Combination Therapy in the Management of Hypertension: Focus on Angiotensin Receptor Blockers Combined With Diuretics

Abstract

There is increasing evidence that combination therapy should be emphasized more than it is at present for the initial treatment of hypertensive patients. Recent guidelines acknowledge the value of combination therapy, although some treatment algorithms fail to echo this message. Observations from major clinical trials in the elderly, diabetics, stroke patients, and African Americans all indicate that combination therapy is necessary to control blood pressure in the majority of these patients. Several combination therapies such as an angiotensin II receptor blocker and a diuretic, an angiotensin‐converting enzyme inhibitor with a diuretic, a β blocker with a diuretic, or an angiotensin‐converting enzyme inhibitor with a calcium antagonist have been shown to be effective in patients who do not respond to monotherapy. The current review focuses on the newest such combination; an angiotensin II receptor blocker and a diuretic may have an added advantage of being well tolerated. Recent studies have shown that angiotensin II receptor blockers, given alone or combined with a diuretic, may prevent some cardiovascular outcomes independent of their blood pressure‐lowering efficacy.

Hypertension affects an estimated 690 million people worldwide and is the major risk factor for stroke. ¹ However, while there have been major improvements in the management of hypertension; the proportion of hypertensive patients who are adequately controlled remains low. ² Not only are patients not achieving blood pressure (BP) goals, BP goals have become stricter in recent years. The current, generally accepted stipulation is to reduce BP to <140/90 mm Hg in the general population and to <130/80 mm Hg in patients with diabetes or chronic kidney disease. ³ , ⁴ , ⁵ However, to achieve systolic goal values of <140 mm Hg may be difficult, particularly in the elderly. ⁴ To bridge this gap between practice recommendations for BP targets and those actually achieved, the approach to antihypertensive therapy needs to be more aggressive than it is today.

When designing an appropriate first‐line therapeutic regimen, the following considerations need to be met: First, it must be effective. It must also be safe and well tolerated; efficacy is immaterial if compliance is poor. To minimize compliance issues, the regimen should be as simple as possible. In these days of formularies and capped budgets, the therapy must be cost‐effective. As increasing age, African ethnicity, and obesity are independently associated with increased hypertension rates, suitable antihypertensive therapy must also be specifically effective in these hard‐to‐treat groups. Finally, the regimen should offer target organ protection beyond that of BP lowering alone (Table). To meet these provisos, there is consensus that most hypertensive patients will require at least two complimentary antihypertensive agents. ⁶ The concept of combination therapy is not a new one; years ago this approach to therapy was being advocated by several investigators. ⁷

The focus of this review will be on renin‐angiotensin system (RAS) inhibitor/thiazide‐type diuretic combinations and particularly the place of angiotensin type II receptor blocker (ARB)/hydrochlorothiazide (HCTZ) combinations. As monotherapy angiotensin‐converting enzyme (ACE) inhibitors, ARBs, and HCTZ (at lower than originally suggested doses) are well established and have shown consistent safety and efficacy profiles over the years. The only serious side effect reported for ACE inhibitors is angioedema. This relatively rare adverse event can be life threatening, but in most cases, its occurrence can be managed with conservative treatment measures, including discontinuation of the medication and/or administration of an antihistamine or steroids. Angioedema can also be seen with ARB therapy, but much less frequently than with ACE inhibitors. Fixed‐dose combinations of a RAS‐inhibitor and a diuretic are also safe, more effective than their component agents are individually (Figure 1) and have proven efficacy in mild‐to‐moderate as well as difficult‐to‐treat hypertension. ⁸ , ⁹

Figure 1.

Percentage of responders (patients with sitting diastolic blood pressure <90 mm Hg or a decrease by >10 mm Hg). From a population of 2002 patients with mild‐to‐moderate hypertension inadequately controlled after 4 weeks of monotherapy. Patients were randomized to treatment with Val 160 mg o.d. (n=666), Val 160 mg/HCTZ 12.5 mg o.d. (n=670) and Val 160 mg/HCTZ 25 mg o.d. (n=666) for 8 weeks. Val=valsartan; HCTZ=hydrochlorothiazide. Reproduced with permission from Blood Press. 2003;(suppl l):36‐43. ⁸

