The Evolution of Combination Therapy in Treating Hypertension


Michael A. Weber, MD, 420 Lexington Avenue, Suite 2525, New York, NY 10170

Hypertension is a chronic condition that in typical patients evolves over several years or even decades. So it is not surprising that the traditional approach to its treatment was based on a deliberative search for particular drugs that were efficacious and well-tolerated for individual patients. This strategy is now changing. First, modern drugs tend to have fewer side effects than their predecessors and no longer produce the adverse effects that could limit patients' ability to perform usual daily activities. Second, clinicians now look for properties of drugs, established by well-conducted clinical trials, that might provide clinical benefits beyond their blood pressure (BP)-lowering actions.

Even so, reducing BP to the recommended target levels remains the single greatest challenge in antihypertensive treatment. Indeed, the most recent recommendations for treating hypertension in the United States focus predominantly on this issue. The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)1 recommends that BP be reduced to <140/90 mm Hg in most patients and to the even lower target of 130/80 mm Hg in patients with diabetes or other major concomitant clinical conditions. This strong interest in BP levels by the JNC 7 is shared by most experts in the field, and it was strongly influenced by epidemiologic data establishing that each 20-mm Hg systolic or 10-mm Hg diastolic increment in BP level, from a starting point of 115/70 mm Hg, has the effect of doubling the risk of fatal coronary and stroke events.2

In turn, these data create an important question: how do we best devise clinical strategies to achieve the relatively aggressive BP goals that we now seek?


There can be little argument that effective reduction of BP helps prevent major cardiovascular events. Recently, clinical trials in hypertension have advanced this concept in 2 additional ways. First, they have demonstrated that differences between treatments in achieved BPs of <5 mm Hg can translate into meaningful differential effects on fatal and nonfatal clinical outcomes. Clinical trials such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),3 the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE),4 and Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)5 revealed that apparently small BP differences resulted in significant differences in end points, including stroke, myocardial infarction, and death.

The second critical lesson learned from these trials is the importance of achieving BP control as rapidly as possible. In each of these major trials,3–5 investigators were actively encouraged to increase drug doses or to add permissible additional drugs to achieve timely BP control in all patients. But despite these exhortations, it was somehow not possible for BP reductions in the less adequately controlled treatment arms to catch up with their comparator arms, even in these long-term trials. This time-to-control concept seems to have definite implications for outcomes. In the VALUE trial, for instance, the degree of BP control achieved by only 1 month of treatment appeared to be predictive of clinical events during the subsequent 5 years of the study.6 Certainly, by 6 months of treatment, controlling systolic BP to <140 mm Hg was highly predictive of subsequent cardiac events, strokes, and mortality.

From these experiences, there appears to be a simple 2-part message: (1) get BP in hypertensive patients under true control, and (2) do it quickly.


A comprehensive survey of community BP levels in the United States by the National Health and Nutrition Examination Survey (NHANES)7 has shown that many hypertensive patients are not being treated at all and that only about one-half of those who are being treated actually have BP levels <140/90 mm Hg. To be fair, management of hypertension in clinical practice may present obstacles not encountered in formal clinical trials. After treatment of hypertension is started, for example, patients may not fully understand the need for further adjustments in therapy to achieve optimal results. They may even regard the addition or substitution of other antihypertensive agents as an indication that the physician may have chosen unwisely in selecting the initial drug and so lose confidence. Also, as a practical matter, it is sometimes inconvenient, or even unaffordable, for patients to make repeated visits to the office or clinic as part of their treatment follow-up. In multi-physician practices or managed care settings, patients may sometimes be seen by practitioners who are not entirely familiar with a particular patient's BP requirements.

Physicians, as well, are not always aggressive in pursuing BP goals. Sometimes they are concerned about potential adverse effects and make a conscious choice to accept only a partial BP response rather than risk having patients complain about undesirable symptoms, an indication of physician “lack of adherence” or “inertia.” In addition, many hypertensive patients have multiple concomitant conditions requiring drug therapy, so there is also a somewhat understandable reluctance to add further medications to an already long list.

One revealing study was conducted in clinics of the Department of Veterans Affairs.8 It was observed that physicians were often reluctant to intensify antihypertensive treatment even when they noted severely elevated BP levels and were concerned by them. More evidence for clinical inertia was documented in a recent survey that likewise found that 30% of patients with unacceptably high BP levels did not have their medications changed.9 Most of the time, physicians are praised for their cautious approach to therapy, and clearly adding drugs unnecessarily should be avoided. All the same, it can be difficult to understand a reluctance to intensify antihypertensive therapy, particularly in an era when most drug choices have been shown to be safe and well-tolerated.


