SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. References

This roundtable discussion, held in December 2003, was convened to discuss the impact of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure's (JNC 7) challenging blood pressure goal objectives for the clinical management of hypertensive patients. The discussion was moderated by Michael Weber, MD, of the State University of New York Downstate College of Medicine in New York City. Participants included leading experts in the field Joseph Izzo, Jr., MD, of the School of Medicine and Biomedical Sciences at the State University of New York at Buffalo; Suzanne Oparil, MD, of the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham; and Jan Basile, MD, of the Ralph H. Johnson VA Medical Center and Department of General Internal Medicine/Geriatrics, Medical University of South Carolina in Charleston. The primary intention of this roundtable is to educate physicians about the importance of achieving the blood pressure goals agreed upon by the JNC 7 Committee and to present practical ways for the attainment of such goals in clinical practice.

DR. WEBER: The current cost of hypertension (HTN) in the United States in terms of both quality of life and financial burden is considerable. An increased risk of morbidity, particularly from coronary disease, stroke, renal failure, peripheral arterial disease, and heart failure (HF), with>46,000 deaths per year, can be directly attributed to HTN.1 Total mortality rises to>250,000 deaths per year when you factor in cases where HTN was listed as a contributing cause of death. HTN has an annual cost of ≈55 billion US dollars.1

Difficulties experienced in lowering blood pressure (BP) to recommended levels in hypertensive patients were seen in data from the most recent National Health and Nutrition Examination Survey (NHANES 1999–2000).2 Of all hypertensives, about one third (all ages) achieved the BP goal of <140/90 mm Hg.3 Of the 58% of hypertensive persons treated, only half achieved control.2 Control rates were significantly lower in women, Mexican Americans, and older people (aged >60 years).2 Only 25% of hypertensive patients with diabetes achieved the more stringent BP goal of <130/80 mm Hg.2

DR. BASILE: The point I always make to practitioners is that, if I were treating every one of the practitioners in the audience, all of whom had HTN, only one in three would have their BP below the minimum goal of <140/90 mm Hg, which is just not acceptable. Healthy People 2000,4 a national health promotion and disease prevention agenda instituted by the Department of Health and Human Services, had set a goal of 50% BP control by the year 2000, but we have done so poorly with BP control that we now have moved that goal date back to 2010.

DR. WEBER: When people ask you how many people have HTN, the Framingham study5 tells us: there are those who already have HTN and those who are going to get it. In the end, almost no one escapes. There are many people with HTN who are not being treated at all, but what is equally worrisome is the number of people who are being treated and do not have their BP controlled. Dr. Izzo, perhaps you can put some perspective on this matter by explaining, as a member of the committee that produced the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), the rationale for convening the Committee and publishing your report.

DR. IZZO: The rationale was the clearly recognized need for an update that included new clinical data, a need to focus more on reducing systolic blood pressure (SBP), and a mandate from physicians to simplify BP classification. Clinical studies have shown that most patients, no matter who they are, will require combination therapy with at least two different classes of drugs to achieve optimal BP control. In addition to setting more stringent BP goals, we also introduced the concept of pre-HTN for people who currently have an SBP of 120–139 mm Hg or a diastolic blood pressure (DBP) of 80–89 mm Hg. It is estimated that 47 million people in the United States (a little more than one fifth of the population) are prehypertensive.3

DR. WEBER: These people not only have a higher risk of becoming hypertensive, with all of its consequences, but also have increased rates of morbidity and mortality; 30% of all myocardial infarctions occur in people in this BP range; and the risk of stroke and HF is increased two- to four-fold.6,7

DR. IZZO: The prevalence of HTN increases with age; almost all people will become hypertensive if they live long enough.5,8 There are higher cardiovascular (CV) risks than people realize, even at low levels of HTN. The JNC 73 states that BP should be reduced to <140/90 mm Hg in most hypertensives and to <130/80 mm Hg in hypertensive patients with diabetes or chronic kidney disease (CKD), where this further lowering of BP may reduce costs and complications. The JNC 7 guidelines have revised the definition of CKD to include patients with a reduced glomerular filtration rate (<60 mL/min) or albuminuria (>300 mg/d). Under the new guidelines, 24 million people in the United States are now defined as having CKD, most of whom do not know that they have it. We need to be more effective in achieving the more stringent BP goal of <130/80 mm Hg in these patients.

