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Diuretics: A modern day treatment option? (Review Article)

MARTIN GALLAGHER

The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

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VLADO PERKOVIC,

VLADO PERKOVIC

The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

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JOHN CHALMERS,

JOHN CHALMERS

The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

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MARTIN GALLAGHER,

MARTIN GALLAGHER

The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

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VLADO PERKOVIC,

VLADO PERKOVIC

The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

Search for more papers by this author

JOHN CHALMERS,

JOHN CHALMERS

The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

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First published: 29 September 2006

https://doi.org/10.1111/j.1440-1797.2006.00598.x

Citations: 10

Professor John Chalmers, The George Institute for International Health, The University of Sydney and The Royal Prince Alfred Hospital, PO Box M201, Missenden Road, Sydney, NSW 2050, Australia. Email: [email protected]

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Abstract

SUMMARY: The choice of drugs to initiate therapy for the management of hypertension remains contentious and diuretics are central to this controversy. Because most of the major trials involve complex treatment algorithms and allow diverse background treatments, one of the greatest challenges lies in separating out true class-specific effects – for example, separating true class-specific effects of diuretics from those of beta blockers. Despite these difficulties, the evidence confirms that diuretics are at least as effective as the newer first line groups in preventing cardiovascular events. The main area of doubt lies in relation to the risk of renal outcomes and of metabolic outcomes, such as new onset diabetes – where the evidence suggests that drugs that inhibit the renin-angiotensin system may be more protective than all other drug classes. These issues are reflected in the most recent international guidelines, all of which include diuretics among the first-line drugs for the treatment of hypertension, although they do differ on the role of diuretics in the initiation of therapy. Diuretics remain important for treating hypertension, especially in combination with other drug classes. The particular place of diuretics in the rank order of drugs must be tailored to suit the clinical situation in the individual patient. This will vary from a preferred option, as in black patients or elderly patients with systolic hypertension, to a second-line option in patients at high risk of developing new onset diabetes.

One of the most contentious issues in the management of hypertension over the past two decades has been the choice of drugs to initiate therapy. This is particularly true for the patient with uncomplicated hypertension, without compelling indicators for any particular drug class. Central to this controversy has been the role of diuretics, which have at various times, and by various authorities, been preferred, avoided or regarded as an equivalent option, compared with other drug classes.^1–14

Although it might have been anticipated that this issue would have been clarified by the plethora of major trials completed since the turn of the century, with head-to-head comparison of various blood pressure-lowering regimens or classes of drugs, this is not so and if anything the heat has increased. There is now disagreement among the most recent major guidelines, with the American⁹ (JNC7) and International⁴ (WHO-ISH) guidelines recommending initiation of therapy with diuretics, whereas the Europeans¹⁰ (ESH/ESC) and Canadians¹⁵ recommend that clinicians should tailor the choice among first-line classes (which include diuretics) according to the clinical profile of the individual patient.

The result of the massive ALLHAT study^16,17 tipped American opinion towards diuretics, as reflected in JNC 7.⁹ In contrast, the results of ANBP₂¹⁸ and more recently of the very large ASCOT-BPLA trial¹⁹ favour initiation with the ‘newer agents’, angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB). Indeed the authors of the ASCOT-BPLA trial, which compared a regimen using CCB and ACEI with one using beta blockers and diuretics, believe that the latter two classes should be relegated to second-line status.¹⁹

Amid this cacophony of dissonant sound, one of the main culprits is the tendency to write about complex blood pressure-lowering regimens, as if each such regimen can be used to extol the virtue or denigrate the value of the first drug used in the regimen, without consideration of the complex interplay with the other drugs used in the trial. This is true of those extolling the virtues of diuretics in the 1990s, for example JNC 5 and JNC 6, which attributed the benefits of the early blood pressure-lowering regimens described by Collins et al. in 1990²⁰ as if all the benefits reflected the virtues of diuretics and beta blockers. The reality is that most regimens were complex and included the use of peripherally acting sympathetic drugs such as guanethidine, centralling acting drugs such as methyldopa or reserpine and vasodilators such as hydralazine. It is equally true of the more recent preference for diuretics based on the ALLHAT study¹⁶ where over 50% of participants had add-on therapy, and for their denigration following the ASCOT-BPLA trial¹⁹ where therapy was initiated with atenolol and the diuretic was used as the second drug in the algorithms.

