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Resistant Hypertension Indication Report
April 12, 2006
Blood pressure is poorly controlled in over half of the 60 million patients with hypertension in the US. Resistant hypertension refers to a subset of these patients, who fail to meet blood pressure goals despite treatment with full doses of a 3 drug regimen, including a diuretic. By our estimates, resistant hypertension affects 10% of patients who are treated for hypertension.
Currently, after contributing causes are investigated, resistant hypertension is treated with drugs that are also used earlier on in the treatment process. These include diuretics, beta-blockers, ACE inhibitors, angiotensin II blockers, and calcium channel blockers. The precise drugs used for resistant hypertension depend on the drugs used earlier on in the treatment process, as well as whether patients have accompanying conditions such as heart disease, diabetes, or renal failure. There are additional drugs that can be used for resistant hypertension, including the alpha 1 antagonists, centrally acting compounds affecting the sympathetic nervous system (a part of the nervous system involved in blood pressure regulation), and direct vasodilators. Use of these agents leads to blood pressure control in an estimated 65% of resistant hypertension patients without a psychological cause for the resistance (such as noncompliance).
The generically available diuretic spironolactone, which blocks the action of the hormone aldosterone on the kidneys, has recently been found to be very effective in the resistant hypertension population, and may lead to higher rates of control, though that has not been adequately demonstrated. A more selective aldosterone antagonist, Inspra (Pfizer), is approved for hypertension and has fewer hormonal side effects. We think Inspra is likely to be similarly beneficial in resistant hypertension, though like spironolactone it can cause elevated potassium levels and hence cannot be used in some groups of patients.
To be successful in resistant hypertension, a new drug will have to displace a currently used drug or be added on to treatment. We believe the most vulnerable currently used drugs are the beta-blockers (though these will still be important in a number of situations, and more information is needed on the beta-blockers that also block alpha receptors) and the set of drugs noted above which are not currently recommended for treatment early on. Depending on the specific drug, competition would be on the basis of better blood pressure control, improved safety (such as less sodium and water retention), beneficial effects on accompanying conditions or risk factors that negatively impact cardiovascular outcomes, synergistic effects with drugs used earlier in treatment, or a particular advantage in specific patient groups.
There are few drugs currently being developed specifically for resistant hypertension. Darusentan (MYOG), an endothelin A antagonist, has demonstrated reasonable efficacy as fourth line treatment. However, we are concerned that elevated rates of peripheral edema (swelling) could be due to fluid retention, which would negate a potential safety advantage. We think it will be a valuable option but face stiff competition in patients who can be controlled with existing treatment. On the other hand, in patients who cannot be controlled, physicians will be eager to try it. More information on its efficacy in this situation is needed, but given its novel mechanism of action, it is likely to work in at least a portion of patients.
Another endothelin A antagonist, TBC3711 (Encysive), recently had clinical testing halted due to unspecified findings in an animal study.
Finally, while drivers such as an aging population and increased obesity are likely to grow the general hypertension market, it is possible that improvements in drugs used earlier on in treatment could negatively impact the resistant hypertension segment. However, no novel drugs currently in development have produced clinical data suggesting that they will have a major impact.
BACKGROUND
Resistant hypertension is currently defined as the failure to achieve blood pressure (BP) goals despite treatment with full doses of an appropriate 3-drug regimen that includes a diuretic (a drug that increases salt and urine excretion, thereby reducing the volume of fluids in the circulation). While this definition is used by national guidelines (see, for example, JNC 7: the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure), it excludes patients who are intolerant of diuretics or full doses of other medications due to side effects.
Uncontrolled hypertension increases the risk for ischemic heart disease, heart failure, and stroke. Currently, goals for hypertension treatment are a systolic/diastolic blood pressure less than 140/90 mm Hg (millimeters of mercury). Systolic blood pressure refers to the maximum pressure in the arteries when the heart contracts, and diastolic refers to the pressure when the heart is at rest. In patients who also have diabetes or kidney disease, the goal is blood pressure lower than 130/80, to minimize end-organ damage from hypertension. Since most patients achieving systolic blood pressure (SBP) goals will also achieve diastolic (DBP) goals, JNC 7 guidelines recommend that SBP be the primary target.
A number of physiological systems are involved in regulating blood pressure, and are hence targets for hypertension treatment in general. These include the cardiovascular, renal, neural, and endocrine systems. Blood pressure is a product of the flow of blood produced by the heart (the volume of blood pumped and the heart rate) and the resistance to flow (determined by the degree of contraction of certain arterial blood vessels). An increase in the volume of fluid in the circulation can increase blood pressure, and this is determined to a large extent by the kidneys. The kidneys regulate volume through the excretion of sodium, which draws water through the tubules of the kidneys and determines urine production. Sodium can be reabsorbed along the tubule, which leads to more water ending up in the circulation. Another important set of interactions is the renin-angiotensin-aldosterone system (RAAS). Renin is released by the kidney into the circulation in response to several factors. Renin is an enzyme that converts angiotensinogen to angiotensin I, which in turn is converted by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II has a number of actions that are relevant for hypertension: it constricts blood vessels and stimulates the release of the hormone aldosterone from the adrenal glands, among other things. Aldosterone then increases sodium reabsorption in the kidneys. Finally, the sympathetic nervous system (SNS) plays a key role in regulating these cardiovascular and renal systems involved in blood pressure control. It can also interfere with blood pressure treatment: if blood pressure drops the SNS may act to increase heart rate, constrict blood vessels, and retain salt and water.
There are a number of potential physiological, treatment, and patient factors that can contribute to resistant hypertension, and these are noted further below.
Prevalence
The number of patients with resistant hypertension depends on the definition used, as well as whether underlying causes for the resistance have been investigated.
At a first glance, there are a large number of patients with hypertension whose blood pressure is not adequately controlled. The table below gives the number of US patients diagnosed with hypertension and various concurrent diseases, the percent treated, and the percent whose hypertension is controlled.
Some authorities use data from long-term comparative hypertension studies to estimate the prevalence of resistant hypertension. These studies (e.g. ALLHAT and CONVINCE), which have the advantage of closer follow-up and free medications, have found that approximately 30% of patients do not achieve blood pressure goals. In addition, 20% to 30% of subjects require 3 or more antihypertensive medications (Oparil S, et al, Hypertension, 2005, p. 616). In ALLHAT, just under 10% of patients were on 4 medications after 5 years, and by our estimates, 22% to 24% of patients were either on 4 medications or uncontrolled on 3, with another 17% of patients uncontrolled on 2 medications (this last group may or may not be able to achieve control with 3 medications). Many of the patients who did not reach control had elevated SBP (DBP goals are generally reached in over 90% of patients) and were not given the maximum doses or numbers of medication, possibly because participating physicians may have been reluctant to prescribe higher doses and more medications to older patients who only had elevated SBP. In addition, there are various other factors that could have affected these numbers of patients not reaching blood pressure control. Factors that could cause these numbers (and those in other large trials) to be overestimates include: most patients were older, certain combinations of therapy were not allowed (i.e. combinations of the medications being compared), and if spironolactone were used it could improve control (spironolactone is an older diuretic that has recently been found to have a marked benefit for patients otherwise thought to be resistant). On the other hand, factors that could cause these numbers to underestimate treatment resistance include: patients with more severe hypertension were excluded and goals for diabetics and those with chronic kidney disease were not lowered to the currently recommended level.
We think the rate of apparent resistance to treatment seen in studies such as ALLHAT overestimates the true prevalence of resistant hypertension. The fact that a number of patients neither received a diuretic, nor maximum doses of medications, means they would not meet the actual criteria for resistant hypertension. In addition, since the use of different combinations of medication was restricted, patients were unlikely to receive optimal care.
Looking at such issues at a more detailed level, one study looked at a cohort of patients referred to a university hypertension clinic. Out of 259 patients referred for “resistant hypertension,” 141 (54%) met the actual criteria for resistant hypertension. Of these patients, an associated cause was found in 96% of cases. While some of the causes were unlikely to be treated with further medication (e.g. noncompliance with treatment), overall the cohort started with an average of 3.74 medications, and ended with an average of 4.06 medications. Using such information based on this study, we conservatively estimate that 60% of patients will still meet the criteria for resistant hypertension after medication adjustments and investigation of potential causes. (If we do not count use of multiple diuretics in the criteria for the number of drugs needed in defining resistant hypertension, we would estimate the number to be 55%).