GUIDELINES AND COMBINATION THERAPY

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ³ and 2003 European Society of Hypertension‐European Society of Cardiology (ESH‐ESC) ⁴ guidelines both acknowledge that combination therapy may be necessary, and indeed is likely as first‐line treatment in hypertension. The JNC 7 goes on to recommend the use of a combination, which should usually include a thiazide diuretic as first‐line therapy for stage 2 hypertension and for patients with ‘compelling indications’ (heart failure [HF], postmyocardial infarction, high risk of coronary disease, diabetes, chronic kidney disease, or previous stroke). Both guidelines also suggest that a two‐drug combination is more likely to achieve target BP in most patients. However, these recommendations are not emphasized in the treatment flowcharts, which favor starting on monotherapy in most cases, particularly with a diuretic. The JNC 7 guidelines recommend diuretics alone as first‐line treatment for stage 1 hypertension (except in very high‐risk patients where two drugs are recommended). Other agents are indicated where there is a compelling indication. ³

The 2003 ESH‐ESC hypertension guidelines were less specific about drug choice, suggesting that all the major antihypertensive drug classes are suitable for initiation and maintenance of therapy and that hypertensive therapy should be started gradually and target BP values achieved progressively. ⁴ Based on data from the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT) ¹⁰ and the Hypertension Optimal Treatment (HOT) ¹¹ studies, the ESH‐ESC guidelines postulated that grade 1 hypertensive patients could mostly be controlled on monotherapy and two thirds to three quarters of patients with grade 2 and 3 hypertension would require combination therapy (Figure 2), while the proportion would be even higher in diabetics. The recommendation is to initiate therapy with either a low‐dose of a single agent or a low‐dose combination, the choice of which would be dependent on baseline BP and the presence of complications. The second‐step recommendations are to switch to a different agent, increase the dose, or switch to combination therapy. In cases where therapy was initiated with a low‐dose combination, the second‐line treatment would be to increase the dose of either agent or to add a third agent. ⁴ The ESH‐ESC guidelines mention that the advantage of initiating with monotherapy is that if the initial agent is not tolerated, switching to another treatment is both the obvious choice and necessary. However, they recognize that the process of switching from one first‐line antihypertensive to another to optimize response is laborious, frustrating for both the patient and the doctor, and may affect compliance.

Figure 2.

Percentages of hypertensive patients receiving antihypertensive monotherapy or combination treatment in the HOT study. ¹³ SBP=systolic blood pressure; DBP=diastolic blood pressure. Reproduced with permission from Blood Press. 2001;(10 suppl 3):18‐2S.

THEORETICAL EVIDENCE FOR COMBINATION THERAPY

As there are multiple pressor mechanisms contributing to raised BP, multiple inhibitory mechanisms are likely to be more effective than a single one. Also, the individual agents in a combination can be selected to counteract feedback mechanisms that act to limit the efficacy of the other antihypertensive component. Combining an ARB, an ACE inhibitor, or a β blocker with a thiazide diuretic are examples of logical combinations. These drugs counteract reactive hyperreninemia induced by diuretics. ⁶

Furthermore, with coadministration, doses are lower than those required when the components are used as single agents. ¹² A once‐daily dose formulation of the combination facilitates dosing and improves compliance. The major theoretical advantage with fixed‐dose combinations is that more patients achieve BP normalization more quickly with initial therapy. Changes in regimens to optimize control contribute to treatment “turbulence” that is associated with the loss of patient confidence and compliance problems. ¹³

An ideal combination should also provide renoprotection and cardiovascular protection beyond that of BP lowering alone. Recent evidence suggests that inhibition of the RAS achieves organ protection features that may go beyond BP control; however, most of the benefit achieved with antihypertensive drug therapy probably is the result of the degree of decrease in BP. ¹⁴

CLINICAL EVIDENCE FOR COMBINATION THERAPY

It was established in the late 1990s that tight BP control achieved the goals of hypertensive treatment, namely a reduction in cardiovascular sequelae and end‐organ damage, more than modest reductions in BP. However, tight BP control is difficult to achieve. In the HOT study, ¹¹ where 90% of patients reached a diastolic BP of <90 mm Hg in patients with stage 2 to stage 3 hypertension, 70% of patients received combination therapy. ¹¹ In the United Kingdom Prospective Diabetes Study, ¹⁴ tight BP control (<150/85 mm Hg) with a captopril‐ or atenolol‐based treatment regimen was compared with more modest BP targets. After 9 years of treatment, 29% of those patients who achieved tight BP control required three or more agents to maintain the BP. Over half of the patient population required two or more drugs after 3 years of therapy to maintain goal BP. ¹⁵

The need for more than one antihypertensive to achieve BP control of <140/90 mm Hg has been shown in a large number of trials. In the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) study ¹⁶ approximately 60% of patients were initiated on therapy with a single antihypertensive, but by 30 months of follow‐up the number of patients controlled on monotherapy had diminished to one third. An even smaller percent of subjects remained on monotherapy in the International Verapamil‐Trandolapril Study (INVEST). ¹⁷ Only 16% of patients in the verapamil arm and 15% in the atenolol arm were still on monotherapy at 24 months.

