The importance of early antihypertensive efficacy: the role of angiotensin II receptor blocker therapy

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1 (2006) 20, & 2006 Nature Publishing Group All rights reserved /06 $ REVIEW The importance of early antihypertensive efficacy: the role of angiotensin II receptor blocker therapy JN Basile 1 and S Chrysant 2 1 Ralph H Johnson VA Medical Center, Medical University of South Carolina, Charleston, SC, USA and 2 Oklahoma Cardiovascular and Hypertension Center and the University of Oklahoma School of Medicine, Oklahoma City, OK, USA Desirable features of antihypertensive agents include efficacy, tolerability, prolonged duration of action and rapid achievement of target blood pressure (BP). Recent studies have examined the relationship between the onset of antihypertensive effect and cardiovascular events. Data from the Valsartan Antihypertensive Longterm Use Evaluation (VALUE), the Study on Cognition and Prognosis in the Elderly (SCOPE), and the Systolic Hypertension in Europe (Syst-Eur) trials support the hypothesis that the time it takes to reach target BP influences cardiovascular outcomes. VALUE, which compared BP-lowering and clinical event rates between patients treated with the angiotensin II receptor blocker (ARB) valsartan or the calcium channel blocker (CCB) amlodipine as well as between those who achieved immediate or delayed BP control, provides the strongest evidence of this to date. Additional data from SCOPE and Syst-Eur suggest that delays of 3 months to 2 years in starting antihypertensive therapy can increase the risk of certain cardiovascular end points, especially stroke. These data suggest that it may be beneficial to examine the efficacy of antihypertensive agents, not only long term, but also at earlier times to assess the onset and impact of early antihypertensive effect. The ARB olmesartan medoxomil (olmesartan) and the CCB amlodipine were compared in a randomized, double-blind, placebocontrolled clinical trial, which demonstrated that the onset of antihypertensive effect of olmesartan is comparable with that of amlodipine. Another study demonstrated that more patients treated with olmesartan achieved target BPs within 2 weeks of treatment compared with the ARBs losartan, valsartan and irbesartan. (2006) 20, doi: /sj.jhh ; published online 5 January 2006 Keywords: angiotensin II type 1 receptor blockers; calcium channel blockers; blood pressure goal rates; early antihypertensive efficacy Introduction Hypertension (blood pressure (BP)X140/90 mmhg) may affect as many as one billion individuals worldwide and is associated with an increased risk of adverse cardiovascular, cerebrovascular and renal events, including stroke, coronary heart disease, heart failure and end-stage renal disease. 1 3 Suboptimal BP control is considered the number one attributable risk for death worldwide, 4 and early treatment of BP may reduce the incidence, as well as the long-term consequences, of clinical hypertension. 5 European and United States (US) guidelines advocate BP treatment goals of o140/90 mmhg and have encouraged aggressive initiation of therapy Correspondence: Dr JN Basile, Blue Primary Care, Ralph H Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401, USA. jan.basile@med.va.gov Received 17 May 2005; revised 1 September 2005; accepted 3 October 2005; published online 5 January 2006 and treatment to target levels, which will often require therapy with two or more antihypertensive agents. 1,2,6 Patients with diabetes or chronic renal disease require even more intensive treatment to achieve a recommended BP goal of o130/ 80 mmhg. 1,2,7 Despite the effective promulgation of treatment recommendations internationally, the diagnosis and treatment of hypertension is frequently suboptimal. The National Health and Nutrition Examination Survey found that only 31% of patients with hypertension had BP controlled to o140/90 mmhg. 3 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends that patients receiving antihypertensive therapy return for follow-up and adjustment of medication at least monthly until BP goal is attained, and that patients with stage 2 hypertension or complicating comorbid conditions return for follow-up more frequently. 1 More frequent followup early in treatment should expedite BP goal achievement.