In the present paper the authors briefly review the evolution in the use of diuretics over the past 50 years, and then review the more recent evidence, gathered over the past 10 years on the relative merits of diuretics and other classes of blood pressure-lowering drugs. The authors then review the recommendations contained in the major guidelines, pointing out the elements of divergence and highlighting the much greater areas of agreement. Finally, the authors present their own recommendations in the light of the most recent evidence.

PHASES IN THE USE OF DIURETICS

When diuretics were introduced in the 1960s they were mainly used as adjunct therapy to more powerful drugs such as the adrenergic agents or hydralazine, used in the treatment of moderate of severe hypertension.¹⁴ By the seventies, beta blockers had been accepted and therapy extended to milder grades of hypertension, using ‘step therapy’, a regimen in which treatment was initiated with a diuretic, with the addition if necessary, of a beta blocker and then of a vasodilator, usually hydralazine. The availability of new classes of blood pressure-lowering drugs – the ACEI, the CCB and the alpha blockers – coincided with the publications of the landmark meta-analysis by Collins et al.,²⁰ which revealed that the expected reductions in stroke were realized but that the reduction in myocardial infarction was disappointing, being much less than predicted by the major observational studies.²¹ Many thought that the diuretics, with their well known metabolic side-effects such as hypokalaemia, dyslipidaema and glucose intolerance might be responsible. Therefore, newer agents gained favour during the eighties, step therapy was discarded and the age of monotherapy was ushered in, with widespread belief that single drug therapy would suffice, with attractive simplicity and efficacy.¹⁴

Three major trials in more elderly subjects published in 1991 and 1992 confirmed that despite their metabolic side-effects, diuretics were very effective in preventing both stroke and coronary heart disease.^22–24 These studies, coupled with the lack of trials demonstrating that ACEI or CCB could prevent these hard end-points, led to a return of diuretics and beta blockers to a position of strength. Thus in the 1990s, diuretics were accepted as first-line drugs once again by all authorities,^2,3^,^7,8^,^11,12 with general agreement that they were especially effective in older people.^4,9^,^10,25^,²⁶ Furthermore, they were actually preferred for initiation of therapy by the American guidelines,^7,8 a point of controversy with the WHO-ISH guidelines that recommended that the doctor tailor the choice of drug for initiating therapy to suit the individual patient, arguing that the benefits of antihypertensive therapy were due to blood pressure lowering per se.^2,3

Now, in the twenty-first century, treatment is spreading to ‘normotensive’ subjects at high risk of cardiovascular events, such as those with established coronary disease, cerebrovascular disease, renal disease or diabetes.^4,9^,^10,25,26 All authorities agree that we have reached the age of combination therapy for the majority of subjects requiring blood pressure-lowering drugs. Although all guidelines agree that diuretics are among the first-line groups of drugs and that they may be used to initiate treatment, the guidelines differ regarding their place in the pecking order. These phases in the use of diuretics are summarized in Table 1.

Table 1. Phases in the use of diuretics

1. 1960s

• ADJUNCT to more potent drugs

• Moderate and severe hypertension

2. 1970s

• First step in STEP THERAPY

• Included in most major trials

3. 1980s

• Transition to MONOTHERAPY

• Metabolic effects: fall from grace

4. 1990s

• FIRST-LINE drugs

• Vindicated by SHEP, STOP, MRC

5. 21st Century

• More controversy: ALLHAT versus ANBP₂ and ASCOT

• Cardiovascular versus Metabolic outcomes

CURRENT EVIDENCE

When reviewing the available evidence on the relative benefits of different classes of blood pressure-lowering drugs in preventing the long-term morbidity and mortality associated with hypertension and with blood pressure-related disease, it is important to be aware that large-scale clinical trials and meta-analyses of such trials have some limitations. These arise from the pooling of data from disparate populations, from the influence of add-on or second-line therapy, from differences between individual drugs within a class of drugs and from differences in dosage between different trials.

