Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S10-S15, July 2008

Achieving blood pressure control in clinical practice

Based on material presented at a Boehringer Ingelheim-Sponsored Meeting held in Madrid, Spain, May 4–5, 2007.

  • Bryan Williams, MD, FRCP, FAHA

      Affiliations

    • Corresponding Author InformationCorresponding author: Bryan Williams, MD, FRCP, FAHA, Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, United Kingdom. Tel: +44 0 116 252 3182; fax: +44 0 116 252 5847.

Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom

Article Outline

Abstract 

There are an overwhelming number of clinical trials that show that the main benefits of antihypertensive treatment are associated with blood pressure (BP)-lowering. Even small improvements in BP, or moving from a “prehypertensive” to a “normal” BP state, can have a dramatic effect on the progression of early-stage cardiovascular disease, and may actually regress the development of atherosclerosis. However, achieving adequate BP control can be very difficult, even under the scrutiny of a clinical trial setting; in general practice it is even harder. If physicians wait to the point at which arterial damage is well established, then we will always be striving to treat difficult or treatment-resistant patients. The difficulty in achieving BP-lowering is further aggravated by the involvement of a renin-angiotensin system-mediated counter-regulatory mechanism that offsets vasodilatory drugs and blunts dose response. Such issues raise the question of whether physicians should contemplate earlier intervention or initial combination therapy in order to prevent the evolution of damage, overcome the counter-regulatory mechanism, and minimize the need for multiple drug use in the long-term. Using combination therapy at an earlier stage would also remove heterogeneity in BP response and may reduce treatment resistance.

Keywords: Blood pressure-lowering, hypertension guidelines, renin-angiotensin system, PRISMA I

 

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Introduction 

It is now recognized that blood pressure (BP) and risk strata should both be considered in the treatment of hypertension, even in the early stages.1, 2 Based on an analysis of 12,269 subjects from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHEFS) trial, antihypertensive treatment of patients with stage 1 hypertension, i.e., systolic blood pressure (SBP) 140 to 159 mm Hg and/or diastolic blood pressure (DBP) 90 to 99 mm Hg and additional risks such as smoking, dyslipidemia, age >60 years, male gender, menopause (women), or a family history of cardiovascular disease (CVD), reduced the risk of mortality.1 In these patients with mild disease, it was estimated that a sustained reduction in SBP of 12 mm Hg over a 10-year period could prevent one death in every 11 treated patients. In higher-risk patients with CVD or target-organ damage, only nine patients would require this SBP reduction to prevent one death. These findings also dispel the myth that we need to treat a substantial number of milder patients in order to see the benefits of treatment; this is clearly not the case when the data are projected over a longer, 10-year period.

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The Benefits of BP-Lowering 

Although risk strata (as described in the preceding text) are clearly important, particularly for making treatment decisions in borderline patients, there are an overwhelming number of trials in clinical practice, including those summarized by the Blood Pressure-Lowering Treatment Trialists' Collaboration (BPLTTC) Trial, which emphasize that the main benefits of treatment are associated with BP-lowering. Achieving adequate BP control needs to be prioritized in our current treatment practices. In one analysis, the BPLTTC investigated the effects of BP-lowering regimens on cardiovascular outcomes and mortality using a prospectively designed systematic overview of 29 randomized, controlled trials involving 162,341 patients.3 These authors found that differences in the risk of stroke or coronary heart disease were directly associated with differences in the weighted mean SBP achieved following randomized treatment comparisons; these data are summarized in Figure 1. Similar associations were observed for major CVD, cardiovascular death, and total mortality.

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  • Figure 1. 

    These pooled data show that the weighted mean differences of SBP between randomized groups are directly related to differences in the RR of stroke or CHD. CHD, coronary heart disease; RR, relative risk; SBP, systolic blood pressure. Reprinted with permission from Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–35.3