With the information from the cohort study in mind, we estimate the prevalence of resistant hypertension to be lower than that seen in trials such as ALLHAT and closer to 10%, or 9% excluding multiple diuretic use. For non-diuretic drugs, the 9% represents the percent of patients eligible. Other published estimates from authorities are 5% to 10% in general medical clinics and the hypertensive population, versus 20% to 40% in hypertensive clinics and 50% in nephrology clinics.
A number of patients with resistant hypertension can meet treatment goals using currently available medications. Using data from the cohort study, we estimate that approximately 65% of patients without a psychological cause for their resistance can reach goals. That could be an overestimate for resistant hypertension since some patients included in that number only required their medications to be adjusted. On the other hand, that number could be higher now, since as noted above, more recently published results showing a marked benefit for spironolactone (discussed below) have made that agent more popular in difficult to treat patients.
Growth of the resistant hypertension market is likely to parallel that of general hypertension, with growth drivers including an aging population (over half of people aged 60 to 69 years old are affected) and obesity. We believe the roughly 2.5%/year growth rate in hypertension seen over the 1990s in the US will continue over the next decade.
CURRENT TREATMENT
When patients are thought to have resistant hypertension, remedial causes are investigated. These can include clinic or white-coat hypertension (where the blood pressure is elevated only in the doctor’s office but not at home), excess fluid in the circulation (volume overload) with inadequate use of diuretics, use of other medications or supplements that raise blood pressure (such as non-steroidal anti-inflammatory agents [NSAIDs]), suboptimal drug regimens, or noncompliance with antihypertensive therapy. If the hypertension persists, a concerted effort should be made to look for diseases that cause hypertension (secondary hypertension). These occur in approximately 5% of general hypertensive patients and include chronic kidney disease (a common cause), various hormonal disorders (some of which can be cured surgically), and other conditions.
In the cohort study noted above, a contributing cause could be found in 94% of resistant hypertension cases, as the following table shows:
Note: patients with known secondary hypertension were screened out prior to the study.
Treatment Setting
In 2004, there were 38.1 million office visits where the primary diagnosis was hypertension or hypertensive heart/kidney disease (37.8 million were for essential hypertension alone). Of these visits, 80% to 85% were to patients’ primary care physicians who were in family practice, general practice, or internal medicine (specialists act as the primary care physician in another 5% of visits). Primary care physicians made 1.6 million referrals (1.5 million excluding hypertensive heart/kidney disease) for these patients, but there were only 1.1 million referrals received where the primary diagnosis remained hypertension or hypertensive heart/kidney disease (the other referrals made by primary care physicians could have been for hypertension patients who needed treatment for other unrelated conditions). The table below shows visits by specialty, as well as which physicians received referrals.
For cardiovascular specialists, in about half of visits where the primary diagnosis is related to hypertension, care is shared with another physician. These visits could be for patients who were newly referred and will be returned to their primary physician after consultation or adjustments in medications, or patients who will be followed long-term by the specialist in addition to the primary physician. We estimate that up to 34% of patients referred to cardiovascular specialists are eventually returned to their primary physician without further specialist follow-up (for patients without a secondary diagnosis clearly related to cardiac or lipid disorders, we estimate up to 44% are returned). Very few of nephrology or hematology/oncology referrals appear to be returned.
While numbers specifically for resistant hypertension are lacking, referral for a consultation is recommended generally when blood pressure is not controlled by two medications, and for all patients not controlled with 3 medications. Most of these patients are likely to go to cardiologists (who may practice at hypertension clinics, which are common at tertiary medical centers), unless there is a disorder related to another specialty, such as kidney failure or an endocrine problem. Given that a number of patients referred to cardiovascular specialists do not likely have true resistant hypertension, the percent of resistant hypertension patient referrals returned to their primary care physician without further specialist care is probably below the 44% estimate given above.
Since 1998, the American Society of Hypertension has been certifying physicians to act as local and regional consultants for the more complex and difficult cases (though physicians do not require this certification to treat hypertension.) The table below gives the medical specialties of physicians certified under the program (since cardiologists are the natural choice for a referral for most patients, many may not have chosen to undergo the certification process).
Current Medications
There are currently no drugs specifically marketed for resistant hypertension: the agents used are largely antihypertension drugs that can be used earlier on in the treatment process as well. The actual drug chosen as the fourth or subsequent step will depend on the regimen the patient is currently on. There are few available studies on drugs in resistant hypertension as it is currently defined and using current practice.
The following table summarizes the classes of antihypertensive drugs, divided by those recommended for use early on in the treatment of hypertension and other drugs. In JNC 7, the thiazide diuretics are recommended as the first step (though this is not universally accepted), and other early use classes are equally recommended to be added in subsequent steps. Combination pills with drugs from two classes are common.
The choice of drugs for each step of treatment depends on a number of factors. Some authorities recommend matching drugs to certain patient characteristics, such as elderly and African-Americans, who are less sensitive to BBs and ACEIs. Others note that while such differences may apply for monotherapy, the effects of different classes of drugs are equalized if a diuretic is in the regimen, and so such classifications are not useful. In addition, an individual patient may simply respond better to one drug than another without any apparent reason.
As indicated in the table above, certain drugs are used to treat or have favorable effects on other medical conditions. As a result, they are recommended for use in patients who have those conditions along with their hypertension, as the following table from JNC 7 summarizes.
Of note, while BBs are the most commonly prescribed antihypertensive agent in the US, results from the recent ASCOT trial, implying poorer cardiovascular results for a BB based strategy versus a CCB based strategy, may shift usage away from BBs in patients who do not need them for other indications. Also, there are concerns that BBs used with thiazide diuretics can increase the onset of diabetes. Their use has come under fire from some experts, and newly proposed guidelines from Britain’s National Institute of Clinical Excellence (NICE) recommend BBs only be used as fourth step agents (the guidelines did note that most trials involved the BB atenolol and outcomes studies for other agents could change recommendations).
Use in Resistant Hypertension
Given the above information, we have summarized in the table below which agents are likely to be used early on in treatment and which agents may end up being used for resistant hypertension, in general and given selected accompanying patient characteristics or medical conditions. Agents listed as being used earlier on in treatment may also be listed for treatment of resistant hypertension, when there are other equally recommended substitutes that can displace them in earlier use. (Though diuretic adjustment is a part of resistant hypertension management, they will be initiated early on in most patients, so with the exception of aldosterone antagonists, we have included them only in the early use category.) The table also lists attributes desirable for treatment. One main point of the table is that there are a variety of current treatments, including some of the major classes of drugs used early on in treatment, that are also potentially used in resistant hypertension.
Left ventricular hypertrophy (LVH)=enlargement of the walls of the main chamber of the heart pumping blood to the body. It can develop in response to the workload of pumping in patients with high blood pressure. A number of current drugs have shown a beneficial effect on LVH, but some studies have demonstrated differences.
Diur=diuretic, ACEI=ACE Inhibitor, ARB=Angiotensin Receptor Blocker, CCB=Calcium Channel Blocker, BB=Beta-blocker, ARA=Alpha 1 Receptor Antagonist, CAA=Central Alpha 2 Agonist, DV=Direct Vasodilator, AA=Aldosterone Antagonist
For more specific detail on what is used in practice, the following table, derived from the cohort study mentioned above, shows the various classes of antihypertensives used when the patient was first referred and after being adjusted by hypertension specialists. It should be noted, though, that this is from one treatment center, and a larger than expected percent of the cohort were African-American, which could skew choice of treatment. In addition, many of the patients were treated prior to the publication of the ALLHAT trial, which led to a reduction in the early use of alpha 1 receptor antagonists. As can be seen, most patients were on diuretics and ACEIs/ARBs initially, with slightly less use of CCBs and BBs. ARAs, central adrenergic agents, and direct vasodilators were used in a minority of patients to bring blood pressure under control. The specialists increased use of diuretics, ACEIs/ARBs, and CCBs, but reduced BB usage. For the less common drugs, they increased use of the ARAs, but decreased use of the central adrenergic agents and direct vasodilators.