Evidence shows us that the primary focus should be on lowering SBP rather than DBP, especially in the older individual. Focus on the systolic goal and the diastolic response will never disappoint you. Focus on the diastolic goal and you will often be disappointed by the lack of systolic response.

DR. BASILE: Absolutely. SBP is a better predictor of CV disease risk than DBP, particularly in the elderly; its reduction results in a lowering of CV event rates. This was shown both in the Systolic hypertension in Europe (Syst-Eur) study9 and in the Systolic Hypertension in the Elderly Program (SHEP).10 SBP control results in significant benefits and often leads to reductions in DBP. To summarize, lower BPs are better than higher, and SBP is a better predictor of CV disease risk than DBP once an individual turns 50 years of age.

Although older people fare worse than younger people with similar BPs, if you bring the SBP to goal, you almost always will have the DBP at goal.

DR. IZZO: You achieve a slightly greater benefit from BP reduction in the younger age groups in terms of relative risk reduction, but because the absolute risk is so high in older people, the number of people we need to treat to demonstrate morbidity and mortality benefits in older people is much lower. In middle-aged and older people, SBP should clearly be our focus, but it is more difficult to control than DBP. The JNC 73 recommends using a thiazide diuretic in most patients with BP ≥140/90 mm Hg, with or without a second agent. Combination therapy using two different classes of antihypertensive drugs should be used in people with BP ≥20/10 mm Hg above target, which includes all individuals with stage 2 HTN (SBP ≥160 mm Hg or DBP ≥100 mm Hg). In patients with diabetes or CKD, initial two-drug combination therapy should begin at 150/90 mm Hg because the target BP in these conditions is <130/80 mm Hg.3

DR. BASILE: This approach is preferable because the BP reduction required to reach the goal in these situations is greater than can be achieved with monotherapy.

DR. WEBER: Remember, though, that the JNC 7 also points out that blockers of the renin-angiotensin-aldosterone system (RAAS) are very appropriate for diabetics, and that all drug classes, including angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors, can be considered for starting treatment in stage 1 HTN.

DR. IZZO: In particular, in some high-risk patients, you may want to consider starting with an ARB or an ACE inhibitor and then add a thiazide diuretic.

DR. BASILE: Absolutely. Adding a thiazide-type diuretic with an ARB or ACE inhibitor will allow more patients to get to goal and conforms to the JNC 7. Also, the guidelines advise that a simple dosing schedule, with well-tolerated agents, should be used to enhance adherence.

DR. IZZO: Regarding high-risk patients, BP reduction is critical, but blocking the RAAS may also be beneficial. My best guess is that the overall benefit in high-risk patients with heart disease, kidney disease, or diabetes is about 90% BP control and 10% RAAS blockade.

DR. OPARIL: Yes, I agree, but you should not ignore that 10%, and once target organ damage is present, new rules apply. The emphasis may change, and blocking angiotensin II (Ang II) may become more important. We know from about 100 years of studies that there are mechanisms that cause both high BP and damage to critical organs such as the brain, blood vessels, heart, and kidneys, the best known of which is Ang II.11 Benefits of some ARBs over other antihypertensives have been shown. For example, benefits in stroke prevention were demonstrated in the Losartan Intervention For Endpoint reduction in HTN (LIFE) trial,12 where losartan was more effective as an initial therapy than atenolol, both of which antagonize the RAAS. It is clear that, especially in high-risk hypertensives, we need to block or inhibit Ang II in addition to lowering BP for maximum effect. We know that HTN is associated with target organ damage, and there is a very strong correlation between the severity and duration of HTN and the risk of target organ damage. By intervening early, we can prevent or slow the progression of target organ damage and improve morbidity and mortality. In targeting the RAAS, specifically by blocking Ang II, we have the added advantage of blocking a mediator that causes target organ damage.

DR. BASILE: I would like to add that there is actually a trial going on right now, the TRial Of Preventing HYpertension (TROPHY),13 that evaluates whether treating prehypertensive patients with an ARB will reduce the incidence of progression to clinical HTN. One might expect that if we prevent HTN in these prehypertensive patients through early pharmacological intervention then we may see a dramatic increase in the health benefits that Dr. Oparil just mentioned for these patients.