The success of a RAS‐inhibitor/diuretic combination as an initial agent for hypertension in the elderly was demonstrated in a study of 383 elderly patients with mild‐to‐moderate hypertension. ¹⁸ A low‐dose perindopril/indapamide (2 mg/0.625 mg) combination maintained a normal BP at all visits in 80% of patients.

Initiation of treatment with combination therapy was tested in some patients in the Veterans Affairs study ¹⁹ and, more recently, in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). ²⁰ PROGRESS established the efficacy of combination therapy for preventing recurrent stroke. Active treatment reduced the risk of stroke by 28% and the risk of total vascular events by 26%. Combination therapy with perindopril plus indapamide reduced BP by 12/5 mm Hg and stroke risk by 43%, whereas single drug therapy with the ACE inhibitor reduced the BP by only 5/3 mm Hg with no discernible effect on stroke risk. In aggregate, these studies illustrate that for most hypertensive patients, combination therapy will be necessary to achieve adequate control.

ARBs AND DIURETICS IN COMBINATION

Both ARBs and HCTZ are well established as antihypertensive monotherapies. HCTZ has long been known to be safe and effective when administered at low dosages (≤25 mg). ³ , ⁴ ARBs have established a record of BP lowering efficacy and placebo‐like safety. Recent outcome studies suggest that ARBs have beneficial effects beyond those expected from BP lowering alone. They appear more effective in preventing stroke than β blockers, as shown with losartan based treatment in patients with left ventricular hypertrophy, ²¹ and also seem to be more stroke‐protective than conventional therapy in the elderly. ²¹ , ²² ARBs may be more effective than β blockers in regressing left ventricular hypertrophy. ²¹ There is also evidence that they prevent renal deterioration in diabetic and nondiabetic nephropathy, ²³ , ²⁴ and recent data with valsartan support the notion of a beneficial effect on the risk of new‐onset diabetes in high‐risk patients. ²⁵ However, in this trial (VALUE), myocardial infarctions were fewer with the comparator medication, amlodipine. This was possibly due to a greater BP decrease with the calcium channel blocker (CCB) in the early months of the trial.

In preliminary studies, the combination of an ARB and a diuretic achieved greater BP reductions than either agent alone, with no significant increase in adverse effects. ²⁶ The combination of HCTZ with an ARB is at least as effective as combinations using other agents, such as ACE inhibitors and CCBs, with better tolerability. ²⁷ , ²⁸ In the blood pressure reduction and tolerability of valsartan in comparison with lisinopril (PREVAIL) study, ²⁷ which compared an ARB, valsartan/HCTZ, and an ACE inhibitor, lisinopril/HCTZ in 1213 patients with mild‐to‐moderate hypertension for 16 weeks, the two treatments were equally effective in controlling BP, but valsartan was better tolerated. The addition of HCTZ to losartan or enalapril has been shown to increase efficacy similarly, but the losartan/HCTZ combination was associated with fewer adverse effects. ²⁹ A 26‐week clinical trial comparing fixed‐dose combinations of candesartan cilexetil/HCTZ 8/12.5 mg and lisinopril/HCTZ 10/12.5 mg also found similar antihypertensive efficacy, but significant differences in tolerability, particularly cough (23% on lisinopril/HCTZ vs. 5% on candesartan/HCTZ) and discontinuations due to adverse effects (12% on lisinopril/HCTZ compared with 5% on candesartan/HCTZ). ³⁰

The usefulness of ARB and diuretic combinations in hypertension has been shown for losartan/HCTZ ²⁸ , ³¹ and for valsartan/HCTZ by the Val‐Syst study ³² and other studies (Figure 3). ³³

Figure 3.

