Article

Telmisartan in High Cardiovascular Risk Patients

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.

  • Views: 4253

  • Likes: 0

  • Downloads: 26

  • Citations: 1

Average (ratings)
No ratings
Your rating

Abstract

The worldwide morbidity and mortality burden of cardiovascular disease (CVD) is overwhelming and caused by increasing life expectancy and an epidemic of risk factors, including hypertension. Therapeutic options targeting different areas of the renin–angiotensin–aldosterone system (RAAS) to disrupt pathophysiological processes along the cardiovascular continuum are available. Angiotensin-converting enzyme (ACE) inhibitors are first-line treatments for CVD and angiotensin receptor blockers (ARBs) are suitable alternatives. Both ACE inhibitors and ARBs prevent CVD by lowering blood pressure (BP). Additionally, several studies have demonstrated that RAAS blockade can reduce cardiovascular risk beyond what might be expected from BP lowering alone. However, the ARBs are not all equally effective. Telmisartan is a long-lasting ARB that effectively controls BP over the full 24-hour period. Recently, the Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET) study showed that telmisartan reduces cardiovascular events in high cardiovascular risk patients similarly to the gold standard ACE inhibitor ramipril beyond BP lowering alone, but with a better tolerability. Based on the results of the ONTARGET and Telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease (TRANSCEND) studies, telmisartan is indicated for the reduction of cardiovascular morbidity. This article aims to review current guidelines for the management of CVD and consider key data from clinical trials and clinical practice evaluating the role of telmisartan in CVD.

Keywords

Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, cardiovascular continuum, cardiovascular risk, hypertension, telmisartan,

Disclosure:The author has no conflicts of interest to declare.

Received:

Accepted:

DOI:https://doi.org/10.15420/ecr.2012.8.1.10

Correspondence Details:Roland Asmar, 11 bis Boulevard Delessert, 75016 Paris, France. E: ra@cmcv.org

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

The greatest burden of cardiovascular disease (CVD) is due to non-fatal morbidity and its consequences; whereas CVD accounts for approximately 17 million deaths each year worldwide, current estimates indicate that CVD associated with asymptomatic disease and target organ damage as a result of undetected cardiovascular risk factors affects 128 million people worldwide.1,2 Moreover, the worldwide incidence of CVD is increasing, not only in line with increasing life expectancy, but also because of an escalating epidemic of risk factors (including hypertension, obesity, diabetes, high cholesterol levels and smoking) that is not restricted to the developed world.2,3 Indeed, hypertension, acknowledged in a World Health Organization report as being among the most significant avoidable reasons for early mortality, affected 972 million people worldwide in 2000, and it is estimated that it will affect 1.56 billion people by 2025.4 Only 2–7 % of individuals are free from CVD risk factors, and >70 % of at-risk individuals have multiple risk factors that act synergistically to potentiate the total risk.1,5,6

The progression of CVD can be thought of as a continuum, from the presence of risk factors to the development of organ damage and diseases – such as atherosclerosis, left ventricular hypertrophy (LVH), coronary artery disease, myocardial infarction (MI), stroke, cardiovascular remodelling and heart failure – and ultimately to death (see Figure 1).7,8 This has led to the idea that intervention at any stage along the CVD continuum can disrupt the pathophysiological process and prevent disease progression.7 A key player in CVD is the renin–angiotensin–aldosterone system (RAAS).9–11 Activation of the RAAS results in the accumulation of the primary effector peptide angiotensin II, which, via angiotensin type I (AT1) receptors, causes inflammation, vasoconstriction, thrombosis, fibrosis and superoxide formation.12 Thus the RAAS has been implicated in thepathophysiological processes underlying CVD10,12 and is a logical target for disruption of the CVD continuum.13,14

Two different classes of agents target the production of angiotensin:angiotensin-converting enzyme (ACE) inhibitors and angiotens in receptor blockers (ARBs).15,16 The principal indication of both drug classes is to alleviate hypertension. Multiple clinical trials have also evaluated different ACE inhibitors and ARBs for preventing cardiovascular-related events – with varying degrees of success. Among these clinical trials, some of the most important ones are (see also Table 1):