It is also important to differentiate the nature of the end-points or outcomes being examined. There are clear differences in the conclusions reached when examining the relative merits of drug classes in preventing cardiovascular outcomes as against their impact on the emergence of metabolic outcomes such as the onset of new diabetes, or their effects on the development of end-stage renal disease. The same holds true with respect to the prevention of cardiovascular events, where the conclusions reached on the relative risks and benefits of the various drug classes may differ for the prevention of heart attack, stroke or heart failure. Therefore, the authors will first consider the prevention of cardiovascular disease and then consider the evidence available on the emergence of metabolic complications.

Prevention of cardiovascular outcomes

When the major guidelines were written and published in 2003, the most recent evidence came from the ALLHAT trial and the second Australian National Blood Pressure Study (ANBP₂), which reported contradictory findings on the relative merits of diuretics and ACEI.^16,18 The massive ALLHAT study reported that the diuretic chlorthalidone, was at least as effective as the ACEI, lisinopril and the CCB, amlodipline, in the prevention of cardiovascular events with no difference in preventing the primary end-point and superiority in preventing stroke and heart failure.¹⁶ However, much of this advantage could be attributed to the greater reduction in blood pressure by chlorthalidone compared with lisinopril (by 2 mmHg systolic and 1 mmHg diastolic). Indeed the advantage in preventing stroke was limited to African Americans, who made up one-third of the study population and in whom the reduction in systolic blood pressure was 4 mmHg greater in the chlorthalidone-treated group compared with the lisinopril group, reflecting the well established differential potency of diuretics and ACEI in lowering blood pressure in black compared with white populations, worldwide.^27–30 The Australian Study, published a few months later, and carried out entirely in a white and slightly older population, reported the opposite: a slight advantage for ACEI in preventing the primary end-point, all cardiovascular events, due mainly to better protection against myocardial infarction.¹⁸

The second cycle of analyses published by The Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) in 2003 reported meta-analyses conducted on the results of some 29 trials, including ALLHAT and ANBP₂, with over 700 000 patient’s years of observation.³¹ These analyses were limited to the effects of blood pressure drugs on the prevention of cardiovascular outcomes. They compared the efficacy of ‘conventional treatment’, grouping diuretics and beta blockers together, ACEI, CCB and angiotensin receptor blocker (ARB) both against placebo and in head-to-head comparisons. The evidence for ARB was limited, so that the placebo-controlled and head-to-head comparisons against other drug groups had to be pooled.

The overall finding from this cycle of analyses was that with the exception of the prevention of heart failure, where CCB were clearly inferior, there was little to choose between drug classes, and the overwhelming benefit in preventing hard cardiovascular end-points came from blood pressure lowering per se. ‘Conventional treatment’ with diuretics and beta blockers held its own against treatment with ACEI, ARB and CCB for the prevention of coronary heart disease, stroke, heart failure and ‘major cardiovascular events’.³¹

A number of blood pressure-lowering studies have been reported since this cycle of overviews with most comparing different classes of agents. The MOSES study compared eprosartan and nitrendipine in 1405 participants with hypertension and a history of recent cerebrovascular disease. In that study, the risk of subsequent major vascular events was reduced to a greater degree by eprosartan (relative risk 0.79, 95% confidence interval 0.66–0.96), despite near identical blood pressure-lowering efficacy.³² Other studies have failed to identify any significant differences between drug classes. The recent very large INVEST study compared a strategy utilizing the CCB verapamil and the ACEI trandalopril with one based on atenolol and hydrochlorothiazide in 22 576 hypertensive participants with known coronary artery disease. These two strategies were shown to be equivalent at reducing blood pressure and at preventing subsequent cardiovascular events.³³ The VALUE trial reported little difference between the ARB, valsartan and the CCB, amlodipine, in the prevention of cardiovascular outcomes with the advantage leaning towards amlodipine, which lowered the blood pressure by 1–2 mmHg more than valsartan.³⁴