Frequency of treatment‐related adverse events (AEs). Most frequently treatment‐related AEs from 373 patients with mild‐to‐moderate hypertension treated with valsartan/HCTZ 160/25 mg o.d. or amlodipine 10 mg o.d. for 8 weeks. HCTZ=hydrochlorothiazide. Reproduced with permission from Blood Press. 2003;12:41‐47. ³³

The ambulatory BP monitoring substudy of Val‐Syst ³⁴ showed that valsartan/HCTZ caused a homogeneous BP lowering effect over 24 hours; the addition of the diuretic appeared to be crucial in achieving this effect. The effectiveness of the ARB/HCTZ combination has been shown in patients who do not respond adequately to monotherapy, such as the elderly, ⁸ African Americans, ³⁵ and in severely hypertensive patients. ⁹

The publication of ALLHAT ¹⁰ reinforced the place of diuretics in hypertension. After an average follow‐up of 5 years, there were no differences among a diuretic, CCB, or ACE inhibitor groups in the primary outcome (fatal coronary disease or nonfatal myocardial infarction) or in all‐cause mortality. However, compared with the chlorthalidone group, the amlodipine group had a significantly higher 6‐year cumulative incidence of heart failure (HF)(7.7% vs. 10.2%) and the lisinopril group had significantly higher 6‐year rates of HF(7.7% vs. 8.7%), stroke (5.6% vs. 6.3%), and angina (12.1% vs. 13.6%). On the basis of these data, the investigators concluded that thiazide diuretics were more effective in preventing HF than ACE inhibitors or CCBs. ¹⁰ These claims have been criticized, as there were no significant differences between the treatments for the primary end points, and the study allowed other drugs to be added if BP was not controlled. ³⁶ Moreover, BP fell slightly more in the chlorthalidone group, especially in black patients where most of the differences in stroke outcome between the ACE inhibitor and diuretic was noted. In non‐black persons, the differences in achieved mean systolic BP and diastolic BP were negligible, ±1 mm Hg—between the amlodipine and chlorthalidone groups and the lisinopril and chlorthalidone groups, and should have had little effect on cardiovascular event rates. In these patients, the observed rates of HF were higher with amlodipine (38%) and lisinopril (15%) than with chlorthalidone. Contrary to ALLHAT, the results of the Second Australian and National Blood Pressure Study (ANBP2), ³⁷ an open label comparison (unblinded) of ACE inhibitors and diuretics for cardiovascular outcomes showed a marginally significant 11% (p=0.05) difference in terms of the primary end point of all‐cause mortality and all cardiovascular events in favor of ACE inhibitors. The between‐treatment difference reached the statistical significance only in men (p=0.02). The recent VALUE trial, in which most patients received a diuretic, showed a trend to less HF but more myocardial infarctions with a valsartanbased than with an amlodipine‐based regimen. As noted, there were some BP differences between the groups. ²⁵ These discrepancies remain unsolved, but the common conclusion to be drawn from ALLHAT, ANBP2, and VALUE is that combination therapy will be needed in most patients and that low‐dose diuretics should be one element of such a regimen. ⁵ , ¹⁰

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study ²¹ was the first major trial to demonstrate possible effects beyond BP lowering with an ARB compared with another medication. As in many other studies, however, combination therapy was required to achieve BP levels of 145/81 mm Hg in LIFE with 90% of patients on two or more agents. The differences in BP lowering were not significant between losartan (−30/−17 mm Hg) and atenolol‐based regimens (−29/−16 mm Hg). However, losartan lowered the rate of the composite primary end point of cardiovascular events significantly more than atenolol (relative risk, 0.87; p=0.021); this benefit was mostly due to markedly reduced rates of strokes on losartan (RR 0.75, p=0.001). ²¹

The effect of an ARB/HCTZ combination on cardiovascular outcomes was explored in the recent VALUE trial. ²⁴ In VALUE, 15,245 patients aged ≥50 at high risk of cardiac events were randomized to valsartan‐ or amlodipine‐based therapy and were followed‐up for a mean of 4.2 years. In keeping with the results from earlier trials, only 31% of patients in VALUE were controlled on monotherapy. As noted, BP was lowered by both treatments, but there were greater early reductions in the amlodipine‐based group. However, there was no difference in the main outcome of cardiac disease (10.6% in the valsartan‐based group vs. 10.4% in the amlodipine‐based group; hazard ratio 1.04; 95% confidence interval, 0.94–1.15; p=0.49). The onset of diabetes was significantly reduced in the valsartan‐based group vs. the amlodipine‐based group (13.1% vs. 16.4% respectively, p<0.0001).

CONCLUSION

Combination therapy is necessary to normalize BP in most patients. The combination of a RAS‐inhibitor and a thiazide diuretic is likely to become widely used, not only as second‐line therapy, but also to initiate therapy. This concept applies particularly to patients with moderate‐to‐severe hypertension or with additional cardiovascular risk factors. The combinations of an ARB and HCTZ offer advantages because they are effective at lowering BP, have an excellent side‐effect profile, and may offer some benefits beyond those of BP lowering alone.