Of note, the above study was conducted prior to recent data showing that the aldosterone antagonist diuretic, Spironolactone, which is available generically, had significant blood pressure lowering effect (25 mm Hg systolic/11 diastolic) in patients with resistant hypertension, whether or not they suffered from a condition of over excretion of aldosterone (called primary hyperaldosteronism). Aldosterone, secreted by the adrenal glands, stimulates sodium reabsorption and potassium secretion by the kidneys, leading to water retention. While spironolactone has a major drawback of sex hormone related side effects, another more specific aldosterone antagonist, Inspra (eplerenone, Pfizer-PFE) has a lower rate of such effects. Already approved for hypertension, Inspra is currently being studied in an investigator-initiated trial looking at prevention of end organ damage in patients with resistant hypertension. Given the benefits seen with spironolactone, Inspra is likely to be increasingly used in resistant hypertension. (As these agents can cause elevated potassium, however, they cannot be used in patients with more severe kidney damage, which increases the risk for life threatening levels of potassium. Inspra is contraindicated for treating hypertension in diabetics with evidence of kidney disease.)
As noted above, approximately 65% of patients without psychological causes for their resistant hypertension can reach BP goals with existing treatment, and this percentage is likely to be higher with the use of spironolactone (we estimate possibly up to 75%). In this group of patients reaching BP goals, a new drug will have to displace one of the existing classes of drugs.
Given what we said above about BBs, they are likely to be more vulnerable than ACEIs/ARBs or CCBs. However, BBs may be needed in conjunction with drugs that dilate blood vessels, to prevent a reflex increase in heart rate, and they may be preferred in patients who need them for ischemic heart disease, and possibly for younger patients, where they tend to be more effective. While they can exacerbate diabetes, many diabetics have coronary artery disease.
Of the drugs that are not recommended for use early on, the alpha 1 antagonists (ARAs) are strong competitors for resistant hypertension, though some specialists recommend the direct vasodilators. The ARAs are also beneficial for enlarged prostate glands in men, have a positive impact on diabetes and lipids, and are generally well-tolerated. On the negative side, they were associated in the ALLHAT trial with poorer cardiovascular outcomes, particularly heart failure due to salt and water retention, though this is ameliorated when a diuretic is also used. They can cause a symptomatic drop in blood pressure when they are first taken, or when the dose is increased rapidly. The direct vasodilators (generically available minoxidil and hydralazine) cause a reflex sympathetic response, which must be counteracted with concomitant treatment such as a BB, and more fluid retention than the ARAs. Minoxidil causes excess facial and body hair growth, which is particularly a problem in women. Hydralazine has the disadvantage of being dosed twice a day and can cause a lupus like reaction. Finally, the centrally acting agents, such as the alpha 2 agonists, are potential competitors, but have a number of side effects related to their sympathetic blockade (such as sedation, dry mouth, and impotence).
In addition to the desirable attributes listed in the table above, there are specific competitive points for displacing the ARAs or direct vasodilators. One is to offer comparable or better efficacy, without reflex sympathetic stimulation and fluid retention. In addition, since the ARAs had negative publicity on cardiovascular outcomes in the ALLHAT trial, comparable outcomes to early use agents could also be a point of differentiation.
Finally, up to 35% of resistant hypertension patients still have uncontrolled BP with current treatment. A low incidence of side effects and drug interactions would of course be particularly important for a new drug added to an existing multi-drug regimen.
Since diastolic BP is relatively easy to control, a new drug will have to be efficacious for systolic BP. Because of side effects, many physicians may likely to be reluctant to use multiple drugs for the elderly when only their systolic BP is elevated. Thus there is an opportunity in this patient population for a drug with low side effects. DRUGS IN DEVELOPMENT
There are few drugs specifically in development for resistant hypertension, since this is a difficult treatment area and a smaller part of the market.
Darusentan – Myogen (MYOG) and Abbott (ABT)
Darusentan is a selective endothelin A (ETA) receptor antagonist that is about to start Phase III testing. Endothelins (ET) are produced in many tissues, but particularly in the endothelium (the interior lining) of blood vessels. Endothelin 1 (ET 1) is the primary one secreted in the endothelium, and acts on ETA or ETB smooth muscle receptors to constrict blood vessels and cause cell proliferation (it has been implicated in atherosclerosis), and on ETB endothelial receptors to dilate blood vessels. It is possible that its effect varies in different vascular beds, though in coronary arteries, ET 1 acts to constrict vessels. ET 1 appears to be primarily involved in moderate to severe hypertension, especially in patients sensitive to the effects of salt (such as African-Americans).
ET has been implicated in kidney disease, and may be responsible for some of the effects of angiotensin II. There is some preclinical evidence that ACEIs may also inhibit ET synthesis. Finally, ET is involved in the synthesis and release of aldosterone. While these actions of ET suggest possible benefits for ET antagonism beyond vasodilation, it will be important to see whether ET antagonism has effects on top of other drugs which affect these pathways.
Darusentan has been studied clinically in heart failure and in hypertension. Results for heart failure have been disappointing. In one study, while there were beneficial hemodynamic effects, there was also a trend towards worsening of heart failure and increased mortality. This may have been due to fluid retention combined with lack of titrating the dose of the drug. In another study, where the dose was titrated, there were no such safety issues, but Darusentan also did not show a benefit in heart failure treatment.
In hypertension, Darusentan has been studied both in patients with mild-moderate and resistant hypertension. In a 6-week dose-titration mild-moderate hypertension study (maximum dose 100 mg), Darusentan improved BP (baseline 168/103) over placebo by up to -11.3/8.3 mm Hg. This was not better than what is seen with existing therapy, and Darusentan had elevated rates of peripheral edema and flushing. It should also be noted that though we do not have specific details for Darusentan, the ETAs have also been found to have significant teratogenic effects in animal studies (causing birth defects).
Regarding resistant hypertension, in a 10-week, 115-patient study, Darusentan improved BP (baseline 149.4/81.5) over placebo by -11.5/6.3. The majority of patients had diabetes or chronic kidney disease. Fifty-five percent of Darusentan patients versus 33% of placebo patients reached JNC 7 goals. There were not significant increases in heart rate from reflex sympathetic stimulation, but the Darusentan group had a higher incidence of edema (17% vs 5%), an effect also seen with other ET inhibitors.
While these results are good, with a significant number of patients able to achieve BP goals, there is little comparative data available in this setting to help assess how Darusentan will fare against other options. The results are not as good as in a small study of the ACEI Altace (King - KG, Sanofi - SNY, and Wyeth - WYE) in patients resistant to treatment with a diuretic, BB, and vasodilator. Altace reduced BP by 29/21 at 8 weeks, and the benefit was maintained for 48 weeks. However, these patients likely had high renin, and in current treatment, ACEIs would be used early on in patients such as these.
Two Phase III trials of Darusentan in resistant hypertension are planned, one as a fourth line agent with the centrally acting, alpha 2 agonist guanfacine (available generically) as an active control and the other with Darusentan as a fifth line agent. We have not seen data on guanfacine in this setting, but based on other results, we think Darusentan is likely to do as well.
In resistant hypertension patients who are able to achieve control on existing medications (which we estimate at 65% of resistant hypertension patients), we think Darusentan will face stiff competition, unless it can show benefits in other measures. We are concerned that side effects such as peripheral edema and flushing do not give it a safety advantage over existing agents such as the ARAs, which do show some peripheral edema but to a much lesser extent. (The mechanism for the edema caused by Darusentan is unclear, but we are concerned it is related to fluid retention, which has been seen in other ET antagonists. Alternatively, the mechanism could be due to local effects, which would be more benign.) An advantage could emerge if Darusentan could show a benefit in outcomes, as suggested by preclinical work suggesting a role for ET in atherosclerosis and renal disease.
For patients whose BP cannot be controlled on existing treatment, we think physicians will want to try Darusentan given its novel mechanism of action. The fifth line Phase III study will give more information on how it will fare in this setting, but we think it is likely to yield a benefit for at least a portion of patients.
Overall, given the information currently available, while we think Darusentan will have a significant role as another option in resistant hypertension, and it will have a modest market share in the 10% of patients with resistant hypertension.
TBC3711 is also an endothelin A antagonist. Though a phase II dose-ranging study in resistant hypertension patients was initiated, clinical study was recently halted due to a finding in an animal that was being tested. It is unclear what the details are, and we currently have the drug suspended pending further notice.