2 170 Benefits of antihypertensive therapy with early onset of effect Recently, studies have emerged that examine the relationship between the onset of antihypertensive effect and clinical events. We examined the literature for outcomes studies that discussed patients who achieved early BP control with antihypertensive therapy vs those who did not. The three trials we identified with the greatest detail on this topic were the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, the Study on Cognition and Prognosis in the Elderly (SCOPE), and the Systolic Hypertension in Europe (Syst-Eur) trial. These studies add support to the hypothesis that the time to reach target BP levels influences clinical outcomes. The VALUE trial VALUE compared cardiovascular outcomes in patients randomized to the angiotensin II receptor blocker (ARB) valsartan or the calcium channel blocker (CCB) amlodipine. 8 The trial design included a response-dependent dose titration scheme, which allowed up-titration of amlodipine or valsartan, addition of hydrochlorothiazide (HCTZ), or the addition of other antihypertensive agents (with the exception of other ARBs, CCBs, or angiotensinconverting enzyme (ACE) inhibitors), as necessary, to achieve a target BP of o140/90 mmhg. Patients were titrated from valsartan 80 to 160 mg/day before HCTZ was added; this is worth noting because addition of a diuretic to the initial dose of valsartan would have had a greater effect on BP reduction than doubling the dose of valsartan. 9 In addition, it should be noted that the combination of a CCB and a diuretic does not have the same beneficial effect as adding a diuretic to an ARB. 10 Patients were seen monthly for the first 6 months and then once every 6 months for the duration of the trial. 11 Of the patients in whom BP trends were analyzed, 92% had their previous antihypertensive therapy stopped at randomization. These patients were directly rolled over to either valsartan or amlodipine treatment without a placebo run-in. BP was reduced further in both randomized groups, with greater BP reductions in the amlodipine group, particularly in the early period of the trial (after 1 month of treatment) when the difference in systolic BP (SBP)/diastolic BP (DBP) was 4.0/2.1 mmhg in favour of amlodipine (Po0.0001). 12 In fact, mean SBP and DBP were significantly lower for amlodipine as compared with valsartan (Po0.0001) at every reported time point. 8 Although there was no statistically significant difference in the primary end point (a composite end point of cardiac morbidity and mortality) between treatment groups over a mean follow-up time of 4.2 years, there was a difference in clinical event rates in favour of amlodipine, which was most evident during the first 6 months of treatment, when BP differences between the treatment groups were greatest. 8 Attenuation in the odds ratios was observed in subsequent months when the difference in BP between the two treatment regimens decreased. Figure 1 shows the odds ratios for the primary end point and secondary end points (myocardial infarction, stroke, heart-failure hospitalizations and allcause death) at selected time intervals during the trial. The most appreciable differences in favour of amlodipine early in the trial (as shown by the higher odds ratio) were for stroke and myocardial infarction. The greater number of strokes among valsartantreated patients, compared with amlodipine-treated patients, is likely attributable to the differences in mean BP between these groups (particularly given that 63% of the entire excess of strokes occurred in the first 6 months when mean BP differences between groups were most marked). The differences in rates of myocardial infarction during the early study period also paralleled differences in mean BP between the two treatment groups. It was concluded that achieving prompt BP control within the first several months of the trial, independent of the type of drug used, was the main determinant of event rates. More direct evidence of a beneficial outcome associated with early onset of antihypertensive Figure 1 Differences in BP between treatment groups, and odds ratios for the primary end point, secondary end points and all-cause death during consecutive time periods in the VALUE study. 8 Bars show 95% CI. If necessary, both treatment regimens allowed addition of HCTZ or other antihypertensive agents (with the exception of other ARBs, calcium antagonists or ACE inhibitors) to reach target BP o140/90 mmhg. Reproduced with permission from Elsevier (The Lancet, 2004; 363: ).

