TANDEM THERAPY
One needs at least two drugs to control blood pressure effectively, so why not just put them in one tablet?
By Roger R. Badillo II, MD
Correspondent
On more than one occasion, the 2003 consensus guidelines on hypertension management forwarded separately by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the European Society of Hypertension-European Society of Cardiology (ESH-ESC) differ along contentious lines.
From nomenclature to diagnostic differences, to choice of first-line drugs and the American preference for diuretics, the differences in recommendations may translate to certain implications on clinical practice.
Common ground
There is always, however, common ground---across both sides of the Atlantic, it is recognized that monotherapy against hypertension will not provide adequate blood- pressure control in a large proportion of patients, and that many patients will experience unacceptable side effects with higher doses of a single agent.
The JNC 7 maintains that "most patients with hypertension will require two or more antihypertensive medications to achieve a goal BP of <140/90 mm Hg or <130/80 mm Hg for patients with diabetes or chronic kidney disease." Combination therapy is also recommended if the BP is >20/10 mm Hg above goal, preferably with a thiazide-type diuretic.
The Europeans share the concern: "With a 10-year risk of cardiovascular disease of 20 percent or more, drug treatment for hypertension is always warranted.... In these guidelines, a number of drugs are considered evidence-based, first-line treatment, and combination treatment is strongly recommended to reach BP targets." Fixed-dose combinations of antihypertensive medications prove a useful, appropriate, and effective treatment option to this large subset of patients.
More power, better tolerability
Combining drugs increases efficacy via a wider range of therapeutic action, providing pressure control by employing two antihypertensive agents with different modes of action. It also enhances compliance by using a single tablet that is taken once or twice daily. At the same time, it improves acceptability and tolerability by lowering the required doses of each drug, minimizing the clinical and metabolic effects that occur with maximal dosages of the individual components of the combined tablet. These potential advantages are such that some investigators have recommended using combination antihypertensive therapy as initial treatment, particularly in patients with target-organ damage or more severe initial levels of hypertension.
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Single-dose combination antihypertensive therapy now provides an important option that combines efficacy of pressure reduction with fewer side effects, at a convenient once-daily dosing for the patient. The following classes of antihypertensives may be combined for superior effect tailored to respond to the specific needs of the patient: diuretics and potasium-sparers, beta-blockers and diuretics, angiotensin-converting-enzyme (ACE) inhibitors and diuretics, angiotensin-2 antagonists and diuretics, and calcium-channel blockers and ACE inhibitors. Each class of antihypertensives would be indicated for a specific comorbid condition.
Universal partner
Diuretics, especially hydrochlorothiazide, are known to induce a dose-dependent blood pressure reduction that levels off with higher dosages. In long-term trials, they have been shown to reduce the incidence of stroke, congestive heart failure, coronary-artery disease, and total mortality from cardiovascular disease. Because they blunt the sodium- and water-retaining effects of the other antihypertensives, they are the most commonly used agents in combination therapy.
Combinations of potassium-sparing diuretic and a thiazide reduce the risk of adverse metabolic effects. Though combination therapy does not necessitate serial monitoring of serum electrolyte levels, it decreases the incidence of thiazide-induced hypokalemia without added risk of hyperkalemia. Low-dose hydrochlorothiazide (12.5 to 25 mg per day) provides significant pressure reduction while minimizing electrolyte problems.
Plus beta-blockers
The rationale for combining beta-blockers with diuretics is twofold: beta-blockers blunt the increase in plasma renin level that can be induced by diuretics, while diuretics decrease the sodium and water retention associated with beta-blockers. The combination produces additive effects compared with monotherapy of either agent alone and is associated with lower incidences of adverse effects (fatigue, dizziness, somnolence, diarrhea).
Plus ACE inhibitors
ACE inhibitors are well tolerated and used extensively as initial agents against hypertension. The renin-angiotensin-aldosterone axis (RAA) is important in maintaining systemic pressure. By causing volume and sodium depletion, thiazide diuretics stimulate the production of renin and angiotensin. This leads to a relative increase in blood pressure and sodium retention, which counteracts some of the antihypertensive effects of thiazides. ACE inhibitors interfere with the conversion of angiotensin 1 to angiotensin 2, effectively decreasing angiotensin-2 levels. These effects lead to lesser sodium retention and an enhanced (synergistic) antihypertensive effect.
Studies show that an ACE inhibitor/diuretic combination achieves blood-pressure control in approximately 80 percent of patients. Cough is the only side effect more prevalent in the combination than in placebo.
Plus ARB
For patients who cannot tolerate an ACE inhibitor/diuretic combination because of cough, angiotensin-receptor blocker (ARB)/diuretic combinations work well. ARBs work by blocking angiotensin 2 subtype 1, selectively inhibiting the vasoactive properties of angiotensin 2.