DR. WEBER: Considering the potential benefits, we can all agree that early antihypertensive intervention is key. As well, we can also agree that some of these antihypertensive drugs offer certain therapeutic advantages in addition to BP lowering, in other words, target organ protection. So let me ask you, when prescribing an antihypertensive agent, do you believe it is more important to use a specific agent and not be quite as concerned about the actual resulting BP reduction or to give a drug that will bring a patient to goal and do so rapidly?

DR. IZZO: I believe that BP reduction to goal or better should be the primary health concern for all patients and that physicians should be more aware of the importance of achieving these BP goals. Each patient should have a BP reduction of at least 20/10 mm Hg because that figure corresponds to a 50% risk reduction.3 A small or partial response is just not good enough, and physicians should no longer be satisfied with such suboptimal performance. For a practical implementation of the JNC 7, patients must also be told that reaching their goal or better, and the sooner the better, is the number one priority. Treatment should be more aggressive, if necessary, to reach BP goals. On balance, our biggest problem is failing to treat aggressively enough.

DR. WEBER: I agree, and experience shows us that if you do not reduce BP quickly, perhaps you never will. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT)14 is a good example of that principle. I also think that one of the big problems we have had in HTN is that too many people have signed off on the concept of responders. In reality, you can be a responder and still have poorly controlled BP. In a sense, we need to make the word “responder” a politically incorrect term. Goal rates, the proportion of patients achieving <140/90 mm Hg or 130/80 mm Hg, depending on their risk category, are the clinically relevant measurements. Bringing patients to goal has a major impact on reducing BP-associated CV pathologies.

DR. OPARIL: For all of the major conditions that are complications of HTN, the recent BP Trialists meta-analysis15 has shown that the extent to which the intervention lowers SBP in relation to any other comparator, either placebo or another drug, is linearly related to the benefit, that is, reduction in death, heart attack, stroke, and so on.

DR. WEBER: Indeed, on average, an SBP reduction of 2 mm Hg translates into a 10% reduction in fatal strokes and a 7% reduction in fatal coronary events.7

DR. OPARIL: Small reductions in DBP also significantly reduce CV risk. Lowering BP to goal has the additional advantage of improving clinical outcomes by reducing or, if intervention is early enough, preventing organ damage. The Hypertension Optimal Treatment (HOT) study16 showed that a DBP reduction of 4 mm Hg, from 85 mm Hg-81 mm Hg, in hypertensive patients with diabetes halved the number of CV events. The UK Prospective Diabetes Study (UKPDS)17,18 showed that, in diabetics, strict BP control reduced the risk of target organ damage more than glucose control; the reduction in stroke was ≈50%. Similarly, diabetes-related end points benefited more from tight BP control than tight glucose control.

DR. WEBER: Let us turn our discussions to the practical aspects of managing our hypertensive patients for a moment. We agree that attaining BP goal is critical in the treatment of HTN, so we should discuss the reasons for the current lack of BP control.

DR. IZZO: In many cases, it is due to a failure on the part of the physician to uptitrate, despite the knowledge that higher drug dosages are more likely to prevent poor outcomes in complex patients with compelling indications.

DR. BASILE: Many doctors still believe that one drug is sufficient to control BP, and, often, the first dose of that initial drug is the final dose prescribed. Conversely, in some cases, the first drug is discontinued too quickly when the BP goal is not achieved and a second drug is substituted rather than added to the initial choice. Other reasons for lack of control are clinical inertia, nonadherence to treatment, poor communication between the patient and the physician, inadequate patient monitoring, failure to use combination therapies, and failure to understand and communicate treatment goals.

DR. IZZO: If the doctor does not appear to care that BP goals are not obtained or that BP never comes down, then the message is rapidly translated to the psyche of the patient that BP does not really matter, which can impact treatment adherence. We also find that, in some cases, when uptitration does occur, it is done too quickly, which can lead to an increase in adverse events that cause termination of therapy, so we must be careful. We do want our patients to attain BP goals quickly, but if adherence becomes an issue because of an increase in adverse events, then it is better to bring them there slowly, rather than not at all, in these particular patients. For example, the Quinapril Titration Interval Management Evaluation (ATIME) study19 compared uptitrating therapy every 6 weeks rather than every 2 weeks and found that similar BP control occurred with fewer side effects in the group uptitrated every 6 weeks as compared with those uptitrated every 2 weeks.