Even small changes in BP can have a dramatic effect on the progression of CVD during its early stages. This is clearly demonstrated in the intravascular ultrasound (IVUS) substudy of the Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT) Trial.4 In the IVUS substudy, 274 patients with ≥1 angiographic coronary stenosis of >20% and DBP <100 mg with or without treatment underwent coronary IVUS before and after 2 years of intervention with amlodipine, enalapril, or placebo. These authors found that the progression of coronary atherosclerosis was significantly related to the in-trial, follow-up BP values, which were defined according to Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) VII recommendations.2 In patients with “hypertensive” BP (SBP ≥140 mm Hg or DBP ≥90 mm Hg), the mean increase in arterial atheroma plaque volume (a measure of coronary artery disease progression) was 12 ± 3.6 mm3 (P = .001 by analysis of variance); patients classified as “prehypertensive” (SBP 120 to 139 mm Hg or DBP 80 to 89 mm Hg) had a lower mean increase in atheroma volume of 0.9 ± 1.8 mm3 (P = not significant [NS]); and patients achieving “normal” BP (<120/80 mm Hg) had a decrease in atheroma volume of −4.6 ± 2.6 mm3 (P < .05). These findings indicate that moving from prehypertension to normal BP was associated with a regression of coronary atheroma.

Although aggressive BP-lowering can be difficult to achieve in clinical trials, it must be noted that many of the included patients are very high risk and can be at the older end of the population, where it is traditionally much harder to lower BP. In an earlier review of several large-scale antihypertensive trials, Mancia and Grassi5 illustrated that treatment in clinical trials does result in a large fall in BP, the magnitude of which was related to baseline values. Many of the agents in these trials achieved mean DBP values that were well below the 90 mm Hg threshold; however, very few managed to achieve SBP values <140 mm Hg; these findings are summarized in Figure 2. These shortcomings in clinical trials of antihypertensive efficacy, where rigorous protocols are in place and patient motivation is high, will be magnified in general practice. As a result, achieving optimal BP levels remains a challenge for many physicians.

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  • Figure 2. 

    The mean SBP and DBP control achieved at baseline (trial entry) and after treatment in patients with essential hypertension. ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Australian National Blood Pressure Study Group; CAPPP, Captopril Prevention Project; DBP, diastolic blood pressure; HOPE, Heart Outcomes Prevention Evaluation Trial; HOT, Hypertension Optimal Treatment Study; INSIGHT, International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment; INVEST, International Verapamil-Trandolapril Study; LIFE, Losartan Intervention For Endpoint reduction in hypertension Study; NORDIL, Nordic Diltiazem Study; PROGRESS, Perindopril Protection against Recurrent Stroke Study; SBP, systolic blood pressure; SCOPE; STONE, Shanghai Trial Of Nifedipine in the Elderly; STOP2, Stent vs. Thrombolysis for Occluded Coronary Arteries in Patients With Acute Myocardial Infarction 2 Study. Adapted from Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens 2002;20:1461–64.5

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BP-Lowering Is More Difficult in High-Risk Patients 

It is paradoxical that the very patients in whom physicians would endeavor to achieve aggressive BP control (i.e., those that would receive the most benefit from BP-lowering) are the ones in which it is more difficult to obtain. The most obvious patients that would fall into this category are those with additional risk factors, such as accelerated aging of the arterial system, diabetes mellitus, renal disease, or clinical atherosclerosis, and smokers. There are numerous clinical trials, which show that the absolute benefits of BP-lowering are greatest in these high-risk patients.6 However, if we wait to the point at which arterial damage is well established then we will always be endeavoring to treat these difficult patients. This raises the question of whether physicians should contemplate earlier intervention in order to prevent the evolution of damage, thus making long-term BP control easier throughout life.

If we consider the evolution of hypertension itself, it not only gives clues as to optimal treatment strategies but also the reasons why treatments may sometimes fail to adequately control BP. Figure 3 illustrates that hypertension can be divided into three phases (prehypertension, hypertension with silent damage, and hypertension with clinical disease). “Prehypertension” represents the early stages of the condition when the hypertension phenotype is just becoming manifest. During this phase, patients generally have structural damage and activation of the renin-angiotensin system (RAS) and sympathetic nervous system (SNS). The condition then passes through a phase of silent damage to the aorta and large vessels, which ultimately culminates in older patients with clinical disease.7

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  • Figure 3. 

