this type of drug and this creates a relevant bias in the final result, because this type of therapy was given many more possibilities to be the winner. Even so, the primary endpoint analysis revealed that there were no significant differences between a diuretic, a dihydropiridine and an angiotensin-converting enzyme (ACE) inhibitor – despite the presence of BP differences, which in the opinion of many experts could explain significant differences in CV outcome [3]. To buttress this argument, the analysis of the Trialist Group [4] revealed that what really matters is BP control.



   The LIFE and ASCOT trials
Top
 The ALLHAT study
 The LIFE and ASCOT...
Renoprotection
 The evidence
 Conclusion
 References
 
Recently, two studies have been published which will presumably force physicians to change past concepts in favour of considering that not all antihypertensive drugs were created equal. These are the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE) [5] and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) [6] trials.

Both studies differed from previous trials in one aspect: they selected patients at earlier stages of CV disease. In particular, the recent Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE) [7] included mostly patients with established CV disease. In contrast, the LIFE study included patients with left ventricular hypertrophy; in other words, patients with target organ damage (TOD) that precedes the development of established CV disease [5]. ASCOT went even further and entered patients only when three or more associated risk factors were present and when there was no history of coronary heart disease or myocardial infarction [6].

To establish a potential difference between two antihypertensive drugs with respect to better CV protection, one has to perform an analysis of the time elapsed till the occurrence of an event conforming to the primary endpoint of the trial. A significant difference in the time elapsed till the development of those events in one of the two arms, when compared with the other, allows to conclude that the drug used in that arm provides more CV protection.

When the VALUE trial was initially designed [8] it was assumed that a sufficient number of events should occur because subjects with a very elevated CV risk were recruited and most had established CV disease. It was hoped that this would permit a clear differentiation between valsartan and amlodipine. However, the time to event analysis revealed that with respect to the primary endpoint there was no significant difference. In our opinion [9], this indicates that small differences in BP are able to drive events in advanced stages of CV disease. We assume that this mechanism contributed to the outcome and explains the finding.

In contrast to the VALUE study, the LIFE and ASCOT studies found significant differences in the capacity to provide CV protection between the two therapies compared. We believe that in these two studies regression of TOD as well as prevention of progression of atherosclerosis occurred in a relevant proportion of patients. If the drug(s) that were compared differed with respect to their capacity to regress TOD and to prevent progression of atherosclerotic plaques, one would have an explanation as to why the beta-blocker and the diuretic were inferior in the LIFE and ASCOT trials.



   Renoprotection
Top
 The ALLHAT study
 The LIFE and ASCOT...
 Renoprotection
The evidence
 Conclusion
 References
 
The same argument may be applicable to the issue of renoprotection and a similar debate is alive in the renal community. The available evidence for renoprotection has been obtained in studies on patients with chronic renal failure and proteinuria, in whom it is practically impossible to attain the BP goal according to guidelines. The argument that ACE inhibitors and angiotensin-receptor blockers (ARB) achieved positive renal results, in particular on albuminuria, in the absence of the desired BP control is totally valid. Studies performed in patients at earlier stages of renal disease could contribute to clarify this point, because in these adequate BP control might be achieved, at least theoretically, in a relevant percentage of cases. This strategy would allow differentiation between the effects on urinary albumin excretion of BP control attained with or without simultaneous suppression of the renin–angiotensin–aldosterone system (RAAS). This strategy was attempted in the paper of Estacio et al. [10], who studied normotensive diabetics and found that nisoldipine and enalapril did not differ in their capacity to prevent the development of microalbuminuria – provided that the control of BP was really strict in a relevant percentage of patients. This result is in contrast to the recently published Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) study in type 2 diabetic patients [11]. The authors compared trandolapril alone or in combination with verapamil. In both arms of the study the result differed significantly from placebo with respect to the primary prevention of microalbuminuria. The result seems to indicate that even in this early stage of renal damage, it is difficult to reach the BP goal (<130/80 mmHg). If one aims to preserve renal function, studies with prolonged follow-up will be required to obtain solid proof of renoprotection, i.e. to obtain a yearly decrease in glomerular filtration rate that is not in excess of what would be expected with advancing age in a normoalbuminuric subject.



   The evidence
Top
 The ALLHAT study
 The LIFE and ASCOT...
 Renoprotection
 The evidence
Conclusion
 References
 
What evidence is available? Results of studies in individuals with advanced renal failure accompanied by proteinuria indicate that even when strict BP control is achieved, progression persists if proteinuria is present [12]. Strict proteinuria control, theoretically even remission of proteinuria, is then required in addition to BP control. Even the excretion of small amounts of protein in the urine, for instance as found in a percentage of patients with nephrosclerosis, is a most potent predictor of a poor outcome of renal function – provided the follow-up is long enough [13]. This strongly favours the argument that it is necessary to suppress the RAAS in all patients presenting with albumin excretion rates, even when this is only in the range of microalbuminuria.

