Patients, in turn, become non-compliant. Another reason for the failure to control blood pressure is that one drug addresses only one physiological pathway of many that leads to hypertension. Multiple mechanisms are involved in the pathogenesis of hypertension.⁵By choosing two drugs from appropriate classes of agents, the primary actions of drugs acting through different mechanisms are put into play, while they oppose the homeostatic compensations that limit the fall in blood pressure. Combination therapy may have an advantage in that it synergistically interferes with pathogenetic mechanisms. Thus, lower doses can be used and the problem of dose-dependent side effects is minimized.

Another rationale for combination therapy is that sustained hypertension often leads to target organ disease in the heart, the kidneys and the brain. Certain antihypertensive drugs, such an angiotensin converting enzyme inhibitors (ACE inhibitors), affect target organ disease independent of their antihypertensive efficacy. Unfortunately, most studies regarding hypertensive disease have focused on monotherapy. Thus, our knowledge of combination therapy in the treatment of hypertension is, to a great extent, extrapolation from monotherapy. This paper will explore the benefits of the ACE inhibitors in combination with calcium antagonists in terms of their efficacy in left ventricular hypertrophy (LVH) and coronary heart disease (CHD).

The importance of blocking multiple physiologic pathways is underscored by studies using a treatment strategy known as ‘‘sequential monotherapy.’’ This approach is based on the observation that BP response to different antihypertensive medications is often quite variable, and BP control should be more readily achieved with monotherapy if patients are exposed to multiple drugs and then treated with the most effective agent.⁶In the Strategies in Treatment of Hypertension study, treatment initiated with a low-dose combination was compared with a monotherapy arm in which patients were first treated with a b-blocker but could be switched to an ACE inhibitor or a CCB if BP remained >140/90 mm Hg. At the end of 9 months, a significantly higher percentage of patients randomized to the low-dose combination achieved target BP compared with those receiving sequential monotherapy (62% vs. 49%, P ¼ .02).⁷

Principles and necessity of combination therapy:

The ability to maintain constant or near-constant BP in response to various stressors is central to homeostasis, and the human organism has redundant physiologic mechanisms for regulating arterial pressure. BP is determined primarily by three factors: renal sodium excretion and resultant plasma and total body volume, cardiac performance, and vascular tone.⁸These factors control intravascular volume, cardiac output, and systemic vascular resistance, which are the immediate hemodynamic determinants of BP. Both the sympathetic nervous system and the renin-angiotensin-aldosterone system are intimately involved in adjusting these parameters on a real-time basis. In addition, genetic makeup, diet, and environmental factors influence BP in individual patients. In addition, drug therapy directed at any one component routinely evokes compensatory (counterregulatory) responses that reduce the magnitude of response, even if it was accurately directed at the predominant pathophysiologic mechanism.

Antihypertensive efficacy of a single drug is often lowered due to the potential stimulation of compensatory mechanisms serving to restore blood pressure to its present levels. Combination therapy allows the use of lower doses of each antihypertensive agent; therefore, compensatory stimulation may be diminished, and, conceivably, the second component of combination may counteract this stimulation. Adding a second drug may also unmask an antihypertensive effect of the first component as in the case of racial differences that were seen in black patients in response to low-dose captopril that were abolished by the addition of hydrochlorothiazide. Whether the combination of two different antihypertensive agents results in an additive, subadditive, or supradditive effect on arterial pressure is unclear.

The aggregate of available data suggests that at least 75% of patients will require combination therapy to achieve contemporary BP targets. This estimate reflects the results of previous studies, the lower BP targets now in place for large segments of the hypertensive population, and the rapidly increasing prevalence of obesity. The latter is important as the presence of obesity further elevates pretreatment BP and increases the magnitude of BP reduction needed to achieve therapeutic targets.⁹The importance of achieving goal BP in individual patients cannot be overemphasized. In major clinical trials, small differences in on-treatment BP frequently translate into major differences in clinical event rates. Recent data also suggest that inadequate BP control is itself an independent risk factor for the development of diabetes in hypertensive patients.¹⁰

As mentioned, using monotherapy often means raising the dose of the antihypertensive agent to levels that can produce toxic effects. Postural hypotension, bradycardia, myocardial ischemia with subsequent myocardial infarction, cardiac arrhythmias, and profound shock are all symptoms that can result from high doses of some older antihypertensive agents. It was documented that to avoid side effects, refrain from increasing the dose of monotherapy drug above one that controls blood pressure in about half of the patients.¹¹Thus, a low-dose combination of two different agents reduces the risk of dose-related adverse reactions while still allowing sufficient blood pressure reduction.