Other Drugs
There are a couple centrally acting agents approved in Europe but not the US, which reportedly have lower side effects than the traditional alpha 2 agonists, and could be used to treat resistant hypertension. These inhibit the sympathetic nervous system through imidazoline I1 receptors. They include Hyperium (rilmenidine – Servier) and Physiotens/Cynt (moxonidine – Solvay and Lilly). Servier does not currently have plans to develop rilmenidine in the US, and development of moxonidine in the US was halted after it resulted in an increase number of deaths in a heart failure trial. These drugs were approved in Europe years ago, and both are available as generics.
Finally, while there do not appear to be other drugs in development specifically for resistant hypertension, if new antihypertensive drugs are significantly better than current ones, their use early on in treatment could shrink the resistant hypertension market.
There are a few notable drugs with novel mechanisms of action. Rasilez (Novartis – NVS, Speedel) is a renin inhibitor, and hence blocks the RAAS system before the ACEIs. One rationale for renin blockade is that the only substrate for renin is angiotensin, so its effects should be relatively specific. ACEIs on the other hand lead to the accumulation of various peptides, which are thought to result in their side effects of cough and angioedema (a form of rapid swelling). In addition, ACEIs do not block all enzymes that convert angiotensin I to II. While Rasilez appears at least as efficacious as existing treatment, it has not demonstrated dramatically better efficacy. There has been limited evidence for a benefit in combination with ACEIs and ARBs, but whether this is better than an ACEI/ARB combination remains to be seen. Since Rasilez avoids some of the side effects of the ACEIs, it may be used in patients who could not tolerate them. Overall, while Rasilez may have some effects on the resistant hypertension market, we do not currently think its effect will be extensive.
Another novel mechanism is dual inhibition of ACE and neutral endopeptidase. These agents are called vasopeptidase inhibitors. Neutral endopeptidase helps degrade the natriuretic peptides, which are also involved in the regulation of blood pressure and plasma volume. They have a number of other substrates, as well. AVE7688 (Sanofi-Aventis – SNY) is one such agent in development. While there is limited clinical information available on this drug, another vasopeptidase inhibitor, Vanlev (Bristol-Myers – BMY), which has apparently been discontinued, has shown some benefit over existing agents, but also has demonstrated significantly higher rates of angioedema. This could be a side-effect that plagues the entire class, though it is possible vasopeptidase inhibitors could be used in more difficult-to-treat cases.
Another dual inhibitor is SLV306 (Solvay), which blocks both neutral endopeptidase and endothelin-converting enzyme (ECE). ECE is involved in the synthesis of endothelin (ET) from its precursor, big-ET. SLV306 is in phase II development in Europe. There is little clinical information available, but as it acts along the same pathway as Darusentan, it is a potential competitor.
Finally, Pharmacopeia recently acquired rights from Bristol-Myers Squibb for an agent with dual angiotensin and endothelin receptor antagonist activity. The drug is still in preclinical development.
REVENUE MODELS
Darusentan – Myogen (MYOG) and Abbott (ABT)
We have revised our revenue model for Darusentan. Overall, we are estimating Darusentan’s peak share at 15% in resistant hypertension. We estimate its ramp to peak share will be over 6 years, as physicians gain experience using it with different combinations of other drugs and learn which patients respond best. Given the more specialized nature of the resistant hypertension market, this is faster than what has been seen for some of the newer drugs used earlier on in treatment, such as the ARBs Cozaar and Diovan, or the ACEI/CCB combination Lotrel.
Pricing
A number of the agents Darusentan will be competing against are generically available, including the ARAs and direct vasodilators. However, we think Darusentan’s use will be dictated by the lack of efficacy or side effects of these other agents in specific patients. Hence, while higher prices may lead to noncompliance in some patients, we think that in major markets, Darusentan could be priced at a slight premium to popular branded hypertensive agents, such as the CCB Norvasc or the ARBs. This would lead to a monthly price in the US of approximately $55. We think such a price will be even easier to justify in the resistant hypertension setting, given the likely high rate of poor clinical outcomes in this population of patients. We note that the aldosterone antagonist Inspra, approved for heart failure and general hypertension, is priced about twice as high and is experiencing a relatively poor ramp-up, which may be partly due to its price relative to other treatments.
Revenue Projections
Our 5 and 10-year revenue projections for Darusentan are $219.8 million and $533.0 million in the US, and $348.5 million and $975.8 million worldwide.
It is unclear what the issue is causing the hold in clinical trials. If TBC3711 were ultimately approved, it would have the disadvantage of coming to market after Darusentan. The drug is likely to share the side effect of edema, as this has been seen with other agents in the class. Hence without clear evidence of a benefit, should development of TBC3711 be restarted, we project 5 and 10-year US revenues of $15.8 million and $193.1 million, with worldwide revenues of $15.8 million and $318.0 million.
EVALUATED COMPANY UPDATES
While a major portion of Myogen’s value is derived from Ambrisentan, Darusentan has the potential to be an important revenue contributor to Myogen. We currently value Myogen’s 5 and 10-year pipeline at $46.28/share and $52.38/share.
Encysive was recently plagued by an approvable letter for Thelin and with the TBC3711 program on hold, we place very little value to it. We currently value Encysive’s 5 and 10-year pipeline at $0.00/share and $3.75/share. While we see TBC3711's possible role in resistant hypertension as small, if Encysive were able to move the program into phase III, we would value its 5 and 10-year pipeline at $0.00/share and $8.25/share, making the importance of continuing the program a large one for Encysive. Combination pills with drugs from two classes are common.
The choice of drugs for each step of treatment depends on a number of factors. Some authorities recommend matching drugs to certain patient characteristics, such as elderly and African-Americans, who are less sensitive to BBs and ACEIs. Others note that while such differences may apply for monotherapy, the effects of different classes of drugs are equalized if a diuretic is in the regimen, and so such classifications are not useful. In addition, an individual patient may simply respond better to one drug than another without any apparent reason.
As indicated in the table above, certain drugs are used to treat or have favorable effects on other medical conditions. As a result, they are recommended for use in patients who have those conditions along with their hypertension, as the following table from JNC 7 summarizes.
Of note, while BBs are the most commonly prescribed antihypertensive agent in the US, results from the recent ASCOT trial, implying poorer cardiovascular results for a BB based strategy versus a CCB based strategy, may shift usage away from BBs in patients who do not need them for other indications. Also, there are concerns that BBs used with thiazide diuretics can increase the onset of diabetes. Their use has come under fire from some experts, and newly proposed guidelines from Britain’s National Institute of Clinical Excellence (NICE) recommend BBs only be used as fourth step agents (the guidelines did note that most trials involved the BB atenolol and outcomes studies for other agents could change recommendations).
Use in Resistant Hypertension
Given the above information, we have summarized in the table below which agents are likely to be used early on in treatment and which agents may end up being used for resistant hypertension, in general and given selected accompanying patient characteristics or medical conditions. Agents listed as being used earlier on in treatment may also be listed for treatment of resistant hypertension, when there are other equally recommended substitutes that can displace them in earlier use. (Though diuretic adjustment is a part of resistant hypertension management, they will be initiated early on in most patients, so with the exception of aldosterone antagonists, we have included them only in the early use category.) The table also lists attributes desirable for treatment. One main point of the table is that there are a variety of current treatments, including some of the major classes of drugs used early on in treatment, that are also potentially used in resistant hypertension.
Left ventricular hypertrophy (LVH)=enlargement of the walls of the main chamber of the heart pumping blood to the body. It can develop in response to the workload of pumping in patients with high blood pressure. A number of current drugs have shown a beneficial effect on LVH, but some studies have demonstrated differences.
Diur=diuretic, ACEI=ACE Inhibitor, ARB=Angiotensin Receptor Blocker, CCB=Calcium Channel Blocker, BB=Beta-blocker, ARA=Alpha 1 Receptor Antagonist, CAA=Central Alpha 2 Agonist, DV=Direct Vasodilator, AA=Aldosterone Antagonist
For more specific detail on what is used in practice, the following table, derived from the cohort study mentioned above, shows the various classes of antihypertensives used when the patient was first referred and after being adjusted by hypertension specialists. It should be noted, though, that this is from one treatment center, and a larger than expected percent of the cohort were African-American, which could skew choice of treatment. In addition, many of the patients were treated prior to the publication of the ALLHAT trial, which led to a reduction in the early use of alpha 1 receptor antagonists. As can be seen, most patients were on diuretics and ACEIs/ARBs initially, with slightly less use of CCBs and BBs. ARAs, central adrenergic agents, and direct vasodilators were used in a minority of patients to bring blood pressure under control. The specialists increased use of diuretics, ACEIs/ARBs, and CCBs, but reduced BB usage. For the less common drugs, they increased use of the ARAs, but decreased use of the central adrenergic agents and direct vasodilators.