3 Figure 2 Hazard ratios (95% CI) for events in immediate responders w vs non-immediate responders using combined data for both valsartan and amlodipine-treated patients in the VALUE study. 13 N ¼ w In patients previously on treatment, no increase in SBP when switched to study drug, and in those not previously treated, a decrease of 10 mmhg or more by 1 month. *Po0.01, **Po0.05 for immediate vss non-immediate responders. effect was found in a subanalysis of the differences in clinical event rates between immediate and non-immediate BP responders. 13 Immediate responders were defined as those patients who, when switched from previous therapy to the initial study drug (92%), had no increase in BP by 1 month, or those patients without prior therapy (8%) who had an initial decrease (at 1 month) in SBP of X10 mmhg. When data for both the valsartan and amlodipine treatment groups were pooled, patients whose BP responded immediately (according to the definition for immediate responders above) were less likely to be at risk of a cardiac event, stroke or death (Figure 2). 13 Overall, after just 1 month of treatment, the BP response predicted events and survival, except for new-onset diabetes mellitus, which was lower with valsartanbased, as compared with amlodipine-based, regimens. 8,13 Although the results of VALUE did not prove its primary hypothesis, that is, that for the same level of BP control, valsartan-based treatment would be superior to amlodipine-based treatment in reduction of cardiac morbidity and mortality, it did draw attention to the importance of early control of BP in regards to cardiovascular outcome. 12,14 Commentary on this trial data noted the importance of prompt BP lowering in patients and stated that stringent initial control of BP should now be an important requirement of treatment. 13,14 The SCOPE trial SCOPE examined cardiovascular events in patients randomized to receive either candesartan or placebo. 15 During the run-in period, any previous antihypertensive medication was standardized to HCTZ 12.5 mg/day, which was maintained throughout the study. If, after 3 months of randomized treatment, SBP remained X160 mmhg or DBP remained X90 mmhg, additional antihypertensive therapy (except other ARBs or ACE inhibitors) could be added. As a consequence of this study design, 84% of patients in the placebo group received antihypertensive therapy (18% HCTZ at baseline and 66% open-label add-on). One interpretation of this study is that the patients in the placebo group were receiving delayed antihypertensive treatment, as they did not begin active therapy until 3 months after those in the candesartan group. The mean difference in BP lowering at the last study visit (mean follow-up 3.7 years) was 3.2/1.6 mmhg in favour of candesartan; mean BP differences between treatment groups during the study were not monitored. Patients in the candesartan group had a non-significant reduction of 10.9% in risk of a major cardiovascular event; however, the risk for non-fatal stroke was significantly reduced by 27.8% in the candesartan group (P ¼ 0.04). This reduction could be a result of the difference in mean BP lowering between treatment groups, but it may also be a consequence of immediate vs delayed antihypertensive therapy and BP control. In addition, a BP-independent stroke-protective effect of candesartan should be considered. In a SCOPE substudy, BP lowering was not significantly different between the treatment regimens in patients with isolated systolic hypertension, but treatment with candesartan resulted in a 42% reduction in the risk of stroke (P ¼ 0.05). 16 Similarly, another substudy found that, despite similar BP-lowering in both treatment groups, candesartan-based therapy was particularly beneficial in patients who entered SCOPE with a previous stroke. 17 The Syst-Eur trial An open-label extension of the double-blind, placebo-controlled Syst-Eur trial in patients 460 years of age who had isolated systolic hypertension invited patients who were still visiting follow-up clinics at the end of the double-blind trial to either start or continue antihypertensive therapy. Those patients who were originally assigned to placebo and started active therapy were defined as receiving delayed antihypertensive treatment, and those who continued from active therapy were defined as receiving immediate treatment. 18 Median follow-up time for the original double-blind trial was 2 years (range 1 97 months). Compared with delayed antihypertensive treatment, immediate treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P ¼ 0.01) and 15% (P ¼ 0.03), respectively; total mortality was reduced by 13% (P ¼ 0.09). 18 In 492 diabetic patients in this study, the corresponding estimates of long-term benefit were more pronounced (60% reduction in stroke, 51% reduction in cardiovascular complications and 38% reduction in total mortality; Po0.05). The study investigators proposed that immediate, compared with delayed, treatment could prevent 17 strokes 171