  • the Heart outcomes prevention evaluation (HOPE) study;17
  • the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) study;18
  • the Prevention of events with angiotensin-converting enzyme inhibitor therapy (PEACE) study;19
  • the Nateglinide and valsartan in impaired glucose toleranceoutcomes research (NAVIGATOR) study;20
  • the Losartan intervention for endpoint reduction in hypertension (LIFE) study;21
  • the Randomized olmesartan and diabetes microalbuminuria prevention study (ROADMAP);22
  • the Atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE I) study;23
  • the Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET);24
  • the Telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease (TRANSCEND);25 and
  • the Telmisartan in haemodialysis patients with chronic heart failure study.26

Furthermore, several of these studies demonstrated that RAAS blockade can reduce cardiovascular risk beyond what might be expected from blood pressure (BP) lowering alone.24,25

The ARB telmisartan is indicated in Europe as monotherapy for both the treatment of hypertension in adults and the reduction of cardiovascular morbidity in patients with manifest atherothrombotic CVD (including history of coronary heart disease, stroke or peripheral arterial disease) as well as in patients with type 2 diabetes mellitus and documented target organ damage.27 This article aims to review current guidelines for the management of CVD and consider key data from clinical trials and clinical practice evaluating the role of telmisartan in CVD.

International Guidelines Recommendations
Hypertension is a primary risk factor for CVD28 and antihypertensive therapy is usually required in addition to lifestyle modifications. Guidelines from the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) favour the use of ACE inhibitors post-MI and in patients with hypertension, heart failure, left ventricular dysfunction, diabetic and non-diabetic nephropathy, LVH, carotid atherosclerosis, proteinuria or microalbuminuria, atrial fibrillation (AF) and metabolic syndrome.29

Moreover, the joint ESH/ESC guidelines favour the direct use of ARBs, not only for hypertension but also post-MI and for heart failure, diabetic nephropathy, proteinuria or microalbuminuria, LVH, AF and metabolic syndrome.29 In a more recent version of the guidelines, these preferences have not changed.30 The ESH/ESC guidelines also favour ARBs in those patients in whom there is an indication for, but who are intolerant to, ACE inhibitors.29 Intolerance to ACE inhibitors is usually due to cough (which may affect up to 35 % of patients) or angiooedema (which could potentially be life-threatening).31–34

Pharmacodynamic and Pharmacokinetic Profile of Telmisartan
Detailed reviews on the properties of telmisartan have been published elsewhere.35–38 Briefly, telmisartan is a potent and selective AT1 antagonist with no apparent affinity for angiotensin type II (AT2) receptors or ACE. After oral administration, maximum plasma levels occur within 0.5–2 hours and peak bioavailability is 57 %. It is almost exclusively eliminated in the faeces (>98 %) and has an elimination half-life of 20–24 hours. This is the longest of all the currently available ARBs and makes a once-daily dosing regimen with telmisartan sufficient for effective lowering of BP over the full 24-hour period. Typical doses are 40 mg or 80 mg once daily, either as monotherapy or in combination with additional antihypertensives if BP is inadequately controlled.

Clinical Uses of Telmisartan in Cardiovascular Disease
Hypertension and beyond Blood Pressure Lowering
The circadian pattern of BP is well known, with a steady increase in BP occurring in the early hours.39,40 Cardiovascular events also exhibit a circadian rhythm with peak occurrence in the first few hours after wakening that may be caused by the early morning surge in BP.39,40 The antihypertensive effectiveness of telmisartan, due to its ability to reduce BP over the full 24-hour period, was evaluated in a meta-analysis of five trials involving a total of 1,566 patients.41 Compared with the first generation ARBs losartan and valsartan, telmisartan offered greater and more consistent systolic and diastolic BP lowering during the morning period (see Figure 2) and over the 24-hour period as a whole.41 Additional, separate trials have demonstrated that telmisartan is more effective in controlling BP than either valsartan or losartan over the full 24-hour period.42–46 Moreover, telmisartan is better able to control BP than valsartan in the event of a missed dose.47 Indirect comparisons indicate that telmisartan is at least as effective as the newer generation ARBs, including candesartan, irbesartan and olmesartan, in reducing BP.48 The effectiveness of telmisartan in reducing BP has also been compared with that of ACE inhibitors. Telmisartan controlled BP more effectively than ramipril during the morning period and over the 24-hour period as a whole,49 and was also more effective than enalapril50 and perindopril,51 and at least as effective as lisinopril.52