Of note, the above study was conducted prior to recent data showing that the aldosterone antagonist diuretic, Spironolactone, which is available generically, had significant blood pressure lowering effect (25 mm Hg systolic/11 diastolic) in patients with resistant hypertension, whether or not they suffered from a condition of over excretion of aldosterone (called primary hyperaldosteronism). Aldosterone, secreted by the adrenal glands, stimulates sodium reabsorption and potassium secretion by the kidneys, leading to water retention. While spironolactone has a major drawback of sex hormone related side effects, another more specific aldosterone antagonist, Inspra (eplerenone, Pfizer-PFE) has a lower rate of such effects. Already approved for hypertension, Inspra is currently being studied in an investigator-initiated trial looking at prevention of end organ damage in patients with resistant hypertension. Given the benefits seen with spironolactone, Inspra is likely to be increasingly used in resistant hypertension. (As these agents can cause elevated potassium, however, they cannot be used in patients with more severe kidney damage, which increases the risk for life threatening levels of potassium. Inspra is contraindicated for treating hypertension in diabetics with evidence of kidney disease.)
As noted above, approximately 65% of patients without psychological causes for their resistant hypertension can reach BP goals with existing treatment, and this percentage is likely to be higher with the use of spironolactone (we estimate possibly up to 75%). In this group of patients reaching BP goals, a new drug will have to displace one of the existing classes of drugs.
Given what we said above about BBs, they are likely to be more vulnerable than ACEIs/ARBs or CCBs. However, BBs may be needed in conjunction with drugs that dilate blood vessels, to prevent a reflex increase in heart rate, and they may be preferred in patients who need them for ischemic heart disease, and possibly for younger patients, where they tend to be more effective. While they can exacerbate diabetes, many diabetics have coronary artery disease.
Of the drugs that are not recommended for use early on, the alpha 1 antagonists (ARAs) are strong competitors for resistant hypertension, though some specialists recommend the direct vasodilators. The ARAs are also beneficial for enlarged prostate glands in men, have a positive impact on diabetes and lipids, and are generally well-tolerated. On the negative side, they were associated in the ALLHAT trial with poorer cardiovascular outcomes, particularly heart failure due to salt and water retention, though this is ameliorated when a diuretic is also used. They can cause a symptomatic drop in blood pressure when they are first taken, or when the dose is increased rapidly. The direct vasodilators (generically available minoxidil and hydralazine) cause a reflex sympathetic response, which must be counteracted with concomitant treatment such as a BB, and more fluid retention than the ARAs. Minoxidil causes excess facial and body hair growth, which is particularly a problem in women. Hydralazine has the disadvantage of being dosed twice a day and can cause a lupus like reaction. Finally, the centrally acting agents, such as the alpha 2 agonists, are potential competitors, but have a number of side effects related to their sympathetic blockade (such as sedation, dry mouth, and impotence).
In addition to the desirable attributes listed in the table above, there are specific competitive points for displacing the ARAs or direct vasodilators. One is to offer comparable or better efficacy, without reflex sympathetic stimulation and fluid retention. In addition, since the ARAs had negative publicity on cardiovascular outcomes in the ALLHAT trial, comparable outcomes to early use agents could also be a point of differentiation.
Finally, up to 35% of resistant hypertension patients still have uncontrolled BP with current treatment. A low incidence of side effects and drug interactions would of course be particularly important for a new drug added to an existing multi-drug regimen.
Since diastolic BP is relatively easy to control, a new drug will have to be efficacious for systolic BP. Because of side effects, many physicians may likely to be reluctant to use multiple drugs for the elderly when only their systolic BP is elevated. Thus there is an opportunity in this patient population for a drug with low side effects.
There are few drugs specifically in development for resistant hypertension, since this is a difficult treatment area and a smaller part of the market.
Darusentan – Myogen (MYOG) and Abbott (ABT)
Darusentan is a selective endothelin A (ETA) receptor antagonist that is about to start Phase III testing. Endothelins (ET) are produced in many tissues, but particularly in the endothelium (the interior lining) of blood vessels. Endothelin 1 (ET 1) is the primary one secreted in the endothelium, and acts on ETA or ETB smooth muscle receptors to constrict blood vessels and cause cell proliferation (it has been implicated in atherosclerosis), and on ETB endothelial receptors to dilate blood vessels. It is possible that its effect varies in different vascular beds, though in coronary arteries, ET 1 acts to constrict vessels. ET 1 appears to be primarily involved in moderate to severe hypertension, especially in patients sensitive to the effects of salt (such as African-Americans).
ET has been implicated in kidney disease, and may be responsible for some of the effects of angiotensin II. There is some preclinical evidence that ACEIs may also inhibit ET synthesis. Finally, ET is involved in the synthesis and release of aldosterone. While these actions of ET suggest possible benefits for ET antagonism beyond vasodilation, it will be important to see whether ET antagonism has effects on top of other drugs which affect these pathways.
Darusentan has been studied clinically in heart failure and in hypertension. Results for heart failure have been disappointing. In one study, while there were beneficial hemodynamic effects, there was also a trend towards worsening of heart failure and increased mortality. This may have been due to fluid retention combined with lack of titrating the dose of the drug. In another study, where the dose was titrated, there were no such safety issues, but Darusentan also did not show a benefit in heart failure treatment.
In hypertension, Darusentan has been studied both in patients with mild-moderate and resistant hypertension. In a 6-week dose-titration mild-moderate hypertension study (maximum dose 100 mg), Darusentan improved BP (baseline 168/103) over placebo by up to -11.3/8.3 mm Hg. This was not better than what is seen with existing therapy, and Darusentan had elevated rates of peripheral edema and flushing. It should also be noted that though we do not have specific details for Darusentan, the ETAs have also been found to have significant teratogenic effects in animal studies (causing birth defects).
Regarding resistant hypertension, in a 10-week, 115-patient study, Darusentan improved BP (baseline 149.4/81.5) over placebo by -11.5/6.3. The majority of patients had diabetes or chronic kidney disease. Fifty-five percent of Darusentan patients versus 33% of placebo patients reached JNC 7 goals. There were not significant increases in heart rate from reflex sympathetic stimulation, but the Darusentan group had a higher incidence of edema (17% vs 5%), an effect also seen with other ET inhibitors.
While these results are good, with a significant number of patients able to achieve BP goals, there is little comparative data available in this setting to help assess how Darusentan will fare against other options. The results are not as good as in a small study of the ACEI Altace (King - KG, Sanofi - SNY, and Wyeth - WYE) in patients resistant to treatment with a diuretic, BB, and vasodilator. Altace reduced BP by 29/21 at 8 weeks, and the benefit was maintained for 48 weeks. However, these patients likely had high renin, and in current treatment, ACEIs would be used early on in patients such as these.
Two Phase III trials of Darusentan in resistant hypertension are planned, one as a fourth line agent with the centrally acting, alpha 2 agonist guanfacine (available generically) as an active control and the other with Darusentan as a fifth line agent. We have not seen data on guanfacine in this setting, but based on other results, we think Darusentan is likely to do as well.
In resistant hypertension patients who are able to achieve control on existing medications (which we estimate at 65% of resistant hypertension patients), we think Darusentan will face stiff competition, unless it can show benefits in other measures. We are concerned that side effects such as peripheral edema and flushing do not give it a safety advantage over existing agents such as the ARAs, which do show some peripheral edema but to a much lesser extent. (The mechanism for the edema caused by Darusentan is unclear, but we are concerned it is related to fluid retention, which has been seen in other ET antagonists. Alternatively, the mechanism could be due to local effects, which would be more benign.) An advantage could emerge if Darusentan could show a benefit in outcomes, as suggested by preclinical work suggesting a role for ET in atherosclerosis and renal disease.