In any case, the argument of selection of ‘renoprotective’ antihypertensive agents is somewhat academic, because combination therapy is needed in most of these patients to lower BP to target levels. This fact alone is a strong argument for considering an ACE inhibitor or an ARB as a part of the combination.

Another interesting argument could contribute to finish this debate. For renal patients, the risk of death from CV causes is greater than the risk of progression to end-stage renal disease. A close association between renal damage and CV disease is present even in early stages of renal disease [14]. This association forces the physician to consider simultaneously the need for CV and renal protection. Recent data show that patients with chronic kidney disease respond particularly well to an ACE inhibitor [15] and to a statin [16] when the CV outcome is considered. Furthermore, data from the Hypertension Optimal Treatment (HOT) study indicated that the prevention of myocardial infarction obtained with aspirin was particularly pronounced in patients with elevated levels of serum creatinine [17]. Calcium antagonists, particularly in association with blockade of the RAAS for renoprotection and CV protection, also confer benefit as recognized in the recent publication of the ASCOT study [6].

In turn, if one aims at CV protection, does one kill two birds with one stone and simultaneously improve renal outcome? Two pieces of evidence in this direction can be mentioned here. First, statins have been shown to ameliorate proteinuria [18]. Second, attenuation of the annual decrease in estimated creatinine clearance, ~1 ml/min/year, was observed in the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) study when patients with established coronary artery disease and angina were treated with a statin and aspirin [19].



   Conclusion
Top
 The ALLHAT study
 The LIFE and ASCOT...
 Renoprotection
 The evidence
 Conclusion
References
 
In summary, in the future an earlier treatment is required for the simultaneous protection of the kidney and the CV system. An earlier intervention will, in most cases, necessitate an integral therapeutic approach comprising strict control of BP (including an ACE inhibitor or an ARB) with the aim of reducing albuminuria, if present, and medication to deal with the associated CV risk factors.

Conflict of interest statement. None declared.



   References
Top
 The ALLHAT study
 The LIFE and ASCOT...
 Renoprotection
 The evidence
 Conclusion
 References
 

  1. 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]
  2. Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572[Abstract/Free Full Text]
  3. Staessen JA, Birkenhager WH. Evidence that new antihypertensives are superior to older drugs. Lancet 2005; 366: 869–871[CrossRef][Web of Science][Medline]
  4. Turnbull F, 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][Web of Science][Medline]
  5. Dahlof B, Devereux RB, Kjeldsen SE et al.; 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][Web of Science][Medline]
  6. Dahlof B, Sever PS, Poulter NR et al.; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906[CrossRef][Web of Science][Medline]
  7. Julius S, Kjeldsen SE, Weber M et al.; VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022–2031[CrossRef][Web of Science][Medline]
  8. Mann J, Julius S. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Blood Press 1998; 7: 176–183[CrossRef][Medline]
  9. Ruilope LM, Segura J. Hope in life and value of blood pressure control. J Hypertens 2004; 22: 2265–2266[CrossRef][Medline]
  10. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002; 61: 1086–9710[CrossRef][Web of Science][Medline]
  11. Ruggenenti P, Fassi A, Ilieva AP et al.; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004; 351: 1941–1951[Abstract/Free Full Text]
  12. De Zeeuw D, Remuzzi G, Parving HH et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309–2320[CrossRef][Web of Science][Medline]
  13. Segura J, Campo C, Rodicio JL, Ruilope LM. ACE inhibitors and appearance of renal events in hypertensive nephrosclerosis. Hypertension 2001; 38: 645–649[Abstract/Free Full Text]
  14. Segura J, Ruilope LM, Zanchetti A. On the importance of estimating renal function for cardiovascular risk assessment. J Hypertens 2004; 22: 1635–1639[CrossRef][Web of Science][Medline]
  15. Segura J, Campo C, Gil P et al. Development of chronic kidney disease and cardiovascular prognosis in essential hypertensive patients. J Am Soc Nephrol 2004; 15: 1616–1622.[Abstract/Free Full Text]
  16. Campese VM, Nadim MK, Epstein M. Are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors renoprotective? J Am Soc Nephrol 2005; 16 [Suppl 1]: S11–S17
  17. Zanchetti A, Hansson L, Dahlof B et al.; HOT Study Group. Benefit and harm of low-dose aspirin in well-treated hypertensives at different baseline cardiovascular risk. J Hypertens 2002; 20: 2301–2307[CrossRef][Web of Science][Medline]
  18. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC; Cholesterol and Recurrent Events Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003; 14: 1605–1613[Abstract/Free Full Text]
  19. Ruilope LM, Kirwan BA, Wagener G et al. Renal function and its evolution as predictors of cardiovascular risk in patients with stable angina. Data from the ACTION study. J Hypertens 2005; 23 [Suppl 2]: S11
Received for publication: 2.10.05
Accepted in revised form: 5.12.05


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