    The three phases in the evolution of hypertension. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium-channel blocker; GFR, glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

In the younger “prehypertensive” patients, the primary cause of BP elevation is vasoconstriction and increased peripheral resistance, which is initially due to vasoactive substances followed by aggressive remodeling of small artery structure. Given that this is, in part, driven by the RAS and SNS, then these patients will primarily have a diastolic-type hypertension with an increase in vascular resistance. Blockade of the RAS will, therefore, be most beneficial in these younger patients. As the condition progresses in elderly patients, it then becomes manifest as a decline in glomerular filtration rate, coupled with sodium retention, volume expansion, and increased cardiac output, which is compounded by a stiff aorta with reduced vascular compliance. Overall, these manifestations lead to a progressive rise in systolic hypertension. In older patients, therefore, physicians need to deal with the consequences of BP elevation (i.e., volume overload), and the most appropriate treatments include calcium-channel blockers (CCBs) and diuretics. During the silent phase, which occurs between these two extreme pathologies, combination treatment approaches are most appropriate.

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Antihypertensive Efficacy: Monotherapy or Combination Therapy 

Observational studies analyzing the efficacy of monotherapy treatments in hypertensive patients generally show that there is a consistent reduction in BP, which is often irrespective of the treatment used. In the Treatment Of Mild Hypertension Study (TOMHS) Trial, 902 patients were randomized to treatment for a median follow-up of 4.4 years.8 After 48 months, the mean reduction in DBP was comparable across treatment groups: −11.5 mm Hg (acebutolol); −12.2 mm Hg (amlodipine); −11.1 mm Hg (chlorthalidone); −11.2 mm Hg (doxazosin); −9.7 mm Hg (enalapril); and −8.6 mm Hg (placebo). In another meta-analysis of 43 published trials in which 11,281 patients were randomized to treatment with losartan, valsartan, irbesartan, or candesartan, the absolute weighted mean reductions in DBP ranged from −8.2 to −8.9 mm Hg.9 The comparable efficacy observed between treatments is not surprising, however, given that these trials are conducted in large, heterogeneous populations. In order to determine the differences in response to antihypertensive monotherapy, it would be necessary to look at individuals, and to try and “tease out” which patient characteristics would predict these differences. This approach would enable physicians to choose the initial antihypertensive agent that would guarantee the best response.

Nevertheless, lowering BP even when it is elevated will always be a difficult challenge. BP is maintained by multiple pressor systems that are designed to resist BP-lowering. Structural damage to small and large arteries will also make the achievement of BP-lowering harder as structural systems are involved in the maintenance of peripheral resistance and systolic pressure over time.

The difficulty in achieving BP-lowering is further aggravated by the involvement of a counter-regulatory mechanism that offsets vasodilatory drugs and blunts dose response. For example, when a patient is treated with a diuretic or CCB, which, via natriuresis and vasodilation, will lower BP, the RAS and SNS counteractivate to limit the fall in BP. As a result, the “net” effect of vasodilatory monotherapy is less than would be expected. The logical approach in most patients would, therefore, be to advocate combination therapy, which promotes natriuresis and induces vasodilation (i.e., a diuretic or CCB) and inhibits the counter-regulation (i.e., RAS blockade). Inhibiting the counter-regulation will also restore the dose response, particularly at higher doses. Such arguments clearly suggest that monotherapy will not work for the majority of patients. Often treatment is initiated too late, when damage is already established, and complex mechanisms involving structural changes can still maintain BP. Counter-regulatory processes can also inhibit the efficacy of some individual antihypertensive treatments, including diuretics and CCBs.

In contrast, the benefits of combination therapy can be clearly seen in clinical trials. For example, the Study of Micardis [telmisartan] in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH) Trial, which compared the effects of hydrochlorothiazide (HCTZ) plus telmisartan or valsartan fixed-dose combination therapies on early morning and 24-hour BP control in 840 patients, showed that there was a significant response with combination therapy (telmisartan plus HCTZ).10, 11 Combination therapy is also more predictive in the sense that it is not necessary to know individual characteristics; it is possible to achieve a positive response irrespective of the population being treated.

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BP-Lowering: Which Drug for Which Patient? 

Initial treatment choice is important as it defines the quality of BP control. If patients have a poor response to the initial drug then it is likely that they will have poorer long-term BP control. The reasons for this are not clearly understood, but may be related to the RAS counteractivation mechanism, which is difficult to suppress once activated. The poor response to initial therapy also predicts the need for more drugs in the long-term. It is, therefore, important to carefully consider the initial drug, and for this very reason, physicians need clear clinical guidance. Primarily, initial treatment choice should be based on the importance of BP control, with a secondary understanding of other properties of drugs for consideration in the longer term.