4 172 or 25 major cardiovascular events per 1000 patients over 6 years. 18 Summary of outcomes trials In summary, these outcomes trials demonstrate the value of early onset of antihypertensive effect in terms of lowering clinical event rates. Prompt BP control reduced the risk of cardiovascular events, 12,13,19 and delays of 3 months to 2 years in starting antihypertensive therapy increased the risk of certain cardiovascular end points, particularly stroke. 15,16,18 Although these observations are interesting, one must bear in mind the caveat that the majority of the patients enrolled in these trials were withdrawn from their current antihypertensive treatment at randomization. This might be more hazardous with regard to clinical events than the initiation and up-titration of therapy in patients receiving antihypertensive treatment for the first time. Studies of onset of antihypertensive effect with ARBs Desirable features of antihypertensive agents include efficacy, tolerability, prolonged duration of action and rapid achievement of target BP goals. Significant differences in the onset of effect of different antihypertensive agents, including ARBs, have been noted in clinical trials Here, we discuss two studies that present data on BP lowering 2 weeks after initiation of therapy with the ARB olmesartan medoxomil (olmesartan). Reports of efficacy of other ARBs at 2 weeks were not found in the literature. Historically, the perception of most physicians is that amlodipine has a relatively early onset of antihypertensive effect whereas most ARBs typically have a later onset of effect. This concept was verified by the VALUE trial, which showed that amlodipine lowered BP significantly more than did the ARB valsartan over the first several months of the trial. 8 A randomized, placebo-controlled, double-blind 8-week study in the US found, in 440 patients with mild to moderate hypertension, that the recommended daily starting dose of the ARB olmesartan (20 mg) produced a reduction in mean BP comparable to that seen with the recommended starting dose of amlodipine (5 mg). 24,25 The primary efficacy variable of this study was the change from baseline in mean 24-h DBP at week 8. Secondary end points and analyses included the change from baseline in mean seated cuff diastolic BP (SeDBP) and systolic BP (SeSBP) and goal rates for SeSBP/SeDBP of o140/90 and o130/85 mmhg at weeks 2, 4 and 8. Although some reduction of BP was observed with placebo, both antihypertensive treatments brought about significant reductions in mean SeDBP and SeSBP at the earliest time point measured (2 weeks) compared with placebo (Po0.001; Table 1). 25 Despite similar decreases in SeSBP/SeDBP with olmesartan and amlodipine, a numerically higher percentage of olmesartan-treated patients achieved the SeSBP/SeDBP goals of o140/90 mmhg and o130/85 mmhg after 2 weeks (Table 1), and these differences reached statistical significance at 4 weeks (data not shown). 26 These data confirm that olmesartan has a similar BP-lowering effect to that of amlodipine. Another multicentre, randomized, double-blind trial conducted in the US compared the efficacy of once-daily starting doses of four ARBs (olmesartan (20 mg), losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg)) for 8 weeks in 588 patients with mild-to-moderate essential hypertension. 27 The primary efficacy variable of this study was the change from baseline in mean SeDBP at week 8. Secondary end points and analyses included the change from baseline in mean SeDBP at weeks 2 and 4, change from baseline in mean SeSBP at weeks 2, 4 and 8, and goal rates for SeSBP/SeDBP of o140/90 and o130/85 mmhg at weeks 2, 4 and 8. Reductions in mean SeDBP and SeSBP after 2 weeks of treatment were greatest with olmesartan compared with losartan, valsartan and irbesartan (Table 2), which led to a significantly greater proportion of olmesartan patients achieving an SeSBP/SeDBP goal of o140/90 mmhg at 2 weeks (Table 2). 26 The proportion of patients achieving an SeSBP/SeDBP goal of o130/85 mmhg (the recommended goal BP for high-risk patients when the study was initiated) 28 was also significantly greater with olmesartan compared with losartan and valsartan at the 2-week time point. Although the results of these trials are interesting, further randomized trials need to be conducted to determine whether attaining BP goal within 2 weeks translates into better clinical outcomes compared with patients who do not attain BP goal as quickly. In addition, although CCBs and ARBs have been shown to have a superior stroke-protective effect compared with beta blockers and ACE inhibitors, 29,30 it remains unclear whether drug selection plays a role in determining long-term outcomes. Table 1 Least-squares mean change from baseline in seated cuff diastolic BP (SeDBP) and systolic BP (SeSBP), 25 and the proportion of patients achieving SeSBP/SeDBP goals after 2 weeks of treatment with olmesartan 20 mg/day or amlodipine 5 mg/day 26 Olmesartan Amlodipine Placebo Mean change in BP (mmhg) SeDBP 10.6* 10.0* 4.5 SeSBP 12.8* 11.9* 4.1 Patients achieving goal BP (%) o140/90 mmhg 26.7 w 19.8 w 6.3 o130/85 mmhg *Pp0.001 vs placebo. w Po0.05 vs placebo.