Metabolism
Metabolic syndrome is not clearly defined but refers to a cluster of interrelated metabolic risk factors for CVD, including insulin resistance or glucose intolerance, visceral obesity, dyslipidaemia and hypertension.53,54 The involvement of hypertension suggests that drugs that target the RAAS may be of therapeutic benefit, particularly ARBs. Telmisartan improved insulin sensitivity in patients with metabolic syndrome compared with valsartan55 or losartan.56 Furthermore, telmisartan was more effective than irbesartan at improving metabolic parameters in diabetic patients with or without hypertension.57,58 Recently, a meta-analysis of two randomised, double-blind, placebo-controlled trials with telmisartan, in which the incidence of new onset diabetes was measured as a pre-specified secondary endpoint, has been performed. This meta-analysis of the TRANSCEND and Prevention regimen for effectively avoiding second strokes (PROFESS) trials indicates that telmisartan can reduce the risk of new onset diabetes by approximately 16 % compared with placebo in high cardiovascular risk patients without heart failure. This antidiabetic effect of telmisartan is similar in its overall magnitude to that observed with ACE inhibitors in placebo-controlled clinical trials in patients without heart failure.59

Left Ventricular Hypertrophy
A sub-analysis of data from the ONTARGET and TRANSCEND studies examined the effects of telmisartan on LVH. The prevalence of LVH at entry into the TRANSCEND study was 12.7 % and treatment with telmisartan reduced prevalence to 9.9 % after five years, whereas prevalence remained at 12.8 % with placebo.60 The rate of new onset of LVH was lower in the telmisartan group than in the placebo group (5.0 % versus 7.9 %, respectively [p<0.001]).25 In the TRANSCEND study, telmisartan statistically significantly reduced LVH overall by 21 % (p=0.0017) versus placebo. The rate of new onset of LVH was statistically reduced by 37 % (p=0.0001) in the telmisartan group versus placebo. LVH regression was similar in both groups. At the end of the ONTARGET study, the prevalence of LVH was lower for telmisartan (9.7 %) than for both ramipril (10.5 %) and combined therapy (10.2 %), but not significantly so.60 It is important to note that new onset of LVH was associated with a higher risk of the primary outcome. The therapeutic equivalence of telmisartan and ramipril was also demonstrated by a decrease in left ventricular mass (LVM) as measured by cardiac magnetic resonance imaging (MRI) in a subgroup of the ONTARGET study.61 The ability of telmisartan to decrease LVM has also been demonstrated in separate studies.62,63

Renal Function
In the ONTARGET study, rates of renal impairment were similar in the telmisartan (10.2 %) and ramipril (10.6 %) groups, but significantly greater in the combination group (13.5 %).24 More specific analysis of renal outcomes demonstrated an equivalence between telmisartan and ramipril for the composite primary outcome of dialysis, doubling of serum creatinine and death (13.4 % versus 13.5 %, respectively) and an increased rate for dual therapy (14.5 %).64 Telmisartan was also associated with lower rates of albuminuria than ramipril.64 A subgroup analysis of patients from the ONTARGET and TRANSCEND studies with low glomerular filtration rates and elevated albuminuria demonstrated no benefits of telmisartan over ramipril or placebo for the primary renal composite outcome of dialysis or doubling of creatinine levels.65 The Incipient to overt: angiotensin II receptor blocker, telmisartan, investigation on type 2 diabetic nephropathy (INNOVATION) study demonstrated the benefit of telmisartan compared with placebo for preventing the transition from incipient to overt nephropathy in Japanese patients with type 2 diabetes66 and for preventing the progression to microalbuminuria.67 Moreover, the non-inferiority of telmisartan compared to a different ACE inhibitor, enalapril, for renoprotection in patients with type 2 diabetes and nephropathy has been demonstrated in the Diabetes exposed to telmisartan and enalapril (DETAIL) study.68