Apart from increased efficacy, several other reasons exist that can lead the clinician to consider combination therapy. For example, the addition of one agent may counteract some deleterious effects of the other. It was reported that adjunctive ACE inhibitor therapy attenuated diuretic-associated hypokalemia, hyperglycemia, hyperuricemia, and hypercholesterolemia. ¹² Vasodilatory edema that occasionally occurs with dihydropyridine calcium antagonists has been reported to diminish when ACE inhibitors were added.

The combination of an ACE inhibitor and a calcium antagonist is conceptually attractive because the calcium antagonist provides primarily arterial vasodilation, whereas the ACE inhibitor adds balance with some venous dilation, a characteristic that applies particularly to the dihydropyridine calcium antagonists, and which produces an almost exclusive arteriolar dilation.¹³ The natriuretic effect of calcium antagonists complements ACE inhibitor therapy much as diuretic therapy does, but it makes it possible to control blood pressure without using a diuretic when that is desirable.¹⁴

Each agent provides theoretical or actual benefits when certain concomitant conditions are present: ACE inhibitors for left ventricular dysfunction/heart failure, diabetic nephropathy, and postmyocardial infarction, and calcium antagonists for angina, certain arrhythmias, and various vasospastic conditions.¹⁴ Both agents have, theoretically, beneficial hemodynamic and nonhemodynamic effects on the kidney, the heart, and the vasculature that are pressure-independent. Therefore, such combinations may be particularly appropriate in patients with diabetic nephropathy, nondiabetic renal disease, and either hypertensive or atherosclerotic heart disease. In the common situation in which a hypertensive diabetic patient has angina and nephropathy, this combination—with or without the addition of a diuretic— would seem to be ideal.

Recent data suggest that the combination of calcium antagonists and ACE inhibitors has a favourable effect on hypertensive target organ disease; possibly exceeding the effect of the reduction of blood pressure per se. It was found that, in hypertensive type 2 diabetics, the combination of reduced doses of an ACE inhibitor and calcium antagonist attenuate both albuminuria and the rate of decline in glomerular filtration rate. Also, high doses of ACE inhibition alone may be detrimental to renal function in late stage diabetics with renal insufficiency. ^15,16 ACE inhibitors in combination with calcium antagonists are particularly efficacious in reducing left ventricular hypertrophy and may be useful in patients with coronary heart disease (CHD).

Efficacy and Tolerability in combination therapy:

Rational combination therapy is based on the deliberate coadministration of two or more carefully selected antihypertensive agents. Inclusion of drugs known to reduce the long-term incidence of CV end points is highly preferred. A fundamental requirement of any combination is evidence that it lowers BP to a greater degree compared with monotherapy with its individual components. This is achieved by combining agents that either interfere with distinctly different pressor mechanisms or effectively block counter regulatory responses. Fully additive combinations are more effective in terms of BP reduction. In general, combining drugs from complementary classes is approximately five times more effective in lowering BP than increasing the dose of one drug.¹⁷ Another important requirement of a combination is pharmacokinetic compatibility (ie, combined drug administration results in smooth and continuous BP reduction throughout the dosing interval).¹⁸ These principles apply regardless of whether agents are included in an SPC or are coadministered as separate drugs.

Improving the overall tolerability of treatment is a key element in designing rational drug combinations. This beneficial effect will occur whenever side effects associated with a particular agent are neutralized by the pharmacologic properties of an added drug.¹⁸ Because most antihypertensive agents produce dose-dependent side effects, high-dose monotherapy may lead to adverse events. In this circumstance, a lower dose of the initial agent in combination with another antihypertensive may be preferable to minimize dose-dependent side effects even if no additional BP reduction is achieved.