For patients whose BP cannot be controlled on existing treatment, we think physicians will want to try Darusentan given its novel mechanism of action. The fifth line Phase III study will give more information on how it will fare in this setting, but we think it is likely to yield a benefit for at least a portion of patients.
Overall, given the information currently available, while we think Darusentan will have a significant role as another option in resistant hypertension, and it will have a modest market share in the 10% of patients with resistant hypertension.
TBC3711 is also an endothelin A antagonist. Though a phase II dose-ranging study in resistant hypertension patients was initiated, clinical study was recently halted due to a finding in an animal that was being tested. It is unclear what the details are, and we currently have the drug suspended pending further notice.
Other Drugs
There are a couple centrally acting agents approved in Europe but not the US, which reportedly have lower side effects than the traditional alpha 2 agonists, and could be used to treat resistant hypertension. These inhibit the sympathetic nervous system through imidazoline I1 receptors. They include Hyperium (rilmenidine – Servier) and Physiotens/Cynt (moxonidine – Solvay and Lilly). Servier does not currently have plans to develop rilmenidine in the US, and development of moxonidine in the US was halted after it resulted in an increase number of deaths in a heart failure trial. These drugs were approved in Europe years ago, and both are available as generics.
Finally, while there do not appear to be other drugs in development specifically for resistant hypertension, if new antihypertensive drugs are significantly better than current ones, their use early on in treatment could shrink the resistant hypertension market.
There are a few notable drugs with novel mechanisms of action. Rasilez (Novartis – NVS, Speedel) is a renin inhibitor, and hence blocks the RAAS system before the ACEIs. One rationale for renin blockade is that the only substrate for renin is angiotensin, so its effects should be relatively specific. ACEIs on the other hand lead to the accumulation of various peptides, which are thought to result in their side effects of cough and angioedema (a form of rapid swelling). In addition, ACEIs do not block all enzymes that convert angiotensin I to II. While Rasilez appears at least as efficacious as existing treatment, it has not demonstrated dramatically better efficacy. There has been limited evidence for a benefit in combination with ACEIs and ARBs, but whether this is better than an ACEI/ARB combination remains to be seen. Since Rasilez avoids some of the side effects of the ACEIs, it may be used in patients who could not tolerate them. Overall, while Rasilez may have some effects on the resistant hypertension market, we do not currently think its effect will be extensive.
Another novel mechanism is dual inhibition of ACE and neutral endopeptidase. These agents are called vasopeptidase inhibitors. Neutral endopeptidase helps degrade the natriuretic peptides, which are also involved in the regulation of blood pressure and plasma volume. They have a number of other substrates, as well. AVE7688 (Sanofi-Aventis – SNY) is one such agent in development. While there is limited clinical information available on this drug, another vasopeptidase inhibitor, Vanlev (Bristol-Myers – BMY), which has apparently been discontinued, has shown some benefit over existing agents, but also has demonstrated significantly higher rates of angioedema. This could be a side-effect that plagues the entire class, though it is possible vasopeptidase inhibitors could be used in more difficult-to-treat cases.
Another dual inhibitor is SLV306 (Solvay), which blocks both neutral endopeptidase and endothelin-converting enzyme (ECE). ECE is involved in the synthesis of endothelin (ET) from its precursor, big-ET. SLV306 is in phase II development in Europe. There is little clinical information available, but as it acts along the same pathway as Darusentan, it is a potential competitor.
Finally, Pharmacopeia recently acquired rights from Bristol-Myers Squibb for an agent with dual angiotensin and endothelin receptor antagonist activity. The drug is still in preclinical development.
REVENUE MODELS
Darusentan – Myogen (MYOG) and Abbott (ABT)
We have revised our revenue model for Darusentan. Overall, we are estimating Darusentan’s peak share at 15% in resistant hypertension. We estimate its ramp to peak share will be over 6 years, as physicians gain experience using it with different combinations of other drugs and learn which patients respond best. Given the more specialized nature of the resistant hypertension market, this is faster than what has been seen for some of the newer drugs used earlier on in treatment, such as the ARBs Cozaar and Diovan, or the ACEI/CCB combination Lotrel.
Pricing
A number of the agents Darusentan will be competing against are generically available, including the ARAs and direct vasodilators. However, we think Darusentan’s use will be dictated by the lack of efficacy or side effects of these other agents in specific patients. Hence, while higher prices may lead to noncompliance in some patients, we think that in major markets, Darusentan could be priced at a slight premium to popular branded hypertensive agents, such as the CCB Norvasc or the ARBs. This would lead to a monthly price in the US of approximately $55. We think such a price will be even easier to justify in the resistant hypertension setting, given the likely high rate of poor clinical outcomes in this population of patients. We note that the aldosterone antagonist Inspra, approved for heart failure and general hypertension, is priced about twice as high and is experiencing a relatively poor ramp-up, which may be partly due to its price relative to other treatments.
Revenue Projections
Our 5 and 10-year revenue projections for Darusentan are $219.8 million and $533.0 million in the US, and $348.5 million and $975.8 million worldwide.
It is unclear what the issue is causing the hold in clinical trials. If TBC3711 were ultimately approved, it would have the disadvantage of coming to market after Darusentan. The drug is likely to share the side effect of edema, as this has been seen with other agents in the class. Hence without clear evidence of a benefit, should development of TBC3711 be restarted, we project 5 and 10-year US revenues of $15.8 million and $193.1 million, with worldwide revenues of $15.8 million and $318.0 million.
EVALUATED COMPANY UPDATES
While a major portion of Myogen’s value is derived from Ambrisentan, Darusentan has the potential to be an important revenue contributor to Myogen. We currently value Myogen’s 5 and 10-year pipeline at $46.28/share and $52.38/share.
Encysive was recently plagued by an approvable letter for Thelin and with the TBC3711 program on hold, we place very little value to it. We currently value Encysive’s 5 and 10-year pipeline at $0.00/share and $3.75/share. While we see TBC3711's possible role in resistant hypertension as small, if Encysive were able to move the program into phase III, we would value its 5 and 10-year pipeline at $0.00/share and $8.25/share, making the importance of continuing the program a large one for Encysive.
The above numbers include patients who may not be receiving optimal treatment, or who may not use their medications for reasons such as cost. Unfortunately, there have not been any large-scale studies looking at the prevalence of resistant hypertension in the general population.
Number
(Millions)Prevalence
of HTNNumber with HTN (%)
Number treated for HTN (%)
Number controlled
(% of Treated)
Overall
196.5
30.7%
60
(100%)37
(61%)16
(43%)
Metabolic Syndrome
31.9
57.8%
18
(31%)12
(67%)5
(42%)
Diabetes
14.0
75.5%
11
(18%)7
(71%)2
(25%)
Kidney Disease
9.5
80.6%
8
(13%)5
(66%)1
(20%)
Stroke
4.2
69%
3
(5%)2
(79%)1
(28%)
Heart Failure
7.8
70.3%
5
(9%)5
(83%)2
(46%)
Peripheral Arterial Disease
5.2
75.1%
4
(6%)3
(74%)1
(29%)
Coronary Artery Disease
9.0
71.9%
6
(11%)5
(85%)3
(49%)
Adapted from Wong, et. al., Prevalence, Treatment, and Control of Hypertension in U.S. Adults, 2001-2002, Overall and With Metabolic Syndrome, Diabetes, Kidney Disease, Stroke, or Coronary Artery Disease; American College of Cardiology, 2006 Annual Scientific Session; Presentation 848-6. The numbers are estimated from the National Health and Nutrition Examination Survey 2001-2002.
Obviously some of these causes, such as patient noncompliance, require treatment other than additional blood pressure medications (unless, for example, the noncompliance is due to side effects).
Cause
% of Patients
% Achieving Goals
After Further Treatment
Suboptimal Therapy
55%
64%
Nonadherence
16%
22%
Psychological (e.g. anxiety leading to elevated BP)
9%
42%
BP elevated only in office, but not at home
6%
25%
Hypertension secondary to other causes
5%
71%
Intolerance to medications
3%
64%*
Interfering substances (sodium, alcohol, illicit drugs)
1%
50%
Unknown
6%
50%
*64% is the overall value for the drug-related group, including suboptimal therapy + intolerance to medications. Adapted from Garg, et al, Resistant hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens. 2005 May;18(5 Pt 1):619-26.