The major new evidence available comes from the large ASCOT-BPLA trial, reported and published in 2005.¹⁹ That study compared two ‘combinations’, one a regimen based on older drugs (starting with atenolol and adding bendroflumethiazide as necessary) and the other a regimen based on newer drugs (starting with the CCB amlodipine and adding the ACEI perindopril as necessary). The study was stopped early because of the superiority of the amlodipine-perindopril regimen over the atenolol-bendroflumethiazide regimen in reducing the risk of all-cause mortality, as well as of the risk of a series of major secondary cardiovascular end-points, including myocardial infarction, stroke, total cardiovascular events and procedures. Once again, as happened with ALLHAT, the regimen that was superior in preventing hard vascular end-points was also superior in reducing blood pressure, in this case by 2.7/1.9 mmHg, a margin similar to that reported in the very successful HOPE trial.³⁵ It is difficult to assess how much if any disadvantage to attribute to the diuretic member of the beta blocker – diuretic regimen, given this difference in blood pressure reduction and given the cloud hanging over the value of atenolol in cardiovascular prevention, as reported in recent reviews and meta-analyses.^36–38 Furthermore, as atenolol was the first and dominant member of the regimen, it seems quite likely that any disadvantage that was not dependent on the blood pressure difference vis-à-vis the CCB-ACEI regimen, might be attributed to the beta blocker rather than the diuretic.

Prevention of metabolic outcomes, particularly new onset diabetes

In the first generation of morbidity-mortality trials in patients with hypertension, diuretics were used in large doses and had the expected metabolic side-effects including hypokalaemia, hyperuricaemia, dyslipidaemia and impaired glucose tolerance. In more recent trials, starting with the three trials in elderly subjects in the early 1990s,^22–24 diuretics have been used in lower doses, often combined with a potassium spring diuretic and as the authors of the present review have reported earlier, continued to be effective in preventing cardiovascular morbidity and mortality. However, it has become evident from trials comparing different drug classes in hypertensive subjects that the onset of new diabetes is substantially lower in those treated with inhibitors of the renin-angiotensin system (RAS), either ACEI or ARB, than those treated with other agents including diuretics. Therefore, in the ALLHAT and ANBP₂ trials, which had contradictory findings in relation to the relative benefits of diuretics and ACEI in preventing cardiovascular outcomes, there was clear agreement on the emergence of new diabetes. In both trials, the diuretic arm had an excess of new diabetes, by 34% in ANBP₂ and by 30% in ALLHAT, even though the diuretic had an advantage in lowering the blood pressure in both trials.

Two recent meta-analyses have confirmed that blockade of the RAS, whether by ACEI or ARB is associated with reductions of 20–30% in the incidence of newly diagnosed diabetes compared with all other therapies tested, including diuretics.^39,40 In the most recent analysis, this reduction was by 27% for ACEI, 23% for ARB and 25% when the two classes were pooled.⁴⁰

