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JOURNAL CLUB - CARDIOLOGY

January 2008

EDITORIAL OVERVIEW

Jonathan Howlett, MD Dalhousie University Halifax, Nova Scotia

PANEL

Pierre Nantel, MD Centre hospitalier Sorel-Tracy Sorel-Tracy, Quebec

Michel White, MD Université de Montréal Montreal, Quebec

Norman Muirhead, MD University of Western Ontario London, Ontario

Jonathan Howlett, MD Dalhousie University Halifax, Nova Scotia

Robert S. McKelvie, MD McMaster University Hamilton, Ontario

Several important principles of hypertension management underscored in a recent review article deserve emphasis (Lancet 2007;370:591-603).

The first is that the most important factor in treating hypertension is blood pressure (BP) control to target values; even smaller BP increases can translate into adverse events. Many patients will require aggressive multiple drug therapy to achieve target BP control. Second, in hypertension, there is a continuous relationship between rising BP values and escalating clinical risks that starts from >120/80 mm Hg. The prehypertensive patient (BP 130-140 mm Hg) has a >50% risk of becoming hypertensive over the next two years and should undergo repeated BP monitoring.

Third, target organ dysfunction and damage begins very quickly in the setting of hypertension, long before such catastrophic events as stroke, myocardial infarction and pro teinuria/nephropathy become apparent. Progressive impairment in endothelial function, a key precursor to end-organ damage, is rapidly detected with progressive increases in BP. Restoring endothelial function, preventing or regressing left ventricular hypertrophy (LVH) and/or microalbuminuria with antihypertensive therapy can be achieved and are key examples of the opportunity to treat end-organ damage at an early stage.

Fourth, while the value of properly conducted office-based measurements cannot be replaced, nonoffice-based BP monitoring methods such as home BP monitoring or ambulatory monitoring are extremely valuable. They provide a corollary to office-based measurements, can assist in the diagnosis of white-coat hypertension and represent the only way in which “masked hypertension” (elevated BP at home with controlled or normal BP in the office, a condition more common than previously thought) may be diagnosed. This last issue is critical since masked hypertension tends to be undertreated, leading to increased cardiovascular (CV) events.

Finally, although BP control is critical, antihypertensive agents differ in their relative protection against target organ damage. Evidence is accumulating that even after control for BP reduction, differences between antihypertensives exist in respect to end-organ damage control and this will vary according to the vascular bed in question. How these differences will play out over the longer term is unknown, as currently available evidence from clinical trials does not address greater than 10-year time frames.

Reviewing Benefits Beyond BP Control

As the authors of the Lancet review point out, the effects of antihypertensive agents seem to differ slightly according to the type of vascular bed in question. They note that cumulative data from meta-analyses suggest that the best data of coronary artery disease prevention come from trials involving ACE inhibitors, calcium channel blockers (CCBs) and thiazide diuretics. Similarly, the best data for stroke prevention appear to be from trials involving angiotensin II receptor blockers (ARBs), CCBs and thiazide diuretics, and for heart failure (HF), researchers list ARBs, ACE inhibitors and diuretics. Although it is difficult to select one type of event against which to offer protection, particularly for primary prevention, it is notable that agents inhibiting the renin-angiotensin system (RAS) figure in all the examples of target organ risk. In addition, several other important end points, such as nephropathy, atrial fibrillation and new-onset diabetes mellitus may be preferentially lowered by RAS-inhibiting agents as compared to other antihypertensive strategies.