Left ventricular hypertrophy

The results of basic and clinical research over the last 30 years have shown that hypertension cannot be treated merely by inducing vasodilation and a fall in blood pressure. The development of hypertension is linked with changes in carbohydrate and lipid metabolism and with the development of organ damage, mainly of the heart and kidneys. We now know that different elements of blood pressure control mechanisms can lead to hypertension, emphasizing the need to select the appropriate type of hypertensive drug in treating different patients. It was noted that calcium antagonists and ACE inhibitors have synergistic effects on sodium and fluid balance and on the renin-angiotensin aldosterone system.¹⁹Thus a combination of these two antihypertensive drug classes is likely to be beneficial in certain subgroups of patients with hypertension. While large trials are needed to truly prove this hypothesis, we recognize that, of all antihypertensive drugs, ACE inhibitors are probably the most effective in reducing LVH. ^20-22

Whether angiotensin II receptor inhibitors, either in monotherapy or in combination, are as efficient as ACE inhibitors in reducing LVH remains undocumented at the present time. Most of the other commonly used combinations, such as diuretics plus beta-blockers, ACE inhibitors plus beta-blockers, as well as beta-blockers plus dihydropyridine calcium antagonists, are prone to reduce LVH in parallel with the fall in arterial pressure. Is there any drug combination that should be avoided in patients with LVH? Drug classes that either stimulate the renin angiotensin system or the sympathetic nervous system, or both, are less likely to reduce LVH than drug classes that do not stimulate these systems. The combination of an arteriolar vasodilator, such as hydralazine or minoxidil, with a diuretic should, therefore, probably not be used in an asymptomatic patient with LVH. Such a combination may also synergistically elicit hypokalemia, which could aggravate or trigger ventricular arrhythmias.

Coronary artery disease

Myocardial ischemia has been shown to be common among hypertensive patients.^{23, 24} This may be due to the development of coronary atherosclerosis, exaggerated reactivity of cardiac arterioles, increased hemodynamic burden of the heart and increase in left ventricular mass. The two drug classes most commonly used to treat coronary artery disease are the calcium antagonists and the beta-blockers.

Whether the combination of an ACE inhibitor and a calcium antagonist is therapeutically justifiable in patients with CHD remains to be seen. Angiotensin, a vasoconstrictive peptide, is now known to be an agent of vascular oxidative stress, vascular growth, and inflammation, and can directly influence the pathophysiology of CHD.²⁵ Angiotensin-converting enzyme inhibition has been shown to improve endothelium-dependent vasodilator responsiveness in patients with CHD. Koh et al showed that ACE inhibitor therapy selectively improves endothelium-dependent vasodilator responsiveness by increased nitric oxide (NO) bioactivity in relation to vascular smooth muscle in such patients, an effect achieved at a lower rate of NO release from the endothelium. ²⁶ These research findings suggest that ACE inhibitors may reduce angiotensin II-induced oxidant stress within the vessel wall and protect NO from oxidative inactivation, an effect that may reduce endothelial NO synthesis required for vasomotor regulation.

New insights from basic laboratory studies and clinical trials have raised the intriguing possibility that the renin-angiotensin-kinin system may play a critical part in the pathophysiology of atherosclerosis. ²⁷ These studies suggest the possibility of an important new therapeutic role for ACE inhibitors: reduction in the risk of atherosclerosis and the complications of coronary artery disease. Ongoing large-scale trials will establish whether the findings from basic laboratory studies and clinical heart failure trials will apply to patients with ischemic heart disease irrespective of the presence or absence of left ventricular dysfunction.

Specific Drug Combinations:

There are seven major classes of antihypertensive drugs and multiple members of each class; therefore, the number of possible combinations is quite large. In this position paper, two-drug combinations involving classes of pharmacologic agents that reduce CV end points (diuretics, CCBs, ACE inhibitors, ARBs, b-blockers) are emphasized. Combinations of three or more drugs are not reviewed. Specific combinations are designated as preferred or acceptable based on the considerations outlined previously. Combinations that are less effective on the basis of efficacy, safety, or tolerability concerns are also identified.