DR. BASILE: Right. We want them to attain BP goals while making sure they are adhering to the therapy. The problem is that physicians stop evaluating the patient's progress toward the targeted BP level.

DR. IZZO: I agree. The problem is that many doctors do not pay adequate attention to BP goals. Consequently, patients stop taking the medicine. Other doctors start with a subtherapeutic dosage, so that no benefits are seen and the drugs are perceived as not being effective. Some physicians may not have explained the health benefits of BP reduction and reaching goal to their patients, and some may still be using the outdated SBP 100 + age rule. In still other cases, illogical drug combinations lead to poor efficacy and a higher incidence of side effects.

DR. WEBER: Given that both ACE inhibitors and ARBs block the RAAS and ACE inhibitors that, in the past, have been so widely prescribed, let us consider whether there are any compelling reasons for choosing one agent over the other.

DR. BASILE: Both drug classes inhibit the RAAS, and some have shown renoprotective and cardioprotective benefits beyond the effects of BP lowering. ARBs, however, have the advantage of producing fewer side effects than ACE inhibitors; they have a safety profile similar to that of placebo even at high dosages. In addition, some ARBs have been shown to reduce CV morbidity and mortality and HF, reduce the risk of left ventricular hypertrophy related to HTN, and slow progression of type 2 diabetic renal disease. Long-term use of ACE inhibitor therapy is thought to result in a phenomenon termed “angiotensin-escape,” in which levels of Ang II actually increase after an initial transitory period of suppression.20 This process is probably due to increased generation of Ang II by non-ACE-dependent pathways. Unlike an ACE inhibitor, the long-term administration of an ARB is not associated with angiotensin escape.

DR. OPARIL: Clearly, results from numerous outcomes trials, such as the LIFE study,12 the Valsartan In Acute myocardial INfarction Trial (VALIANT),21 the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)22–25 study, the Irbesartan type 2 Diabetic Nephropathy Trial (IDNT)26 and the Reduction of Endpoint in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL)27 trial have demonstrated that certain high-risk conditions, such as HF, type 2 diabetes with proteinuria, and CKD, are compelling indications for the use of some ARBs. Including a thiazide diuretic with an ARB,particularly when the patient has underlying HTN, will allow more patients with these compelling indications to reach their goal. In addition, this regimen incorporates the treatment guidelines contained in the JNC 7.

DR. WEBER: Let's consider the most appropriate therapeutic option for a patient who needs a BP reduction of >20/10 mm Hg and is still unable to achieve this result with combination therapy using two agents.

DR. IZZO: In this case, a multiple drug strategy or a stepped care approach would be effective in most patients. The first agent is initiated and titrated, if necessary, to maximum BP effect. The second agent is then added and similarly titrated to the maximum BP-lowering dosage. If necessary, a third agent is added and titrated until the BP goal is attained.

DR. BASILE: I agree. We should not be afraid of using more than two agents.

DR. WEBER: Yes, Dr. Joel Neutel and his colleagues used this strategy in a trial referred to as the “Treat to Goal” study.28 Patients were enrolled in a stepped care study with the idea that they would leave the trial as soon as they reached a BP of ≤130/85 mm Hg. Patients began treatment with the starting dosage of olmesartan 20 mg and were then titrated to 40 mg. If that dosage did not bring them to goal, then 12.5 mg of hydrochlorothiazide were added, and, if needed, 25 mg of hydrochlorothiazide. Investigators then added a 5-mg dosage of amlodipine; finally, a 10-mg dosage of amlodipine could be employed. Using this strategy, the “Treat to Goal” study showed that, even in a population where ≈70% of patients had stage 2 HTN, olmesartan plus hydrochlorothiazide therapy resulted in mean SBP reductions of 29.3 mm Hg and mean DBP reductions of 16.1 mm Hg and achieved BP goal rates of 83% for a target of ≤140/90 mm Hg and 69% for a target of ≤130/85 mm Hg. Note that goal rates, and not response rates, were used as the primary end point. On the addition of amlodipine, if needed, 93% of patients achieved a BP goal of ≤140/90 mm Hg and 88% achieved a goal of ≤130/85 mm Hg. Bear in mind that, when amlodipine was added, the nonresponders comprised the most resistant patients, so the final proportion of participants achieving goal is impressive. This study shows us that reaching target BPs is possible in most patients but does, at times, require aggressive management.