The reason behind the high number of hematology/oncology visits is unclear, since most of the second diagnoses do not appear to be specifically related to these specialties: the referrals may be for patients who have vague symptoms to ensure there is no malignancy. These numbers may not capture all referrals for diseases related to hypertension, since these cases may have another primary diagnosis.Percent of Total Visits and Referrals Received with Primary Diagnosis
of Hypertension or Hypertensive Heart/Kidney Disease
Percent of Visits
Percent of Referrals Received
Family/General Practice
42.43%
7.95%
Internal Medicine
46.89%
8.69%
Cardiovascular Disease
5.34%
62.16%
Hematology/Oncology
1.75%
8.21%
Nephrology
1.52%
6.50%
Endocrinology
0.20%
8.69%
Other
1.87%
6.50%
Based on 2004 National Ambulatory Medical Care Survey (NAMCS)
Specialty
% of Certified Hytn Specialists
Cardiology
11%
Endocrinology
7%
Nephrology
47%
Primary Care/Adult Medicine
15%
Other
4%
Not disclosed
16%
Class (Examples)
Mechanism
Comment
Drugs Recommended for Use Early On
Diuretic
triamterene
spironolactoneIncrease urine output by blocking sodium reabsorption by the kidneys. This reduces circulatory volume.
Different types act at different sites in the kidneys. Thiazides and loop diuretics also cause potassium to be excreted, which can result in low levels in the body. Potassium-sparing diuretics, including aldosterone antagonists, avoid this, but can cause elevated potassium levels.
Beta Blocker (BB)
Toprol XL (metoprolol)
Coreg (carvedilol)
bisoprolol
Inderal LA (propanolol)
Block the binding of epinephrine and norepinephrine, either secreted by nerves or by the adrenal glands, to beta-adrenergic receptors, resulting in slower heart rate and weaker heart contractions. Also inhibit the release of renin by the kidneys. Some BBs also block alpha 1 receptors (see below), but whether this offers any advantage in the treatment of hypertension is still unclear.
Since they reduce the workload of the heart and heart rate, BBs are also important in treating patients with ischemic heart disease, arrhythmias, and heart failure.
Angiotensin Converting Enzyme Inhibitors (ACEI)
enalapril
Altace (ramipril)
quinapril
Block the conversion of angiotensin I to angiotensin II in the RAAS system, though other mechanisms may be involved in long term effects (such as inhibiting the degradation of the vasodilator bradykinin).
Particularly important in treating heart failure and slowing the progression of renal failure. Benefit in cardiovascular disease (though there is question whether this extends beyond their reduction in blood pressure) and stroke.
Angiotensin II Receptor Blockers (ARB)
Cozaar (losartan)
Block the effects of angiotensin II.
Like ACEIs, have a particular benefit in heart failure and stroke. Evidence that they have effects complementary to ACEIs, and so nephrologists are increasingly using them in combination for protecting the kidneys.
Calcium Channel
Blockers (CCB)
Lotrel (amlodipine/benazipril)
Block the entry of calcium into heart and blood vessel muscle cells, reducing their contraction. Also increase salt and water excretion by kidneys.
Two types: Dihydropyridines, which have a greater effect on dilating blood vessels, and non-dihydropyridines, which have a greater effect on heart contractions. Because of this, the non-dihydropyridine CCBs should be avoided in patients with heart failure and used with caution in combination with beta-blockers.
Drugs for Later Use
Alpha 1 Receptor Antagonists (ARA)
prazosin
terazosin
Block the constricting effects of norepinephrine, secreted by nerves of the sympathetic nervous system, on blood vessels, with little or no effect on heart rate or amount of blood ejected by the heart.
Have fallen into relative disfavor since ALLHAT trial found an increased risk of cardiovascular disease, especially heart failure compared to the diuretic arm (but heart failure may have been due to fluid retention, which according to the study design could not be countered with a diuretic). ARAs also reduce the size of the prostate, so may be a preferred choice in men with enlarged prostates.
Central Alpha 2 Agonists (CAA) and Drugs Acting on Sympathetic Nerves
guanfacine
guanabenz
CAAs stimulate receptors in the central nervous system which suppress the sympathetic nervous system. This reduces heart rate, volume of blood pumped, and blood vessel contraction. Other drugs act on other central receptors or deplete stores of the sympathetic neurotransmitters.
These agents are no longer used early on in treatment due to side effects, such as hypotension upon standing, sedation, impotence, depression, and dry mouth.
Direct Vasodilators (DV)
minoxidil
These drugs directly dilate blood vessels through various mechanisms. Sometimes nitrates, which are primarily angina drugs, are included in this category.
By dilating blood vessels, these drugs cause reflex activation of the sympathetic nervous system (stimulating heart rate) and fluid retention, so they should be given with a BB and diuretic and not be used in patients with coronary artery disease. Despite the fluid retention when used alone, minoxidil is used frequently in severe hypertension associated with kidney disease. However, an annoying side effect for female patients is unwanted hair growth.
Compelling Indications for Drug Classes
in the Management of Hypertension (JNC 7)
Recommended Drugs
Compelling Indication
Diuretic
BB
ACEI
ARB
CCB
Aldo ANT
Heart Failure
X
X
X
X
X
Post–myocardial infarction
X
X
X
High coronary disease risk
X
X
X
X
Diabetes
X
X
X
X
X
Chronic kidney disease
X
X
Recurrent stroke prevention
X
X
BB=beta-blocker; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; Aldo ANT=aldosterone antagonist, a type of potassium-sparing diuretic.
% of Patients*
Agents used early in treatment
Agents Potentially for Resistant Hypertension
Desirable Attributes for Drugs
General
Diur+, ACEI/ARB, CCB, BB
ACEI/ARB, CCB, BB, ARA, CAA, DV, AA
-Better efficacy for systolic BP control
-Low side effects, especially with use of multiple agents.
-Low drug interactions.
-Synergistic mechanism of action.
-Avoid fluid retention.
-Beneficial effect on the development of diseases that contribute to poor outcomes along with hypertension (e.g. cardiovascular, diabetes, kidney disease).
-Particular advantage in a specified patient group.
Diabetes
21%
ACEI/ARB, CCB, Diur
BB**, ARA, CAA, DV, (AA)
-Beneficial effect on blood sugar control, cardiovascular risk factors, and kidney function.
Ischemic Heart Disease
11%
BB, CCB, Diur, ACEI***
ACEI/ARB, ARA, CAA, DV, (AA)
-Do not suppress heart function further when used with BB and CCB.
-Beneficial effect on cardiovascular risk factors/atherosclerosis-inflammation and LVH.
-Improve oxygen supply to heart muscle/reduce heart muscle oxygen consumption without worsening ischemia.
Heart Failure
9%
Diur, ACEI/ARB, BB
CCB, ARA, CAA, DV, (AA)
-Some variation depending on the cause of the heart failure.
-Beneficial effect on heart failure without increasing heart workload.
-Beneficial effect on renin-angiotensin-aldosterone and sympathetic nervous systems.
-Beneficial effect on cardiovascular risk factors and LVH.
Chronic Kidney Disease
28%
ACEI/ARB, Diur, (CCB, BB)
CCB, BB, ARA, CAA, DV
-Beneficial effect on kidney function.
-Improvement in cardiovascular risk factors.
-Avoid fluid retention.
Elderly/ African-American
42%/27%
Diur, CCB, ACEI
ARB, BB, ARA, CAA, DV
-These patients tend to have lower renin levels/responsiveness and less responsiveness to BBs. While some authorities believe in using such patient characteristics to guide treatment, others note that the effects of the drugs are equalized if a diuretic is in the regimen.
*Groups may be overlapping. Ischemic Heart Disease, Heart Failure, Elderly, and African-American percentages are taken from NHANES survey in general hypertension population. Other percentages from Garg, et al, Resistant hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens. 2005 May;18(5 Pt 1):619-26.
**While BB were recommended for diabetics in JNC 7, they may raise blood sugar, and there are increasing questions over whether they should be a preferred agent early on. They would be used, though, in patients with concurrent diabetes and heart disease.