Some of the earliest evidence of end-organ protection was generated by the SAVE (Survival and Vascular Endpoints) and SOLVD (Studies of Left Ventricular Dysfunction) trials, which associated ACE inhibitors with attenuation of cardiac remodelling and reduction of morbidity and mortality in patients with dilated LV function and HF. These findings were thought to be independent of BP lowering since these effects were not seen with the use of other antihypertensives such as CCBs or diuretics. Since then, a newer class of RAS inhibitors, the ARBs, has been evaluated in many of the same clinical situations and has demonstrated benefit in these patients. Moreover, the possibility that ACE inhibitors and ARBs could be combined to provide greater effect in patients with HF due to systolic LV dysfunction was evaluated in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity)-Added trial. In this trial, the benefit of an ARB, when added to an ACE inhibitor, was tested. The combination of candesartan plus an ACE inhibitor provided a 15% reduction (P=0.01) in the primary end point of CV death or hospital admission for worsening HF relative to placebo and an ACE inhibitor. In addition, this trial also showed in another arm—CHARM-Alternative—that the administration of an ARB to ACE-intolerant patients with HF due to systolic LV dysfunction provided a clinically significant benefit.

Published evidence confirms the benefits of ARB therapy for patients with hypertension and microalbuminuria, proteinuria and nephropathy. Basic research studies have shown nearly linear dose response of proteinuria reduction with ARB therapy, raising the possibility that supramaximal doses of these agents (with minimally further BP reduction) can bring about further clinical benefits. Most recently, the SMART (Supra Maximal Atacand Renal Trial), presented at the American Society of Nephrology meeting, provided another apparent example of target organ protection by comparing different doses of an ARB for relative control of proteinuria. In this study, 269 patients with a baseline proteinuria >1 g/24 hr present for more than six months were randomized to receive candesartan 16 mg, 64 mg or 128 mg for 30 weeks. Mean baseline BP was 132.5/77.5 mm Hg and baseline median urinary protein excretion rate was 2.66 g/24 hr. At the 128-mg dose, there was a 44.34% reduction in proteinuria (P<0.0001) for the per protocol patient population relative to the 16-mg dose, even though differences in BP were minor. The reduction for the intention-to-treat was 33.05%. The 128-mg daily dose was well tolerated and no differences in serum potassium levels were observed between study groups.

Risk Management: How Early Can We Treat?

More data are needed to evaluate the role of ARB/ACE inhibitor combinations for target organ protection in late-stage disease, but it is notable that a RAS inhibitor was employed to demonstrate inhibition of the pathological process of hypertension at its earliest stages. In TROPHY (Trial of Preventing Hypertension), 409 individuals with a systolic BP between 130 and 139 mm Hg and a diastolic BP of 8 9 mm Hg were randomly assigned to the ARB candesartan or placebo and then followed for four years. In the first two years, the ARB provided a 66.3% (P<0.001) reduction in developing hypertension, defined as a BP >140/90 mm Hg, relative to placebo. By the end of four years, the relative reduction was still 15.6% (P<0.007). There was no significant difference in adverse events. The TROPHY authors highlighted the high rate of development of hypertension over a relatively short time frame, which underscores the need f
p of these patients.

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The emphasis on risk management has traditionally been to find patients who are at high risk to ensure they are receiving treatment for a relatively imminent risk of events. Patients considered to be more than a decade away from their event have been treated less urgently. However, the question raised by several studies is whether RAS inhibitors might be used much earlier in the process before organ damage has occurred and multiple pathological processes have been initiated. One example of the potential of early treatment is the protection from new-onset diabetes observed in several studies with RAS inhibitors such as ALLHAT, CHARM, VALUE, SCOPE, LIFE and HOPE. In contrast, beta-blockers and diuretics, despite potent antihypertensive effects, have both been associated with a modest increase in the risk of new-onset diabetes (Lancet 2007; 369(9557):201-7, Am J Cardiol 2007;100(8):1254-62). This is particularly troubling in the face of the growing obesity and diabetes epidemic in many industrialized countries, including Canada. Since it is well known that diabetic patients tend to manifest CV events several years after diagnosis, this difference in new-onset diabetes may well translate into a much greater health impact over the long term.

Is the Renin-angiotensin System Key?