DR. BASILE: This is what might be called a “reverse stepped care approach,” that is, it starts with neurohormonal antagonism and adds the thiazide.

DR. WEBER: That is a nice way of putting it, and you could argue that, for the population that many of us treat, it is a logical approach because we are starting with a drug likely to work in a majority of our patients. Even if the ARB does not reduce BP as much as we need, it is not going to prevent the diuretic from being effective when you add it, so, if we are going to use a logical approach, it is the right way to do it for most of our patients.

DR. IZZO: I am not a big fan of starting a diuretic alone either. I do not believe in the ALLHAT approach. I think you make a good case that either an ARB or an ACE inhibitor is an attractive foundation and that a diuretic is an ideal second-step agent. Having said that, almost all patients are better off taking a diuretic-ACE inhibitor or a diuretic-ARB combination.

DR. WEBER: What practical steps can we suggest that the physician take, in addition to selection of the appropriate agent and use of a treatment algorithm, to help increase BP goal attainment?

DR. IZZO: There are many practical steps to improve goal rates. The most obvious step is for patients to know their goal and their current BP and then, as the JNC 7 advises, for the physician to write down the BP goal for the patient, even on the medication bottle.

DR. BASILE: I agree. When I write a prescription for a patient it says, “Take one every day to get the top number of BP to <140 mm Hg or <130 mm Hg.” That is what it says right on the bottle. In addition, have patients bring their medications to the clinic, not just their list, so that whenever you add or take away a medication, you can really show them what you are trying to do. Furthermore, encourage them to take their own BP measurement out of the doctor's office, and persuade them to bring a family member to the office so that they too can be educated on the importance of achieving goal BP. Let them know it will probably require more than one drug to reach the goal. Finally, tell patients to call the office if they ever stop their BP-lowering medicine, regardless of the reason. It is unacceptable to find out the medicine was unknowingly stopped 1 or 2 months beforehand. Have the patients call the office immediately and discuss why they stopped the medicine.

DR. OPARIL: This approach will also ensure that they understand the benefits of achieving their BP goal.

DR. IZZO: Although our main objective is to achieve goal BP, we also have to keep hammering home the message that every 20/10 mm Hg reduction in BP cuts the risk of CV events in half. Tell patients they may not be at goal yet, but they have already dramatically reduced their chance of stroke and other CV events. Realistic expectations will improve adherence to therapy.

DR. WEBER: If physicians are serious about following the JNC 7 guidelines and they start treating patients more aggressively to reach their goal, does the Healthy People 2010 initiative of 50% of patients achieving BP goal seem realistic?

DR. IZZO: Given what is going on in the world, we would be doing phenomenally well to bring 50% of patients to their goal BP. At the 34% identified in NHANES 1999–2000,2 we are not doing as badly as people think, but we have a long way to go. Even if everyone were treated optimally, the maximum control rate would probably be ≈70%. Remember, as was previously mentioned, we have two issues here: first, only 58% of hypertensive people are being treated, and, second, only 53% of those treated are reaching goal.2 So, to achieve the 70% maximum achievable goal, we must first attempt to identify all hypertensive patients and then treat them all optimally. As for the remaining 30% who may never reach the JNC 7 goals, 10% will fail because the SBP is very high because of stiff arteries; 10% have severe reactive or “white coat” HTN, which does not respond well to antihypertensives; and 10% will always be noncompliant. I truly believe the other 70% can be controlled.