The AMADEO (A trial to compare telmisartan 40 mg titrated to 80 mg versus losartan 50 mg titrated to 100 mg in hypertensive type 2 diabetic patients with overt nephropathy) and VIVALDI (Investigate the efficacy of telmisartan versus valsartan in hypertensive type 2 diabetic patients with overt nephropathy) studies evaluated the effect of telmisartan on macroalbuminuria. In the AMADEO study, telmisartan reduced the urinary protein:creatinine ratio significantly more than losartan after 52 weeks (29.8 % versus 21.4 % frombaseline, respectively [p=0.027]), despite similar BP control.69 In the VIVALDI study, telmisartan 80 mg provided identical reductions in urinary protein excretion (33 % from baseline) to valsartan 160 mg,70 but urinary 8-iso-prostaglandin F2α levels decreased by 14 % with telmisartan and by 7 % with valsartan (p=0.040).

Atrial Fibrillation
Data from the ONTARGET study demonstrated equivalence for the onset of new AF between telmisartan (6.7 %), ramipril (6.9 %, relative risk 0.97, 95 % confidence interval [CI] 0.86–1.09) and dual therapy (6.5 %, relative risk 0.96, 95 % CI 0.85–1.07).24 Similarly, the TRANSCEND study demonstrated equivalence between telmisartan (6.4 %) and placebo (6.3 %) (hazard ratio 1.02, 95 % CI 0.83–1.26, p=0.829) for the onset of AF.25 However, telmisartan is effective in preventing AF recurrence in hypertensive patients with a history of AF71 and more effective than ramipril in reducing the recurrence (telmisartan 12.9 %, p<0.01 versus amlodipine and p<0.05 versus ramipril; ramipril 25.5 %, p<0.01 versus amlodipine) and severity of AF in hypertensive patients with metabolic syndrome.72

Endothelial Function and Arterial Stiffness
The endothelium is a principal regulator of vascular homoeostasisand endothelial dysfunction is thought to play a role in hypertension-associated vascular change.73 Telmisartan had more favourable effects on functional parameters associated with endothelial function than valsartan in hypertensive patients, despite similar BP-lowering effects.74 Telmisartan and ramipril had similar effects on renal endothelial function in patients with hypertension and type 2 diabetes, but, in the Telmisartan versus ramipril on renal endothelium function in type 2 diabetes (TRENDY) study, telmisartan also improved resting renal plasma flow whereas ramipril did not.75 In addition, telmisartan reduced arterial stiffness to a greater extent than placebo in hypertensive patients with type 2 diabetes.76

Inflammation
Angiotensin promotes atherosclerosis through pro-inflammatory mechanisms,77 therefore RAAS blockers may be therapeutically beneficial in CVD. Telmisartan has been shown to reduce markers of inflammation, such as C-reactive protein and interleukin-6, at least as effectively as ACE inhibitors, including ramipril, or other ARBs, such as valsartan and olmesartan, in hypertensive or diabetic patients.78–81

Cardiovascular Risk Reduction in High-risk Patients
In addition to the ability of ARBs to reduce BP, the Candesartan in heart failure assessment of reduction in mortality and morbidity (CHARM Alternative) study demonstrated their ability to reduce cardiovascular death and hospitalisation for congestive heart failure in patients with previous heart failure.82 The ability of telmisartan to reduce cardiovascular morbidity and mortality in high-risk patients with CVD or diabetes mellitus and end-organ damage – but not heart failure – was examined in the ONTARGET study in a population similar to that studied in the HOPE trial (see Table 1).83 The primary outcome was a composite of death from cardiovascular causes, MI, stroke or hospitalisation due to heart failure. A total of 25,577 patients were followed until a primary event occurred or until the end of the study (median 56 months).24 At study onset, 85 % of patients had CVD, 69 % had hypertension and 38 % had diabetes. Comparison of the three treatment groups (telmisartan alone, telmisartan with ramipril and ramipril alone) showed that the rate of primary events was similar for patients receiving telmisartan (16.7 %) or ramipril (16.5 %), with no additional benefit from combined therapy (16.3 %) (see Figure 3).