Significant antihypertensive effect occurs with the combination losartan and hydrochlorothiazide. In one study, diastolic pressure was reduced by 10 mm Hg or greater in 78 percent of patients.
CalciumACE
ACE inhibitors and calcium-channel blockers (CCBs) work effectively in combination to lower blood pressure. Although calcium antagonists exert their antihypertensive effect through vasodilatory action, they also have diuretic and natriuretic properties. ACE inhibitors, on the other hand, blunt the stimulation of the RAA system that may result from diuresis.
Both drugs work together to favorably influence target-organ disease, such as promoting renal protection, reducing left ventricular mass, and decreasing mediators of vascular disease. However, the relatively low dose of an ACE inhibitor in some combinations may not confer the same degree of renal or cardiac protection demonstrated at higher doses. The combination also translates to fewer effects than occur with either agent alone, such as reduction in the incidence of peripheral edema and reflex tachycardia. Neither class of medications has prominent metabolic side effects, an advantage for patients with diabetes and renal disease.
Miscellaneous combination agents
Other combination antihypertensives include diuretics with a direct-acting vasodilator (hydralazine-hydrochlorothiazide [Apresazide]), a central alpha-adrenergic agonist (methyldopa-hydrochlorothiazide [Aldoril] and clonidine-chlorthalidone [Combipres]) or a peripheral alpha-adrenergic blocker (prazosin-polythiazide [Minizide]). No trials have indicated survival benefit with their use.
Combination bisoprolol-hydrochlorothizide effective as first-line therapy in hypertension
The Seventh Report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure (JNC 7) in 2003 affirmed that keeping systolic and diastolic blood pressure below 140/90 mm Hg is "associated with a decrease in [cardiovascular-disease] mortality."
Lifestyle modification remains an important component of the prevention, control, and management of hypertension. This involves eating a balanced diet (the so-called DASH eating plan), maintaining one's ideal weight, engaging in physical activity, quitting smoking, and taking only moderate amounts of alcohol.
As for coming up with the appropriate pharmacologic intervention, JNC 7 recommended that thiazide-type diuretics be used as initial therapy for most patients, whether alone or in combination with an ACE inhibitor, angiotensin-receptor blocker, beta-blocker, or calcium-channel blocker. However, the European Society of Hypertension (2003) and World Health Organization/International Society of Hypertension (1999) suggested that BP lowering per se--whether the agent used is an ACEI, ARB, CCB, BB, or diuretic, whether alone or in combination--is the most important factor that lowers CV morbidity and mortality.
Single or combo
In the past a stepped-care approach was used in the management of hypertension. This starts with a single low-dose agent, and titrating the dose upward if necessary. If BP control is not achieved with the high dose of the initial agent, a second drug is added.
This approach has been associated with a number of problems, such as dose-dependent adverse reactions. To solve these problems the use of low-dose combinations of different classes for initial therapy has been widely explored.
The first such combination to appear as first-line therapy in mild to moderate hypertension is bisoprolol-hydrochlorothiazide (Ziac), a beta-blocker-diuretic combination.
Initial studies (such as Weir, 1993) showed that the once-daily administration of the bisoprolol-hydrochlorothiazide combination offer the following: additive antihypertensive effects, absence of postural hypotension, reduced dose-related toxic reactions, safety, lack of tolerance, and convenient administration. The BP-lowering ability of the combination compared with bisoprolol or hydrochlorothiazide alone was also demonstrated by Frishman et al. (1994). Also, Prisant et al. (1995) showed that the combination is as effective as single-agent drugs, without the adverse events often associated with full-dose monotherapy. Lewin et al. (1993) also showed that the combination was effective over a 24-hour period, as seen in ambulatory BP-monitoring.
Meanwhile, Neutel et al. (1996) compared the efficacy and safety of the combination with single-agent amlodipine and enalapril. It was demonstrated that combination bisoprolol-hydrochlorothiazide led to reductions in systolic blood pressure greater than enalapril (p = 0.003), but the difference with amlodipine was not significant (p = 0.22). The combination also registered more significant decreases in diastolic blood pressure than the two other agents. As for safety, fewer patients on the combination (29 percent) reported drug-related adverse events than those on amlodipine (34 percent).
Papademetriou et al. (1998) compared losartan (alone or in combination with hydrochlorothiazide) with the bisoprolol-hydrochlorothiazide combination, and showed that in terms of diastolic blood pressure, more patients on the bisoprolol-hydrochlorothiazide combination (71 percent) than losartan alone or the losartan/hydrochlorothiazide combination (29 percent).
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