5 Table 2 Least squares mean change from baseline in seated cuff diastolic BP (SeDBP) and systolic BP (SeSBP), 27 and the proportion of patients achieving SeSBP/SeDBP goals after 2 weeks of treatment with olmesartan 20 mg/day, losartan 50 mg/ day, valsartan 80 mg/day, or irbesartan 150 mg/day 26 Olmesartan Losartan Valsartan Irbesartan Mean change in BP (mmhg) SeDBP 10.7* SeSBP 13.0 w Patients achieving goal BP (%) o140/90 mmhg 29.0 z o130/85 mmhg 9.7 y *Po0.05 vs valsartan and irbesartan and Po vs losartan. w Po0.05 vs irbesartan and Po0.005 vs losartan and valsartan. z Po0.05 vs losartan and irbesartan and P ¼ 0.05 vs valsartan. y Po0.05 vs losartan and valsartan and P ¼ NS vs irbesartan. Rationale for selecting an antihypertensive agent with significant early BP lowering Several lines of reasoning support the use of antihypertensive agents that enable BP goal attainment in a timely fashion. These include the potential benefits in terms of clinical outcomes, practical considerations in relation to prescribing and adjustment of therapy, and the possibility of greater patient acceptance of therapy. One hypothesis for an early antihypertensive onset having a beneficial effect on cardiovascular outcomes is that early and effective BP lowering may interrupt detrimental processes that occur early in cardiovascular disease progression, such as endothelial dysfunction. Endothelial dysfunction is thought to play a major role in cardiovascular disease, being a precursor of structural vascular changes that lead to clinical events. 5,31,32 Accumulating evidence points to the long-term benefits of targeting the endothelium for intervention, and studies of ARBs have noted beneficial effects of these agents on endothelial function. 33,34 Other benefits of ARBs have also been noted, including tolerability, stroke prevention, prevention of diabetes and benefits in patients with albuminuria. 29,30,35,36 Antihypertensive agents demonstrating early BP lowering may also offer clinical benefits to patients who require combination drug therapy to lower BP to recommended levels. Because many patients will require two or more agents to achieve BP goals, JNC 7 recommends the addition of a second drug from a different class when a single agent in adequate doses fails to achieve the goal. 1 Evidence of reductions in BP earlier in therapy may help to effectively guide physicians as to whether up-titration or the addition of another agent is going to be necessary to achieve BP treatment goals. Earlier attainment of BP goals may also allow for a decrease in the number of patient follow-up visits. In addition to the clinical benefits of achieving BP goals (e.g., lower risk of cardiovascular disease), there may be psychological benefits to the patient as well. One study reported that a feeling of hopelessness towards hypertension and frustration with treatment were associated with poor BP control. 37 Although this phenomenon has not been studied directly, BP goal achievement may help reduce these negative feelings and thereby indirectly increase BP control. Additional findings provide further rationale for selecting an initial agent that has the potential to achieve BP goals at an earlier time point in the course of treatment. An examination of 800 men with hypertension over a 2-year period found that many physicians are not aggressive enough in their approach to hypertension and often delay making changes to treatment, even when they are closely monitoring BP levels in their patients. 38 The same study also found that more intensive treatment led to better outcomes in terms of control of hypertension. Another descriptive survey study revealed that clinicians are unwilling to lower BP to target levels because they are satisfied with higher BP levels in their patients. 39 JNC 7 also outlines the problem of clinical inertia in titrating to a goal and recommends several approaches for helping clinicians and patients achieve target goals in a timely fashion. 1 For example, it is recommended that patients receiving antihypertensive therapy return for follow-up and adjustment of medication at least monthly until BP goal is reached, which should help patients to attain goals more rapidly. 1 Conclusions Although the diagnosis and treatment of hypertension in asymptomatic patients is critical, the importance of treating hypertension aggressively to ensure attainment of recommended BP goals is also well established. An early onset of antihypertensive effect has been shown to provide additional advantages in terms of lowering clinical event rates. The VALUE trial, which compared BP-lowering and clinical event rates between patients who achieved immediate vs delayed BP control provides the strongest evidence of this to date. 13 Additional data from other trials 15,16,18 suggest that delays of 3 months to 2 years in starting antihypertensive therapy can increase the risk of certain cardiovascular end points, particularly stroke. Although older guidelines have advocated that patients be started on the lowest dose of an antihypertensive agent and that up-titration and addition of other agents be performed slowly, current data support more aggressive treatment to get patients to BP goal faster. Comparison of olmesartan and amlodipine demonstrated that the onsets of antihypertensive effect of the two agents were similar. 24,25 Another study 173

6 174 demonstrated that more patients treated with olmesartan achieved target BPs within 2 weeks of treatment compared with the ARBs losartan, valsartan and irbesartan. 26,27 However, it remains to be seen whether early attainment of target BPs translates into better clinical outcomes for these patients. Selecting an initial antihypertensive agent that provides a more favourable early antihypertensive effect may overcome existing barriers to therapy, including poor patient acceptance of therapy and clinician inertia in attaining BP targets. An early, significant antihypertensive effect may also permit a more rapid assessment of patient status and efficient adjustment of therapy (e.g. up-titration, addition of other agents), if required. Acknowledgements This work was supported by Sankyo Pharma Inc. References 1 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL et al. 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