Three major issues arise in relation to blood pressure-lowering drugs and diabetes. The first is whether the advantage of RAS inhibition compared with other drug classes in preventing new onset diabetes reflects a specific protective effect of RAS blockade, or unwanted deleterious effects of the other drug classes, including the diuretics. The authors have extended and reanalysed the available data to produce a new meta-analysis of the available data broken down by comparator arm (Fig. 1). This demonstrates an almost identical protective effect of RAS inhibitors for new onset diabetes when the comparator included a diuretic as compared with studies where the comparator was either placebo or a CCB. This suggests that the differences observed are explained more by a protective effect associated with RAS inhibition, than by a deleterious effect of diuretics or other drug classes. Nevertheless, the possibility that diuretics contribute to the emergence of new diabetes remains and should influence the use of these drugs in subjects at particular risk of developing diabetes, as indicated later.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Meta-analysis of trials reporting the effects of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) overall and broken down by comparisons: (i) studies where an ACEI or ARB was compared with placebo; (ii) studies where an ACEI or ARB was compared with calcium channel blockers (CCB); (iii) studies comparing an ACEI or ARB with a diuretic (*comparison arm allowed the use of either a diuretic or beta blocker). Adapted from the study by Abuissa *et al*.⁴⁰ with permission from the American College of Cardiology Foundation.

The second issue is the mechanisms whereby inhibitors of the RAS prevent or reduce the onset of type 2 diabetes, and it has to be said that this remains speculative and is beyond the scope of the present paper.^39–41 The third issue is the failure of this advantage exhibited by blockade of the RAS to translate into a parallel advantage in preventing major cardiovascular events in patients with established diabetes.^42,43 Thus a meta-analysis conducted by the BPLTTC reported that the approximate equivalence in the prevention of major cardiovascular events in the second cycle of analyses in 2003 was present not only in the pooled results,³¹ but also when the subjects were separated into those with diabetes and those without⁴²(Fig. 2). The most common argument advanced to explain this disparity is that the duration of most clinical trials, limited to 3–5 years is insufficient to demonstrate the full development of cardiovascular complications that might require 10 years or more.^44–46 Although this might hold for some end-points such as coronary heart disease events, it is unlikely to explain the failure to demonstrate a benefit in preventing stroke, as the lifetime benefit predicted by observational studies²¹ has typically been fully realized within the duration of most clinical trials.²⁰

Prevention of renal outcomes

Marked elevations in blood pressure have long been known to be associated with an increased risk of kidney disease and failure. Most guidelines currently suggest a target blood pressure of 135/85 or less for individuals with kidney disease, although the majority of the evidence supporting this comes from observational studies. Relatively few randomized-controlled trials have examined the benefits of blood pressure lowering on the risk of progressive kidney dysfunction specifically in people with established kidney disease. The Modification of Diet in Renal Disease study and the African American Study of Kidney Disease examined the effect of usual compared with low target blood pressures (140/90 vs 125/75 mmHg) on progressive kidney dysfunction in a total of 1934 non-diabetic participants with reduced glomerular filtration rate at baseline.^47,48 Both studies failed to identify any clear protective effect overall; however, participants with significant proteinuria at baseline were shown to derive significant benefit.^47,48 A recent report describes the outcomes in participants from the Modification of Diet in Renal Disease study during several further years of observation, and reports that the risk of kidney failure was significantly lower in those participants originally randomized to the lower blood pressure target (relative risk 0.68, confidence interval 0.57–0.82).⁴⁹

A number of studies of both ACEI and ARB specifically performed among individuals with proteinuric nephropathies have demonstrated a protective effect associated with these agents that appears to be at least partly independent of blood pressure lowering, although this point has been challenged by a recent meta-analysis.⁵⁰ The REIN study performed in non-diabetic proteinuric kidney disease clearly demonstrated that the ACEI ramipril reduced the risk of these individuals reaching a composite renal end-point.⁵¹ Similar studies in proteinuric diabetic nephropathy have demonstrated that both ACEI⁵² and ARB^53–57 protect against kidney failure in this population. Little data exist regarding the efficacy of diuretics on the progression of renal failure.

There is some evidence that the diuretic indapamide may have a specific protective antiproteinuric effect. Comparisons with enalapril, of indapamide alone or in a fixed-dose combination with perindopril, have demonstrated that indapamide at least held its own against enalapril⁵⁸ or did better than enalapril when combined with perindopril,⁵⁹ in reducing albumin excretion rates. The benefits in reducing protein excretion appeared to persist after adjustment for a slightly greater reduction in blood pressure.⁵⁹

The effects of other classes of agents on progressive nephropathy are much less well understood, as are the effects of different classes in the absence of proteinuria.