RAAS Inhibitor and Diuretic

The combination of an ACE inhibitor, ARB, or direct renin inhibitor with a low-dose, thiazide-type diuretic results in fully additive BP reduction.^28–32 Diuretics initially reduce intravascular volume and activate the RAAS, leading to vasoconstriction as well as salt and water retention. In the presence of a RAAS inhibitor, this counterregulatory response is attenuated. Addition of a RAAS inhibitor to a thiazide-type diuretic also improves its safety profile by ameliorating diuretic-induced hypokalemia,³³but can result in hyperkalemia in susceptible patients. Based on their safety, efficacy, and favorable performance in long-term

trials, combinations of an ACE inhibitor or an ARB with a low-dose diuretic are classified as preferred. Most FDCs containing a diuretic use hydrochlorthiazide (HCTZ). Because chlorthalidone is more effective than other diuretics in reducing BP over 24 hours ³⁴ and was the agent used in all but one large US-based hypertension outcome trial, some authorities favor its use over HCTZ. Because it is not currently aligned in any SPC with an ACE inhibitor or ARB, it can be administered as a separate agent.

Thiazide Diuretics and Potassium-sparing Diuretics:

Hypokalemia is an extremely important dose-related side effect of thiazide diuretics. By attenuating hypokalemia, the combination of HCTZ with a potassium-sparing diuretic such as triamterene, amiloride, or spironolactone improves its safety profile.³⁵ Because of the risk of hypokalemia that can lead to cardiac arrhythmias, and sudden death, HCTZ 50 mg and chlorthalidone 25 mg should generally be used in combination with a potassium-sparing agent (or an inhibitor of the RAAS). Given the latest data demonstrating the importance of aldosterone blockade in obese patients and the efficacy of aldosterone blockade in helping achieve BP goals, the spironolactone/HCTZ combination is particularly well-suited in such individuals.³⁶ The addition of amiloride to HCTZ reduces hypokalemia and results in variable BP reduction.^37,38 These combinations are classified as acceptable in people with relatively well-preserved kidney function (ie, estimated glomerular filtration rate >50 mL/min/1.73 m2). At glomerular filtration rate levels below this, the risk for hyperkalemia increases and the diuretic efficacy of HCTZ starts to diminish.³⁹

CCBs and b-Blockers

The pharmacologic effects of these two drug classes are complementary, and their combination results in additive BP reduction. In one study, a low-dose combination of felodipine ER and metoprolol ER produced BP reduction comparable to maximum doses of each agent with an incidence of edema similar to placebo.^{40, 41} The combination of a b-blocker and a dihydropyridine CCB is acceptable. b-blockers should not generally be combined with nondihydropyridine CCBs such as verapamil or diltiazem because their additive effects on heart rate and A-V conduction may result in severe bradycardia or heart block.

RAAS Inhibitor and CCB

The combination of an ACE inhibitor or ARB with a CCB results in fully additive BP reduction.^42-44 Addition of either of these two RAAS inhibitors significantly improves the tolerability profile of the CCB. In addition, RAAS inhibitors partially neutralize the peripheral edema, which is a dose-limiting side effect of these CCBs.⁴⁵ The cause of the edema is believed to be arteriolar dilation, resulting in an increased pressure gradient across capillary membranes in dependent portions of the body. RAAS blockers are thought to counteract this effect through venodilation. The Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension trial tested whether initial fixed-dose combination therapy with an ACE inhibitor and CCB differs from initial fixeddose combination therapy with an ACE inhibitor and diuretic on clinical outcomes in high-risk hypertensive patients. Despite comparable BP reduction, the ACE inhibitor/ CCB combination reduced the combined end point of cardiovascular death, myocardial infarction, and stroke by 20% compared with the ACE inhibitor/diuretic combination. ⁴⁶ Of note, 60% of patients were diabetic, and a large percentage had evidence of underlying ischemic heart disease.⁴⁷ These results suggest the superiority of a CCB over a diuretic when used in conjunction with a RAAS blocker in this high-risk population. ACE inhibitor/CCB combinations are classified as preferred. In view of end point studies demonstrating comparability between ACE inhibitors and ARBs, ARB/CCB combinations are considered to be equivalent.48

B-Blockers and Diuretics:

Although b-blockers reduce CV end points in placebocontrolled trials, meta-analyses (based primarily on the performance of atenolol) suggest that they are less effective than diuretics, ACE inhibitors, ARBs, and CCBs.^49–51 The antihypertensive effects of b-blockers are mediated through reduction in cardiac output and suppression of rennin release.⁵² As with the ACE inhibitors and ARBs, b-blockers attenuate the RAAS activation that accompanies the use of thiazide diuretics, and their combination results in fully additive BP reduction.^53–55 Addition of diuretics also improves the effectiveness of b-blockers in blacks and others with low renin hypertension.⁵⁶ These combinations are classified as acceptable, recognizing that their use is associated with increased risk of glucose intolerance, fatigue, and sexual dysfunction.

Renin Inhibitor and ARBs

The combination of a renin inhibitor with an ARB produces partially additive BP reduction and is welltolerated. In a study in which maximum approved doses of valsartan and aliskiren were combined, a 30% additional BP response was observed compared with either monotherapy. ⁵⁷ The side effect profile of this acceptable combination was comparable with placebo. There are no cardiovascular outcome data with this combination to date.

CCBs and Diuretics

The combination of a diuretic and a CCB results in partially additive BP reduction.^58,
59Presumably, this partial effect reflects overlap in the pharmacologic properties of the two drugs. CCBs increase renal sodium excretion, albeit not to the same extent as diuretics. Moreover, long-term treatment with both classes is associated with vasodilation, given that volume depletion does not occur with diuretics. From an endpoint perspective, this combination performed well in the Valsartan Antihypertensive Long-term Use Evaluation

trial in which HCTZ was added as a second step in patients randomized to amlodipine.⁶⁰ As opposed to ACE inhibitor/CCB or ARB/CCB combinations, the CCB with diuretic has no favorable effect on either drug’s side effect profile. These combinations are classified as acceptable.

Less Effective Combination therapy available:

ACE Inhibitors and ARBs:

Although sometimes useful for proteinuria reduction and in the treatment of symptomatic patients with heart failure, the combination of an ACE inhibitor and an ARB is not recommended for the treatment of hypertension. ACE/ ARB combinations produce little additional BP reduction compared with monotherapy with either agent alone. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, patients receiving the ACE inhibitor/ARB combination showed no improvement in cardiovascular end points despite additional BP reduction averaging 2.4/1.4 mm Hg.⁶¹There were also more side effects with the combination than with individual agents. These combinations are classified as less effective.

RAAS Inhibitor and b-Blocker

These drug classes are both cardioprotective and are frequently coadministered to patients with coronary heart disease or heart failure. When these agents are combined, however, they produce little additional BP reduction compared with either monotherapy.⁶² For this reason, they constitute a less effective combination when BP reduction is the principal goal. They can, however, be used together in patients with coronary artery disease or heart failure when outcome improvement is the primary objective.

CONCLUSION:

Using multiple drug therapy in hypertension to achieve maximal therapeutic benefits seems logical based on clinical evidence. Unfortunately, most studies regarding target organ damage in hypertension were carried out by focusing on the effects of monotherapy. Extrapolating from these studies, however provocative and suggestive they are, may not always prove to be beneficial in terms of hard end points, i.e. morbidity and mortality. Therefore, the exact benefits of any particular combination therapy will have to be defined by prospective, carefully designed, randomized trials. The role of ACE inhibitor-calcium antagonist combinations in reducing hypertensive end-organ damage, especially renal and cardiac, is promising but is yet to be fully clarified. In the meantime, for patients in whom a multidrug antihypertensive regimen is desirable, these fixed-dose combinations of ACE inhibitors and calcium antagonists offer a convenient, once-daily, effective and well-tolerated addition to our therapeutic options. Hopefully, the cost to the patient will also be less than the two agents prescribed separately. Because many hypertensive patients are already taking a regimen that includes both of these classes of drugs, we should carefully assess whether a fixed-dose preparation would benefit many of our patients.

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Received on 29.01.2013

Modified on 24.02.2013

Accepted on 28.02.2013

Research J. Pharmacology and Pharmacodynamics. 5(1): January –February 2013, 19-25