The JNC VII recommendations1 suggest that the majority of patients (i.e., those without compelling indications and with stage 1 hypertension: SBP 140 to 159 mm Hg or DBP 90 to 99 mm Hg) could be initially treated with a thiazide-type diuretic.

An alternative treatment strategy, which is outlined by the British Hypertension Society/National Institute for health and Clinical Excellence (NICE) guidelines (2006),12 is based on the stratification of patients according to age and the likelihood of responding to a specific treatment, as outlined in Figure 3. According to this philosophy, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) would be recommended as initial therapy for younger patients and CCBs or diuretics would be most appropriate for older patients or Black patients (i.e., those of African or Caribbean descent). Recent concerns about the efficacy of beta-blockers (atenolol) and the increased risk of diabetes when used with thiazide-type diuretics has limited the use of this agent as initial therapy.13, 14 If BP control remains suboptimal, then the logical combination would be an ACE inhibitor (or an ARB in intolerant patients) plus a CCB or diuretic, moving to the use of all three if BP is not controlled. In very severe patients, a further diuretic could be added. This algorithmic-type strategy also targets two different age-related aspects of the condition; ACE inhibitors and ARBs can help to regress any structural change and prevent metabolic complications in younger patients, and CCBs or diuretics are primarily aimed at BP-lowering in older patients.

However, we must also consider that many of these recommendations advocate the use of one agent as initial therapy. Given the counter-regulatory hypothesis previously described, we must consider the possibility of advocating combination therapy as the initial choice for the majority of hypertensive patients. Combining BP-lowering therapies could block the counter-regulatory responses at the outset, and increase the prospect of an effective BP-lowering response, irrespective of age, ethnicity, or renin/sodium status. This approach could also result in better long-term control using fewer drugs and minimal adverse effects.

Recently, there has also been some debate on whether to use initial therapy with an ACE inhibitor, an ARB, or even both, particularly in younger patients. Hopefully, the answer to this important question will come from the ONtarget Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Study, in which more than 25,000 high-risk patients have been randomized to receive telmisartan, ramipril, or both, with a follow-up period of 6 years.15, 16, 17 The primary outcome of ONTARGET is a composite of cardiovascular death, stroke, acute myocardial infarction, and hospitalization for congestive heart failure. At the basic level, the outcome of ONTARGET could be affected by two simple differences between these drug classes; the first is duration of action and the second is tolerability.

In the Prospective, Randomized, Investigation of the Safety and efficacy of telMisartan vs. ramipril using Ambulatory BP monitoring (PRISMA I) Trial, 801 patients were randomized to treatment for 14 weeks.18 Telmisartan 80 mg produced a significantly greater reduction in BP during the last 6 hours of dosing (the primary endpoint), and over the entire 24-hour period, than ramipril 10 mg (as shown in Figure 4). The 24-hour duration of action observed with telmisartan will have an important bearing on the outcome of ONTARGET. With respect to tolerability, findings from the GPRDS (United Kingdom General Practice Research Database, 2006), using a sample of 109,454 patients, showed that antihypertensive withdrawal can be quite high. Antihypertensive discontinuation occurred in 20.3% at 6 months and 28.5% at 12 months.19 Overall, ARBs were the better tolerated of all the classes analyzed with the longest median time to discontinuation. Again, higher tolerability with an ARB such as telmisartan could also be reflected in the outcomes of the ONTARGET Trial.

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  • Figure 4. 

    The effect of telmisartan or ramipril on early morning and 24-hour BP control. BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure. Adapted from Williams B, Gosse P, Lowe L, Harper R, on behalf of the PRISMA I Study Group. The prospective, randomized, investigation of the safety and efficacy of telmisartan vs. ramipril using ambulatory blood pressure monitoring (PRISMA I). J Hypertens 2006;24:193–200.18

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Conclusion 

Although there are differences between drugs, it is important to emphasize that BP-lowering remains a key objective of hypertensive treatment. As physicians generally treat later, most patients will require drug combinations. It is interesting to speculate as to whether future guidelines will advocate earlier or initial intervention with combination therapy in order to obtain optimal BP control in the majority of patients. Such an approach would also remove heterogeneity in BP response and may reduce the resistance to drug therapy.

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References 

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 Conflict of interest: none.

PII: S1933-1711(08)00040-5

doi:10.1016/j.jash.2008.03.009

Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S10-S15, July 2008

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