RECOMMENDATIONS FROM CURRENT INTERNATIONAL GUIDELINES

The most recent editions of the major international guidelines – the American, the European and the World Health Organization–International Society of Hypertension (WHO-ISH) were all published in 2003.^4,9^,¹⁰

Concordance between guidelines

There was broad agreement among these three sets of guidelines on a number of key recommendations:

1
Recognizing the unsatisfactory control of hypertension worldwide, all the guidelines stressed the importance of combination therapy using two or more drugs. They also recommend the use of fixed-dose combinations where appropriate, especially fixed-low-dose combinations.
2
All three guidelines determined that there were five classes of first-line blood pressure-lowering drugs that could be used to initiate treatment: diuretics, beta blockers, ACEI, ARB and CCB. All three recommended that treatment could be initiated with combinations of two drugs, and two of them agreed that it was permissible to start with fixed-low-dose combinations of two first-line drugs.^4,10

Divergence among guidelines

The main divergence between the three sets of guidelines was in relation to the choice of drugs to initiate blood pressure-lowering therapy. Although all three agreed that treatment could be initiated with any one of the first-line groups including the diuretics, or with an appropriate combination of two such drugs, they differed on their preferences. Thus the American and WHO-ISH guidelines recommended that when there were no clinical factors favouring particular drugs in an individual patient, diuretics should be preferred for initiating treatment, whereas the European guidelines recommended that even in this situation the physician should tailor the choice of drugs to the individual patient.^4,9^,¹⁰ All three guidelines recommended that diuretics provided a good option for first-line therapy, two proposed they should be preferred and none recommended they should be relegated to the second line.^4,9^,¹⁰

Need for revised, updated guidelines

Unfortunately, these three sets of guidelines were all published in 2003, and are thus limited to the evidence available at that time. Some of the major lines of evidence and themes that have emerged since they were published include:

•
Much more evidence on the use and value of ARB^34,60–64
•
Much more emphasis on the emergence of new-onset diabetes, with increasing evidence on the relative advantages of inhibitors of the RAS and on the disadvantages of all other groups, including the diuretics^16,18^,^19,39^,⁴⁰
•
A new focus on the value of beta blockers, particularly atenolol, with suggestions that they should be relegated to second line^36–38
•
New evidence from the ASCOT trial, suggesting that the combination of CCB and ACEI is superior to the combination of atenolol and diuretics, with the suggestions that both the latter should be relegated to second line¹⁹

These major guidelines from 2003 clearly need updating.

Recent guidelines from Canada, 2006

The most recent international guidelines published are those issued by the Canadian Hypertension Education Program, published early in 2006.¹⁵ These guidelines clearly retain the diuretics among the first-line classes of blood pressure-lowering drugs. However, they relegate beta blockers to second line for patients under the age of 60 years and ACEI to second line for black patients. These Canadian recommendations again place a heavy premium on the use of combination therapy, with particular emphasis on the use of fixed-dose combinations to improve adherence to therapy and achievement of target blood pressures.¹⁵

Need for updated analyses from various trialist collaborations

The wealth of new trial evidence and the emergence of the new themes call for new meta-analyses, so as to inform the practising doctor, as well as the writers of new guidelines. A number of issues must be dealt with, including:

•
Separate analyses of diuretics and beta blockers, against the newer agents
•
An updated comparison of diuretics versus beta blockers, using all the available data, both new and old
•
Updated comparison of ARB against other classes
•
An updated cycle of analyses of all five groups, including analyses of their efficacy in preventing the onset of new diabetes, as well as the incidence of major cardiovascular events
•
A new analysis estimating the effects of blood pressure lowering per se and of different classes of blood pressure-lowering agents on the risk of progressive kidney failure

Summary

The major guidelines available at the time of writing, all agree that diuretics comprise a good option for first-line therapy, either alone or in combination with other first-line drugs. Some of these guidelines have a preference for initiating therapy with a diuretic, and none regard them as second line. However, new data published since these guidelines became available in 2003, call for their early revision.