***Nitrates, which are not typical hypertensive agents but do lower BP, may also be used.
Antihypertensive Medication
% Patients Using Upon Study Entry
Final Use
Diuretics
84%
91%
Beta-blockers (BB)
50%
32%
Alpha 1 Receptor Antagonists (ARA)
19%
36%
Central adrenergic (e.g. Alpha 2 Agonists)
22%
14%
ACE Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB)
84%
90%*
Calcium Channel Blocker (CCB)
69%
82%*
Direct Vasodilator (DV)
13%
6%
*ACEIs/ARBs were used together in 4% on entry and 11% after adjustment. Two calcium channel blockers (a dihydropyridine and a non-dihydropyridine) were used in 0 patients on entry and 14% after adjustment.
Class (Examples)
Mechanism
Comment
Drugs Recommended for Use Early On
Diuretic
triamterene
spironolactoneIncrease urine output by blocking sodium reabsorption by the kidneys. This reduces circulatory volume.
Different types act at different sites in the kidneys. Thiazides and loop diuretics also cause potassium to be excreted, which can result in low levels in the body. Potassium-sparing diuretics, including aldosterone antagonists, avoid this, but can cause elevated potassium levels.
Beta Blocker (BB)
Toprol XL (metoprolol)
Coreg (carvedilol)
bisoprolol
Inderal LA (propanolol)
Block the binding of epinephrine and norepinephrine, either secreted by nerves or by the adrenal glands, to beta-adrenergic receptors, resulting in slower heart rate and weaker heart contractions. Also inhibit the release of renin by the kidneys. Some BBs also block alpha 1 receptors (see below), but whether this offers any advantage in the treatment of hypertension is still unclear.
Since they reduce the workload of the heart and heart rate, BBs are also important in treating patients with ischemic heart disease, arrhythmias, and heart failure.
Angiotensin Converting Enzyme Inhibitors (ACEI)
enalapril
Altace (ramipril)
quinapril
Block the conversion of angiotensin I to angiotensin II in the RAAS system, though other mechanisms may be involved in long term effects (such as inhibiting the degradation of the vasodilator bradykinin).
Particularly important in treating heart failure and slowing the progression of renal failure. Benefit in cardiovascular disease (though there is question whether this extends beyond their reduction in blood pressure) and stroke.
Angiotensin II Receptor Blockers (ARB)
Cozaar (losartan)
Block the effects of angiotensin II.
Like ACEIs, have a particular benefit in heart failure and stroke. Evidence that they have effects complementary to ACEIs, and so nephrologists are increasingly using them in combination for protecting the kidneys.
Calcium Channel
Blockers (CCB)
Lotrel (amlodipine/benazipril)
Block the entry of calcium into heart and blood vessel muscle cells, reducing their contraction. Also increase salt and water excretion by kidneys.
Two types: Dihydropyridines, which have a greater effect on dilating blood vessels, and non-dihydropyridines, which have a greater effect on heart contractions. Because of this, the non-dihydropyridine CCBs should be avoided in patients with heart failure and used with caution in combination with beta-blockers.
Drugs for Later Use
Alpha 1 Receptor Antagonists (ARA)
prazosin
terazosin
Block the constricting effects of norepinephrine, secreted by nerves of the sympathetic nervous system, on blood vessels, with little or no effect on heart rate or amount of blood ejected by the heart.
Have fallen into relative disfavor since ALLHAT trial found an increased risk of cardiovascular disease, especially heart failure compared to the diuretic arm (but heart failure may have been due to fluid retention, which according to the study design could not be countered with a diuretic). ARAs also reduce the size of the prostate, so may be a preferred choice in men with enlarged prostates.
Central Alpha 2 Agonists (CAA) and Drugs Acting on Sympathetic Nerves
guanfacine
guanabenz
CAAs stimulate receptors in the central nervous system which suppress the sympathetic nervous system. This reduces heart rate, volume of blood pumped, and blood vessel contraction. Other drugs act on other central receptors or deplete stores of the sympathetic neurotransmitters.
These agents are no longer used early on in treatment due to side effects, such as hypotension upon standing, sedation, impotence, depression, and dry mouth.
Direct Vasodilators (DV)
minoxidil
These drugs directly dilate blood vessels through various mechanisms. Sometimes nitrates, which are primarily angina drugs, are included in this category.
By dilating blood vessels, these drugs cause reflex activation of the sympathetic nervous system (stimulating heart rate) and fluid retention, so they should be given with a BB and diuretic and not be used in patients with coronary artery disease. Despite the fluid retention when used alone, minoxidil is used frequently in severe hypertension associated with kidney disease. However, an annoying side effect for female patients is unwanted hair growth.
Compelling Indications for Drug Classes
in the Management of Hypertension (JNC 7)
Recommended Drugs
Compelling Indication
Diuretic
BB
ACEI
ARB
CCB
Aldo ANT
Heart Failure
X
X
X
X
X
Post–myocardial infarction
X
X
X
High coronary disease risk
X
X
X
X
Diabetes
X
X
X
X
X
Chronic kidney disease
X
X
Recurrent stroke prevention
X
X
BB=beta-blocker; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; Aldo ANT=aldosterone antagonist, a type of potassium-sparing diuretic.
% of Patients*
Agents used early in treatment
Agents Potentially for Resistant Hypertension
Desirable Attributes for Drugs
General
Diur+, ACEI/ARB, CCB, BB
ACEI/ARB, CCB, BB, ARA, CAA, DV, AA
-Better efficacy for systolic BP control
-Low side effects, especially with use of multiple agents.
-Low drug interactions.
-Synergistic mechanism of action.
-Avoid fluid retention.
-Beneficial effect on the development of diseases that contribute to poor outcomes along with hypertension (e.g. cardiovascular, diabetes, kidney disease).
-Particular advantage in a specified patient group.
Diabetes
21%
ACEI/ARB, CCB, Diur
BB**, ARA, CAA, DV, (AA)
-Beneficial effect on blood sugar control, cardiovascular risk factors, and kidney function.
Ischemic Heart Disease
11%
BB, CCB, Diur, ACEI***
ACEI/ARB, ARA, CAA, DV, (AA)
-Do not suppress heart function further when used with BB and CCB.
-Beneficial effect on cardiovascular risk factors/atherosclerosis-inflammation and LVH.
-Improve oxygen supply to heart muscle/reduce heart muscle oxygen consumption without worsening ischemia.
Heart Failure
9%
Diur, ACEI/ARB, BB
CCB, ARA, CAA, DV, (AA)
-Some variation depending on the cause of the heart failure.
-Beneficial effect on heart failure without increasing heart workload.
-Beneficial effect on renin-angiotensin-aldosterone and sympathetic nervous systems.
-Beneficial effect on cardiovascular risk factors and LVH.
Chronic Kidney Disease
28%
ACEI/ARB, Diur, (CCB, BB)
CCB, BB, ARA, CAA, DV
-Beneficial effect on kidney function.
-Improvement in cardiovascular risk factors.
-Avoid fluid retention.
Elderly/ African-American
42%/27%
Diur, CCB, ACEI
ARB, BB, ARA, CAA, DV
-These patients tend to have lower renin levels/responsiveness and less responsiveness to BBs. While some authorities believe in using such patient characteristics to guide treatment, others note that the effects of the drugs are equalized if a diuretic is in the regimen.
*Groups may be overlapping. Ischemic Heart Disease, Heart Failure, Elderly, and African-American percentages are taken from NHANES survey in general hypertension population. Other percentages from Garg, et al, Resistant hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens. 2005 May;18(5 Pt 1):619-26.
**While BB were recommended for diabetics in JNC 7, they may raise blood sugar, and there are increasing questions over whether they should be a preferred agent early on. They would be used, though, in patients with concurrent diabetes and heart disease.
***Nitrates, which are not typical hypertensive agents but do lower BP, may also be used.
Antihypertensive Medication
% Patients Using Upon Study Entry
Final Use
Diuretics
84%
91%
Beta-blockers (BB)
50%
32%
Alpha 1 Receptor Antagonists (ARA)
19%
36%
Central adrenergic (e.g. Alpha 2 Agonists)
22%
14%
ACE Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB)
84%
90%*
Calcium Channel Blocker (CCB)
69%
82%*
Direct Vasodilator (DV)
13%
6%
*ACEIs/ARBs were used together in 4% on entry and 11% after adjustment. Two calcium channel blockers (a dihydropyridine and a non-dihydropyridine) were used in 0 patients on entry and 14% after adjustment.
DRUGS IN DEVELOPMENT