DR. WEBER: Okay. This point is probably a good place for us to end our discussion, so I would like to thank all our participants for their time and enthusiastic contributions. Considering all of the information presented in today's roundtable discussion, I think we have the basis for making a strong statement about the importance of achieving goal BP in managing HTN, particularly in light of the evidence giving us the challenge of bringing BPs below 140/90 mm Hg and down even lower, to <130/80 mm Hg, in special populations. We have good evidence that BP control is critical and drugs that block the RAAS have an important role in lowering BP. Additionally, some drugs have the benefit of enhancing CV and renal protection. We also have good evidence that ARBs are effective, either alone or in combination with a diuretic or, if needed, with a third-line drug. When choosing an antihypertensive agent, the factors to consider should be the biggest BP reduction, bringing the most people to goal BP, and good tolerability.

In addition to prescribing the right agent from the start, based on the individual needs of the patient, physicians need to be more aggressive in bringing their patients to goal. They should closely monitor the BP and not be afraid to uptitrate the current dosage and add a second complementary agent if their patients are not reaching their goal in a timely manner. Experience has shown that, in most cases, BP goals must be achieved sooner rather than later for patients to have the best chance of reaching a controlled BP. Lastly, physicians need to partner with their patients, which means communicating the message of reaching goal, having patients monitor their own BP out of the office, involving other family members in this monitoring process, encouraging patients to stay with the treatment regimen, and using positive reinforcement based on the BP reduction already achieved.

Disclosure: This roundtable discussion was supported by Sankyo Pharma Inc. and Forest Laboratories, Inc.

References

  1. Top of page
  2. Abstract
  3. References
  • 1
    American Heart Association. Heart and Stroke Statistics—2004 Update. Available at: http://;www.americanheart.org/downloadable/heart/1079736729696HDSStats2004UpdateREV3-19-04.pdf. 2003. Accessed on March 29, 2004.
  • 2
    Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA. 2003;290:199206.
  • 3
    Chobanian AV, Bakris GL, Black HR, et al. The Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:12061252.
  • 4
    Healthy People 2010. Office of Disease Prevention and Health Promotion, US Department of Health and Human Services. 2004. Available at: http://www.healthypeople.gov/ . Accessed on March 30, 2004.
  • 5
    Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA. 2002;287:10031010.
  • 6
    Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Health Technol Assess. 2003;7:194.
  • 7
    Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:19031913.
  • 8
    Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345:12911297.
  • 9
    Staessen JA, Fagard R, Thijs L, et al. Randomised doubleblind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757764.
  • 10
    Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265:32553264.
  • 11
    Carson P, Giles T, Higginbotham M, et al. Angiotensin receptor blockers: evidence for preserving target organs. Clin Cardiol. 2001;24:183190.
  • 12
    Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:9951003.
  • 13
    Nesbitt SD, Julius S. Prehypertension: a possible target for antihypertensive medication. Curr Hypertens Rep. 2000;2:356361.
  • 14
    Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4:393404.
  • 15
    Effects of different blood pressure lowering regimens on major cardiovascular events. Second cycle of prospectively designed overviews. Blood pressure lowering treatment trialists' collaboration. Lancet. 2003;362:15271535.
  • 16
    Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:17551762.
  • 17
    Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837853.
  • 18
    Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703713.
  • 19
    Flack JM, Yunis C, Preisser J, et al. The rapidity of drug dose escalation influences blood pressure response and adverse effects burden in patients with hypertension: the Quinapril Titration Interval Management Evaluation (ATIME) Study. ATIME Research Group. Arch Intern Med. 2000;160:18421847.
  • 20
    Sica DA. Angiotensin-Converting Enzyme Inhibitors. In: IzzoJL, Jr., BlackHR, eds. Hypertension Primer: The Essentials of High Blood Pressure. 3rd ed. Philadelphia , PA : Lippincott Williams & Wilkins; 2003:426429.
  • 21
    Pfeffer MA, McMurray J, Leizorovicz A, et al. Valsartan in acute myocardial infarction trial (VALIANT): rationale and design. Am Heart J. 2000;140:727750.
  • 22
    Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777781.
  • 23
    Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772776.
  • 24
    McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767771.
  • 25
    Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759766.
  • 26
    Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851860.
  • 27
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861869.
  • 28
    Neutel JM, Smith DH, Weber MA, et al. Masonson HN. Use of an olmesartan medoxomil-based treatment algorithm for hypertension control. J Clin Hypertens (Greenwich). 2004;6:168174.