Although the mechanism of protection from new-onset diabetes is not clearly understood, the ability of RAS inhibition to provide protection against CV and renovascular diseases is at least in part attributed to inhibition of angiotensin II, a hormone generated by up regulated RAS. Angiotensin II has a wide range of adverse effects, such as inducing oxidative stress in the vessel walls, hypertrophy in the myocardium, and protein loss from the renal circulation. ACE inhibitors reduce production of angiotensin II, while ARBs block the AT1 receptor, which is the final common pathway of the deleterious effects of angiotensin II. These actions inhibit the vasoconstrictive effects of angiotensin II that lead to hypertension, but they also block the target organ damage mediated by this hormone, which may explain their BP-independent benefits.

The RAS inhibitors are not a solution in and of themselves to the risks posed by essential hypertension. Lifestyle changes, such as weight loss, increased exercise and sensible diets, should be the first line of defense against hypertension and its associated risks. In those who do not achieve BP targets with lifestyle changes alone, drug therapy is appropriate and the single most important goal should be to bring patients to currently recommended targets. In the Lancet review, the authors noted that regimens with less effective BP control have never shown superiority to regimens with more effective BP control for reducing risk of events. They also emphasized that most patients with hypertension require combination therapies. It is within these combination therapies that RAS inhibitors make sense in the ultimate goals of inhibiting the underlying pathological processes. Lastly, they noted hypertension should prompt a global risk assessment. In particular, many individuals who require an antihypertensive agent will also benefit from low-dose ASA and a cholesterol-lowering agent.

Summary

It is important for the treating physician to remember that the prehypertensive patient is at increased risk; target organ dysfunction and damage begins very soon in the hypertension continuum; non-office-based BP monitoring methods can assist in the diagnosis of white-coat hypertension and represent the only way to identify “masked hypertension;” antihypertensive agents differ in their relative protection against target organ damage; and most importantly, bringing BP to target values. These are important strategies for identifying patients at high risk of CV disease through risk assessment tools predicting the 10-year risk of an event, but treatment should not be withheld until patients develop advanced disease. Early treatment of hypertension offers an opportunity to prevent target organ damage with the potential of greater long-term benefits than waiting until patients already have significant atherosclerosis, LVH or albuminuria. Tight BP control is essential for target organ protection, but there is now strong evidence that RAS inhibitors have BP-independent benefits. However, such agents should be used within a regimen that brings patients to recommended BP targets. -

Questions and Answers With:

Dr. Pierre Nantel • Dr. Michel White • Dr. Norman Muirhead • Dr. Jonathan Howlett • Dr. Robert S. McKelvie

Q. How important is selection of antihypertensive drug therapy regarding protection against endorgan dysfunction?

Dr. Nantel: Preventing end-organ damage is really what we are trying to achieve. After all, we do not treat hypertension just to lower BP values. The goal is to protect the organs from the damage produced by elevated BP. If we can prevent target organ damage independent of and over BP reductions, then that will, of course, be a very important advantage, a kind of “bonus effect.”

Dr. White: Beyond its efficacy, it is the most important aspect for such an agent.

Dr. Muirhead: While achieving target BP is the single most important aspect of hypertension management, there is increasing evidence that, for a given target BP, the type of antihypertensive agent used may have a major impact on development or progression of target organ damage. For example, in type 2 diabetes, ARBs have been found to reduce progression of diabetic nephropathy in patients with microalbuminuria or clinical proteinuria and to allow regression of microalbuminuria. These benefits of ARBs are independent of changes in BP.

Dr. Howlett: It seems to me that protection from end-organ damage that occurs over and above that afforded by BP reduction is a valuable asset and that this would in part depend upon the vascular territory in question. Thus, if a patient were to have, say, LV dysfunction, or perhaps microalbuminuria, then this would represent a compelling reason to use RAS inhibitors, given their known additional end-organ protection benefits over and above that achieved by BP control to target.

