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PRIORITY PRESS - 19th European Meeting on Hypertension

Milan, Italy / June 12-16, 2009

The key attributes for any antihypertensive drug prescribed with the goal of sustained blood pressure (BP) lowering is dose-dependent efficacy with dose-independent tolerability. Antihypertensive agents with the angiotensin receptor blocker (ARB) class are alone in sustaining tolerability even when relatively high doses are employed to achieve BP control.

Stepwise Combination Strategies

Recent data with the ARB candesartan demonstrated a stepwise increase in BP control as doses were raised from 16 mg q.d. to 32 mg q.d., then to 32 mg q.d. together with 12.5 mg and then 25 mg of the diuretic hydrochlorothiazide (HCTZ) (Bonner et al. Blood Press Suppl 2008;2:22-30). These are critical data in supporting a practical clinical strategy.

“The dose-response analysis from this study demonstrated additive effects even at patients starting at higher pressures,” reported Dr. Peter Trenkwalder, Department of Internal Medicine, Starnberg Hospital, Starnberg, Germany. Emphasizing that most hypertensive patients will require a combination of drugs, he indicated that the high degree of tolerability from a dependable ARB facilitates the process when trying to bring the patient to goal without losing the patient to adverse events. The efficacy of candesartan has long been established, but the recent data reinforce an important dose-response in the absence of an escalating risk of tolerability issues.

Improved BP control with sustained tolerability is not necessarily a feature of other antihypertensive agents. Similar data with the scheme studied by Bonner et al., which entered 3521 patients into a run-in of candesartan 16 mg q.d. before a randomization to three treatment arms (32 mg q.d. monotherapy, 32 mg with 12.5 mg HCTZ or 32 mg with 25 mg HCTZ), are not available even for other RAS inhibitors. Each intensification produced a highly significant (P<0.001) advantage in BP over the next less intensive regimen. There were no significant differences in adverse events. The data support this ARB as an anchor as patients step up to achieve BP goals.

Guidelines and Recommendations

The evidence of stepwise efficacy for intensification of an ARB therapy is important because it is now well recognized that most hypertensive patients require some combination to reach BP goals. Major guidelines, including JNC VII (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) and those from the ESC-ESH (European Society of Cardiology–European Society of Hypertension) now recommend moving quickly to a combination or, when the likelihood of efficacy from a single agent is low, using a combination as initial therapy. Although the guidelines do not specify which combination to use, ARBs are increasingly recognized as an important component because of the potential for target organ protection.

Dr. Trenkwalder told delegates, “When we look at the continuum of vascular disease that starts with hypertension, progresses to endothelial dysfunction and left ventricular hypertrophy, before reaching end-stage events such as myocardial infarction and heart failure, upregulated RAS is a consistent pathogenic factor. BP-independent benefits from inhibiting RAS can be anticipated even in early disease.” Nearly the same statement was made about RAS inhibition relative to renal disease. According to Dr. Trenkwalder and as corroborated by several other experts, “One of the components of almost any antihypertensive combination should include a RAS inhibitor.”

The studies associating RAS inhibition with target organ protection have been conducted with both ACE inhibitors and ARBs. In the large multinational studies comparing these agents, outcomes have typically been almost indistinguishable except for tolerability, which is better on ARBs. This is a key issue for treatment of hypertension, a typically asymptomatic condition for which adherence to chronic therapy requires a high degree of tolerability and convenience even when BP elevations require combination treatments.

The Role of the Diuretic

New data suggest an ARB combined with a diuretic preserves a high level of tolerability even when relatively high doses are needed to achieve goals. “A diuretic is a very attractive partner for a RAS inhibitor because it reduces plasma volume to reduce stimulation of RAS, potentiating the effect of the RAS inhibitor. When added to a RAS inhibitor, a very modest dose of diuretic can produce very substantial BP reductions,” confirmed Dr. Sverre Kjeldsen, Professor of Cardiology, Ullevål University Hospital, Oslo, Norway. He also cited results of the Bonner study as evidence that important stepwise improvements in BP control can be achieved when candesartan 32 mg is coupled with increasing doses of a HCTZ diuretic. Regarding side effects, he referred to a trial that found the tolerability profile of an ARB and a HCTZ diuretic to be similar to placebo except those on active therapy had less headache, an effect likely due to BP lowering.

The efficacy and safety of an ARB and a diuretic is likely to place this among the most commonly used strategies in BP control for individuals who require a combination, particularly as single-pill combinations become available. However, Dr. Kjeldsen acknowledged that there are other combinations which might be used more selectively. For example, just as diuretics potentiate RAS inhibitors, RAS inhibitors can attenuate the edema associated with calcium channel blockers, making this combination, which would also be expected to be well tolerated, a reasonable choice in patients with a significant metabolic disorder.

In contrast, the combination of an ARB and an ACE inhibitor no longer appears to be viable based on a series of large studies that were unable to find any additive effect. As discussed here at the ESH, the most significant of these studies was ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), but other studies, such as VALIANT (VALsartan In Acute myocardial iNfarcTion), also demonstrated an increased risk of adverse events with no increased protection against end-stage events. According to Dr. Peter Meredith, Division of Cardiovascular and Medical Science, University of Glasgow, UK, the concept of dual RAS blockade initially had several theoretical advantages, particularly in protection against renal disease; however, the trial data are now sufficient to conclude that these agents should not be routinely combined except in selected patients with uncontrolled proteinuria or heart failure.

Encouraging Compliance

The issue of adverse events is raised periodically because the data repeatedly demonstrate very high dropout rates when hypertensive patients placed on therapy are observed over time. In data presented here by Dr. Giuseppe Mancia, San Gerardo Hospital, University of Milan-Bicocca, Italy, more than 70% of patients from a large prospective database maintained in Italy were no longer on therapy at the end of five years. He identified adverse events as the main reason. When he differentiated dropout rates by class, ARBs were the only one to produce a favourable hazard ratio (0.92) for adherence. However, he also suggested that lack of control with the assigned regimen is also a reason for dropout when patients become frustrated that their adherence does not lead to treatment goals. In these cases, Dr. Mancia attributed the problem to the consulting physician.

“If [they] want to control BP, physicians are going to have to be prepared to step up therapy and use more combination therapy,” Dr. Mancia stressed to delegates. He showed data in which more than 40% of patients in one survey did not receive a new prescription despite office BPs above goal. He indicated that rates of control would be even worse if patients underwent 24-hour ambulatory BP monitoring. Although combination therapy alone will not solve the problem of inadequate BP control, it is a meaningful step for many patients.

Summary

Current treatment guidelines for hypertension endorse early introduction of combination therapy, or even initiating therapy with a combination in patients not expected to reach goals on single agents. An ARB is a rational anchor for a combination because of the target organ protection associated with RAS inhibition and a favourable side effect profile. In a study of more than 3500 patients that evaluated candesartan combined with step-up doses of HCTZ, highly significant improvements in BP control were observed with each stepwise increase in intensification with no significant change in tolerability. Single-pill combinations may facilitate this approach as a standard of care.