Moreover, the telmisartan group had significantly lower rates of cough (1.1 % [p<0.001]) and angiooedema (0.1 % [p=0.01]) than the ramipril group (4.2 % and 0.3 %, respectively) and than the combination group (4.6 % and 0.2 %, respectively). It was associated with significantly fewer discontinuations of therapy than in the ramipril and combination groups (23 % versus 24.5 % [p=0.02] and 29.3 %, respectively).24 Despite offering similar cardiovascular prevention to ramipril, telmisartan therefore has a better overall efficacy:tolerability ratio.84

In the companion TRANSCEND trial, a total of 5,926 patients were randomised to telmisartan or placebo and the primary outcome was a composite of cardiovascular death, MI, stroke or hospitalisation for heart failure.83 The rate of primary events favoured telmisartan (15.7 %) over placebo (17.0 %), but not significantly so.25 However, telmisartan did significantly reduce the rate of the secondary outcome, a composite of cardiovascular death, MI and stroke (which was the primary endpoint in the HOPE study) compared with placebo (13.0 % versus 14.8 %, respectively [p=0.048]). The rate of permanent discontinuations again was in favour of telmisartan (21.6 %) over placebo (23.7 %), but not significantly so. Telmisartan therefore offers cardiovascular prevention compared with placebo, particularly from cardiovascular death, MI or stroke.

Safety and Tolerability of, and Adherence to, Telmisartan
In a retrospective analysis of 50 double-blind studies with a total of 8,023 hypertensive patients, telmisartan monotherapy was associated with a lower incidence of adverse events (AEs) (2.03 per patient-year) compared with placebo (2.73 per patient-year).85 When double-blind and open-label studies were evaluated (total 16,416 patients), discontinuation of treatment due to AEs was similar between the telmisartan monotherapy (4.5 %) and placebo (4.6 %) groups.85 Moreover, in a post-marketing survey of 19,870 patients with a substantial proportion at higher risk of AEs receiving telmisartan, only 1.9 % of patients reported an AE and global tolerability was rated as good or very good by 96.8 % of patients.86 In terms of adherence to treatment, in a cohort of hypertensive patients, the highest levels of treatment persistence were observed in those patients receiving ARBs (18.8 %), including telmisartan as monotherapy. Treatment adherence to ACE inhibitors was 11.4 %. Telmisartan was well tolerated and showed favourable safety.87

Discussion
In selecting a treatment to prevent CVD, consideration should be given to agents whose actions extend beyond BP lowering. In addition to treating hypertension, telmisartan is indicated for cardiovascular prevention. However, target BP levels have yet to be clearly defined and aggressive antihypertensive treatment may be associated with increased adverse outcomes; for instance, the incidences of all the individual components of the primary composite endpoint from the ONTARGET study, except stroke, were associated with a J-shaped curve in relation to BP.88 Nonetheless, the ONTARGET study results show that treatment with telmisartan confers significant benefits to a wide range of high-risk CVD patients, including those with manifest atherothrombotic disease and diabetes with end-organ damage, who represent the majority of patients seen in primary and secondary care practices worldwide. Moreover, the findings from the TRANSCEND study demonstrate that telmisartan is a suitable therapeutic alternative to ramipril in those individuals who are intolerant to ACE inhibitors. However, the cardiac and renal preventive effects of telmisartan may not be solely explained by its antihypertensive action, but by additional benefits arising from its effects on markers of inflammation, metabolic factors and endothelial dysfunction.

The prolonged action of telmisartan relative to other ARBs, its favourable safety, tolerability and good patient adherence make it an attractive option for the long-term treatment of hypertension and reduction of cardiovascular morbidity compared with agents showing equivalent cardiovascular preventive effects. Telmisartan is the only ARB shown to offer cardiovascular morbidity prevention in patients with complicated diabetes or evidence of coronary artery disease without heart failure. Based on the outcomes of the ONTARGET and TRANSCEND trials, telmisartan can be considered as an effective treatment strategy for CVD prevention in patients at high vascular risk.