THE AUTHORS’ RECOMMENDATIONS

Overall: yes, diuretics remain a modern day treatment option

It is the authors’ opinion that diuretics remain a good option for lowering blood pressure in patients with hypertension and that they should be retained in the armamentarium of the practising physician (Table 2). This opinion is based on:

Table 2. Place of diuretics in treating hypertension

Three different situations for initial therapy

1. Undifferentiated, uncomplicated hypertension

• Equal among first-line drugs

2. Specific indications for diuretics

• Elderly with systolic hypertension

• Black subjects

• Cerebrovascular disease (with angiotensin-converting enzyme inhibitors)

• Heart failure

3. Avoid diuretics in patients at particular risk of new diabetes

• Impaired glucose tolerance (IGT)

• Impaired fasting blood sugar (IFG)

• Overweight and below 60 years of age

• Metabolic syndrome

1
The fact that the weight of evidence available from randomized clinical trials, as summarized by the Blood Pressure Trialists Collaboration (2003),³¹ indicates that ‘conventional therapy’ based on diuretics and beta blockers is at least as effective as other drug classes in preventing major cardiovascular events, stroke, coronary heart disease, heart failure and cardiovascular death.
2
The fact that this evidence is strongest when diuretics per se form the basis of the active regimen, as in ALLHAT,¹⁶ and is only seriously challenged when the beta blocker, atenolol, constitutes the first drug in the active treatment regimen, as in ASCOT-BPLA.¹⁹
3
The fact that most recent editions of the major international guidelines and particularly the latest Canadian recommendations in 2006 all classify diuretics among the five groups of first-line agents, along with ACEI, ARB, beta blockers and CCB.
4
The overwhelming evidence and acceptance that combination therapy is needed to reach target blood pressures, in both low-risk and high-risk patient populations, and that diuretics combine well with the other drug classes to make up some of the most effective combinations.

Specific situations and indications

There are a number of specific situations that the major guidelines list as ‘compelling indications’ for diuretics as blood pressure-lowering agents. These include:

1
Elderly subjects with systolic hypertension.
2
Black subjects, at least those of African origin.
3
Subjects with established cerebrovascular disease (in combination with ACEI).
4
Subjects with heart failure or ventricular dysfunction.

One caveat

In contrast, it is clear that inhibitors of the RAS such as ACEI or ARB have a marked advantage in the prevention of new onset diabetes. The authors recommend that in patients at particular risk of new onset diabetes, such as the overweight, and those with impaired glucose tolerance, impaired fasting glucose, or with the metabolic syndrome, ACEI and ARB be used as the agents of choice, and that when diuretics are used in these situations, they should be used in combinations with one of these two classes of drugs, and their use should be reviewed periodically.

Conclusion

Therefore, the authors’ overall conclusion is that YES! Diuretics continue to be a good modern day option for lowering blood pressure and YES! For the majority of patients diuretics can be used as first-line therapy. The authors do not believe there is convincing evidence to prefer any particular class of drugs to initiate therapy at this time, in the uncomplicated and undifferentiated patient with hypertension. Rather, the authors would endorse the statement by the authors of the ESH/ESC Guidelines, that ‘The emphasis on first choice drugs is outdated, given the predominant role of combination therapy’, and agree that the choice should be tailored in accord with the clinical situation in the individual patient.

CONFLICT OF INTEREST

John Chalmers has received research grants from Servier, administered by the University of Sydney, as Co-Principal Investigator for ADVANCE and PROGRESS. He has also received honoraria from Servier for scientific presentations regarding these two trials.

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Citing Literature

Volume11, Issue5

October 2006

Pages 419-427

Diuretics: A modern day treatment option? (Review Article)

Abstract

PHASES IN THE USE OF DIURETICS