Dr. McKelvie: I think protection against end-organ damage is very important with regards to the selection that agents reducing BP to the same degree don’t necessarily have the same effects to reduce end-organ damage, morbidity and mortality. Also, the other effects of the drugs (for example, hydrochlorothiazide) being used have to be taken into consideration because the treatments are used long-term and thus adverse effects may develop over time.

Q. Do subtle signs of organ damage, such as presence of LVH or microalbuminuria, influence treatment strategies in hypertension?

Dr. Nantel: Evidence of organ impairment is certainly going to be a motivation to be more aggressive in therapy, but the question is how much effort and cost are you going to incur to obtain this information. For example, screening for microalbuminuria is easy to do and inexpensive and we should look for microalbuminuria in every patient; evidence of LVH is more difficult and expensive to get. Although we can derive evidence of LVH from an electrocardiogram, I do not think we need to perform echocardiography on every patient. It may not be worth the cost.

Dr. White: Yes, they do [influence treatment strategies].

Dr. Muirhead: At present, there are substantial epidemiological data that indicate that such patients have an enhanced risk of adverse CV events. The use of drugs that specifically target the renin-angiotensinaldosterone system (RAAS) would be expected to reduce CV events in such patients and might thus be a useful early choice for BP management in such patients.

Dr. Howlett: Evidence of end-organ damage in a hypertensive patient is a clear signal to “get cracking” and treat vascular risk factors aggressively. I feel antihypertensive therapy should be tailored to target the specific end organ in question and should be instituted early and aggressively.

Dr. McKelvie: I think these subtle findings of endorgan damage should influence the type of drug used. These findings represent increased risk to the patient, including an increased risk of developing heart failure and an increased mortality risk. It has been demonstrated that patients with LVH, for example, are at increased risk of mortality compared to those without LVH, even in the absence of heart failure; so it would be important to aggressively treat the LVH to try and decrease the patient’s risk.

Q. In the TROPHY study, an ARB was found to prevent hypertension in patients with prehypertension. Would this be a reasonable treatment strategy in a particular patient population?

Dr. Nantel: I do not think that the concept of prehypertension has taken hold in Canada yet. We know that risk is on a continuum that begins at approximately 115 mm Hg systolic, but we do not have the data to tell us that treating very mild elevations in BP will significantly reduce risk of events. The TROPHY study did point out that hypertension is a progressive condition in many patients and that early treatment may some day be an option to inhibit this process in patients at high risk, but we cannot say that now.

Dr. White: Patients at higher risk such as those with diabetes or atherosclerosis, for example, will be ideal candidates to decrease the risk of hypertension and also its complications.

Dr. Muirhead: At present, there are insufficient grounds to recommend drug management for prehypertension. However, to the extent that patients with prehypertension are at increased risk for fixed hypertension and for adverse CV events, there may be a future role for active treatment of such patients. ARBs would be a good choice in such patients because of their excellent tolerability and their efficacy in preventing worsening hypertension.

Dr. Howlett: We do not yet have the evidence that all such patients should be treated in order to prevent hypertension in prehypertensive patients. However, we must watch them closely and in particular, if they show any signs at all of end-organ damage, one should strongly consider masked hypertension and this should be sought by home or ambulatory BP monitoring.

Dr. McKelvie: I think the patient population might be quite limited to use this treatment strategy. It might be best used in patients with other comorbidities such as those with impaired fasting glucose or other findings that may justify the use of an ARB, for example. So I think at present, the results of the TROPHY study would be limited and can’t be generalized to treat everyone with pre hypertension. However, it is important to remember that these individuals with prehypertension most likely have other risks such as impaired glucose tolerance or hyperlipidemia, so there should be a complete approach to the patient regarding all the issues rather than just focusing on the BP alone

Q. In hypertensive patients who require combination therapy for BP control, do you feel a RAS inhibitor is often appropriate, usually inappropriate, or does it depend on the patient?