Prescribers have to consider not only efficacy but also tolerability, and therefore think in terms of the efficacy:tolerability ratio. In large-scale trials, ARBs, and mainly telmisartan, have been shown to be as efficient as ACE inhibitors and their gold standard, ramipril. Elsewhere, these same trials have shown advantages of telmisartan over ramipril in terms of tolerability and drug discontinuation. Therefore consideration of the efficacy:tolerability ratio favours ARBs, including telmisartan.

It has been suggested that results observed with telmisartan may be considered as a “class effect” and therefore could be extrapolated to the other ARBs. Such extrapolation is contradictory to the available data. Telmisartan has unique pharmacological properties, which differ from those of other ARBs and are likely to have clinical implications. Furthermore, results from large clinical trials using different ARBs may support the available data, and have led to different indications (see Table 2). Finally, results from the ONTARGET study suggested no additional benefit from the combination of telmisartan and ramipril, in comparison to ramipril monotherapy. It should be noted that extrapolation of these negative results to other combinations and to other populations would be arbitrary and hazardous. Further studies using other combinations of two inhibitors of the RAAS, such as a direct renin inhibitor with an ARB or anti-aldosterone in different populations are needed.

Future Developments
The worldwide burden of CVD will further increase, principally due to the inadequate implementation of prevention approaches, the rising obesity epidemic, the ageing population and the existence of cardiovascular risk factors. The ONTARGET study showed that telmisartan offers similar cardiovascular prevention to ramipril in high-risk patients, while being better tolerated and associated with greater treatment adherence, which is likely to be significant in the future long-term management of cardiovascular risk. Further analysis of the ONTARGET study findings may establish the role of therapy in the long-term decrease of overall cardiovascular burden, in particularabsolute risk reduction, and may also help in the development of risk estimation scores populated with real-life data. Further studies of ACE inhibitors and ARBs in the development of new-onset diabetes and in patients with metabolic syndrome are still necessary. With respect to telmisartan, trials are currently in progress or recruiting to assess its efficacy in AF and stroke.89,90 Outcomes from these studies will allow improved distinction between ARBs in terms of their efficacy in decreasing cardiovascular risk in hypertensive patients and in those without hypertension. In the future, clinicians will most likely be learning much more about the many functions of ARBs beside their antagonism of the angiotensin II receptor.