Published guidelines in both the United States and Europe have now recommended that physicians consider starting treatment of hypertension with 2 drugs when BP levels are at least 20/10 mm Hg above the desired treatment goal.1,10 These recommendations appear attractive because they provide a strong probability that many hypertensive patients will have their BP levels brought under control by the first treatment to which they are exposed. The articles that follow in this supplement provide evidence that starting antihypertensive therapy with 2 drugs, typically in the form of a fixed-dose combination, is not only efficacious but also safe and well-tolerated.

Evidence in support of these observations comes from recently published data from the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial.11 This study is comparing the effects of 2 types of fixed combinations in preventing cardiovascular outcomes. Of particular note, the early still-blinded data from this trial have established the highest ever reported BP control rates in a major hypertension study.


It is already widely accepted that well-selected drug combinations are a valuable approach to treating hypertension. Drug classes can have complementary mechanisms of action that provide powerful additive BP effects when combined. This allows the use of lower drug doses than might otherwise be needed, helping to reduce the incidence of dose-dependent adverse effects. It is also possible that the actions of one drug might counteract the unwanted effects of the other, thereby improving tolerability as well as efficacy. It is also more practical, when using a fixed combination, to take 1 tablet or capsule rather than 2, a factor that may enhance patient compliance with treatment. Further, it is likely that there will be cost savings associated with the use of combination antihypertensive treatments as compared with monotherapy. As discussed earlier, however, the use of combination treatment is now being considered as the initial step in therapy, thereby enhancing the all-critical probability of achieving goal BP levels in a timely fashion.

A further strong incentive for this approach is its applicability across the full spectrum of hypertensive patients. The clinical trial Irbesartan/Hydrochlorothiazide BP Reductions in Diverse Patient Populations (INCLUSIVE)12 has demonstrated this concept. In patients who had not responded adequately to previous monotherapy treatment, the fixed combination of irbesartan with hydrochlorothiazide was shown to achieve high goal BP rates in elderly as well as young patients; to a similar extent in white, black, and Hispanic patients; and to be efficacious and safe regardless of whether patients had evidence for diabetes or for the metabolic syndrome. These results provide incentives for combination therapy in patients for whom prompt and efficacious BP level reductions are required.


For the many hypertensive patients who have stage 1 hypertension (BP levels between 140/90–159/99 mm Hg), it is still perfectly appropriate to start treatment with monotherapy. A relatively high proportion of these patients will respond adequately to a single agent, particularly if it is thoughtfully selected with the characteristics of the individual patient in mind. Of interest, in a follow-up report of the VALUE trial describing patients whose BP could be controlled by monotherapy,13 it was noted that these high-risk hypertensive patients received strong protection from major events when their monotherapy effectively reduced BP. For patients with stage 2 hypertension (BP levels ≥160/100 mm Hg), it now appears that starting therapy with 2 drugs is the most prudent course of action.


The articles in this supplement describe in detail pivotal trials designed to explore the efficacy and safety of fixed-dose combinations of the angiotensin receptor blocker irbesartan and the thiazide diuretic hydrochlorothiazide. These studies were designed specifically to address the issue of whether initiating treatment with such a combination in patients with high baseline BP—colloquially referred to as severe or moderate hypertension—can demonstrate efficacy superior to conventional monotherapy while maintaining an acceptable safety profile.

The results of these studies are encouraging. In the first article in this supplement, Weir and colleagues14 discuss the fixed-dose combination of irbesartan and hydrochlorothiazide given as initial therapy to patients with moderate or severe hypertension (stage 2 by JNC 7 criteria). They report substantial reductions in BP levels, regardless of patient age, weight, or diabetic status. Of note, this treatment was well tolerated: symptoms that could be indicative of potentially excessive BP-lowering effects were uncommon. In a further analysis of these data, the article in this supplement by Franklin and colleagues15 focuses on the relationship between pretreatment BPs and the likelihood of achieving targets of <140/90 mm Hg or <130/80 mm Hg. The authors have established the relationship between baseline BP and attainment of goals, and they also demonstrate the superiority of combination treatment, as compared with monotherapy, in achieving the desired results.

Recommendations by the guidelines committees1,10 are now being supported and further emphasized by growing clinical trial evidence. The experience with the combination of an angiotensin receptor blocker and a thiazide diuretic described in detail in this supplement provides further support for the concept of initiating antihypertensive therapy with combination treatment in the large numbers of patients who can benefit from such a strategy.


Michael A. Weber, MD, is a member of the Speakers' Bureaus for Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Forest Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sanofi-Aventis and is a consultant for Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Forest Pharmaceuticals, Gilead, Merck, Novartis, and Takeda Pharmaceuticals.