Dr. Nantel: None of the antihypertensive therapies are capable of reducing systolic BP more than 20 mm Hg as a single agent, so we will need combinations even as initial therapy for those who need reductions greater than this. One reason to consider a combination right away is that the data suggest we want to achieve BP control relatively quickly. The RAS inhibitors are very attractive, particularly as we know that angiotensin II plays a major role in pathogenic processes. For this reason, it makes sense to consider a RAS inhibitor as one of the components of a combination regimen in most patients.

Dr. White: It is appropriate most of the time. I foresee such combinations growing in the future .

Dr. Muirhead: Hypertension is a progressive disease. Most patients will thus require combination therapy at some stage of the illness, particularly if aggressive BP targets are to be reached or maintained. Drugs that target the RAAS are well tolerated in the short and long term and patients are more likely to adhere to therapy with such agents over the long term. Coupled with the proven efficacy of such agents for target organ protection, inclusion of drugs that target the RAAS in any multiple drug regimen for hypertension seems prudent.

Dr. Howlett: I routinely use combination therapy with RAS inhibitors as part of the combination whenever the patient’s BP is more than 20 mm Hg over target systolic or more than 10 mm Hg target diastolic.

Dr. McKelvie: I think a RAS inhibitor is often required in patients who require combination therapy for BP control. These patients often have multiple comorbidities that may benefit from RAS inhibition. There may be impaired glucose tolerance or the presence of some degree of LV hypertrophy, both of which potentially could benefit from RAS inhibition.

Q. In the recently reported SMART, high doses of an ARB—up to 128 mg of candesartan—were compared to a conventional dose (16 mg) and found to reduce proteinuria significantly despite similar BP control. In light of these results, would you consider using higher doses of an ARB to obtain increased target organ protection?

Dr. Nantel: Like SMART, there are some other studies that have suggested that you can push the dose of an ARB to get extra benefit with no change in BP. This suggests that we could use doses over the one recommended for control of BP to maximize the benefit on reducing microalbuminuria. Of course, before advocating this, we need more studies like SMART. The combination of ARBs and ACE inhibitors is another strategy to increase blockade of the effects of angiotensin II. We need studies comparing the effect of such a combination vs. the high dose of ARB to learn which is the more efficacious.

Dr. White: I believe we now have good evidence to use very high doses of ARBs, candesartan in particular, in this setting. The impact on the kidney strongly suggests an overall CV protective effect. However, we need more scientific evidence for such a global CV effect.

Dr. Muirhead: The SMART study certainly suggested that additional reductions in proteinuria would occur with higher doses of candesartan. This would be expected to result in a decline in the rate of progression of chronic kidney disease, though it was not possible to discern such a benefit, given the relatively short duration of follow-up in SMART. I would certainly consider increasing candesartan dose in patients with proteinuric renal disease at risk of progression. Highdose candesartan in such patients in the SMART protocol was remarkably safe and well-tolerated.

Dr. Howlett: The SMART study showed that further reduction of proteinuria is associated with “supramaximal” ARB dosage. Once we combine this with the clinical correlate—slowing of further renal dysfunction or of prevention of end-stage renal disease—then this should be a routine therapy.

Dr. McKelvie: This is an interesting question because it is asking for extrapolation of the results of this study to target organ protection generally. The results of the SMART are interesting; however, it must be remembered it was a smaller study of 269 patients. I think the results are very encouraging and support the idea that control of BP is not the only thing that should be done in patients with hypertension. Also, that if only BP is monitored and things such as microalbuminuria or LVH are ignored, then we may not be treating our patients as effectively as we should. Certainly, these results would encourage me to be more aggressive in patients who have persistent microalbuminuria, and might make me cautiously further increase the dose of an ARB in those individuals who have not had a reduction in LVH or have further progression of cardiac hypertrophy. So I think these data are encouraging but I think further studies are required before it can be strongly encouraged to go beyond recommended dose levels in the majority of patients at this point in time. -