References

  1. Dahlof B, Cardiovascular disease risk factors: epidemiology and risk assessment, Am J Cardiol, 2010;105:3A–9A.
    Crossref | PubMed
  2. Ezzati M, Vander Hoorn S, Lawes CM, et al., Rethinking the “diseases of affluence” paradigm: global patterns of nutritional risks in relation to economic development, PLoS Med, 2005;2:e133.
    Crossref | PubMed
  3. Bhatt DL, Steg PG, Ohman EM, et al., International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis, JAMA, 2006;295:180–9.
    Crossref | PubMed
  4. Kearney PM, Whelton M, Reynolds K, et al., Global burden of hypertension: analysis of worldwide data, Lancet, 2005;365:217–23.
    Crossref | PubMed
  5. Wilson PW, Kannel WB, Silbershatz H, D’Agostino RB, Clustering of metabolic factors and coronary heart disease, Arch Intern Med, 1999;159:1104–9.
    Crossref | PubMed
  6. Zanchetti A, The hypertensive patient with multiple risk factors. Is treatment really so difficult?, Am J Hypertens, 1997;10(10 Pt 2):223S–229S.
    Crossref | PubMed
  7. Dzau V, Braunwald E, Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement, Am Heart J, 1991;121:1244–63.
    Crossref | PubMed
  8. Dzau VJ, Antman EM, Black HR, et al., The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease), Circulation, 2006;114:2850–70.
    Crossref | PubMed
  9. Probstfield JL, O’Brien KD, Progression of cardiovascular damage: the role of renin-angiotensin system blockade, Am J Cardiol, 2010;105:10A–20A.
    Crossref | PubMed
  10. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM,Renin-angiotensin system and cardiovascular risk, Lancet, 2007;369:1208–19.
    Crossref | PubMed
  11. Ferrario CM, Strawn WB, Role of the renin-angiotensinaldosterone system and proinflammatory mediators in cardiovascular disease, Am J Cardiol, 2006;98:121–8.
    Crossref | PubMed
  12. Mehta PK, Griendling KK, Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system, Am J Physiol Cell Physiol, 2007;292:C82–97.
    Crossref | PubMed
  13. Werner C, Poss J, Bohm M, Optimal antagonism of the Renin-Angiotensin-aldosterone system: do we need dual or triple therapy?, Drugs, 2010;70:1215–30.
    Crossref | PubMed
  14. Hoogwerf BJ, Renin-angiotensin system blockade and cardiovascular and renal protection, Am J Cardiol, 2010;105(1 Suppl.):30A–5A.
    Crossref | PubMed
  15. Burnier M, Brunner H, Angiotensin II receptor antagonists,Lancet, 2000;355:637–45.
    Crossref | PubMed
  16. McFarlane SI, Kumar A, Sowers JR, Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease, Am J Cardiol, 2003;91:30H–37H.
    Crossref | PubMed
  17. Yusuf S, Sleight P, Pogue J, et al., Effects of an angiotensinconverting- enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators, N Engl J Med, 2000;342:145–53.
    Crossref | PubMed
  18. Fox KM, Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronaryartery disease: randomised, double-blind, placebocontrolled, multicentre trial (the EUROPA study), Lancet, 2003;362:782–8.
    Crossref | PubMed
  19. Braunwald E, Domanski MJ, Fowler SE, et al., Angiotensinconverting- enzyme inhibition in stable coronary artery disease, N Engl J Med, 2004;351:2058–68.
    Crossref | PubMed
  20. McMurray JJ, Holman RR, Haffner SM, et al., Effect of valsartan on the incidence of diabetes and cardiovascular events, N Engl J Med, 2010;362:1477–90.
    Crossref | PubMed
  21. 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;359:995–1003.
    Crossref | PubMed
  22. Haller H, Ito S, Izzo JL Jr, et al., Olmesartan for the delay orprevention of microalbuminuria in type 2 diabetes, N Engl J Med, 2011;364:907–17.
    Crossref | PubMed
  23. Yusuf S, Healey JS, Pogue J, et al., Irbesartan in patients with atrial fibrillation, N Engl J Med, 2011;364:928–38.
    Crossref | PubMed
  24. Yusuf S, Teo KK, Pogue J, et al., Telmisartan, ramipril, or both in patients at high risk for vascular events, N Engl J Med, 2008;358:1547–59.
    Crossref | PubMed
  25. Yusuf S, Teo K, Anderson C, et al., Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensinconverting enzyme inhibitors: a randomised controlled trial, Lancet, 2008;372:1174–83.
    Crossref | PubMed
  26. Cice G, Di Benedetto A, D’Isa S, et al., Effects of telmisartan added to Angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure a double-blind, placebo-controlled trial, J Am Coll Cardiol, 2010;56:1701–8.
    Crossref | PubMed
  27. European Medicines Agency, Micardis (telmisartan), European Public Assessment Report product information. Available at: www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/ human/medicines/000209/human_med_000901.jsp&mid=W C0b01ac058001d124 (accessed 16 December 2011).
  28. Kannel WB, Blood pressure as a cardiovascular risk factor. Prevention and treatment, JAMA, 1996;275:1571–6.
    Crossref | PubMed
  29. Mancia G, De Backer G, Dominiczak A, et al., 2007 guidelines for the management of arterial hypertension. The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), J Hypertens,2007;25:1105–87.
    Crossref | PubMed
  30. Mancia G, Laurent S, Agabiti-Rosei E, et al., Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document, J Hypertens, 2009;27:2121–58.
    Crossref | PubMed
  31. Dicpinigaitis PV, Angiotensin-converting enzyme inhibitorinducedcough: ACCP evidence-based clinical practice guidelines, Chest, 2006;129:169S–173S.
    Crossref | PubMed
  32. Israili ZH, Hall WD, Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy, Ann Intern Med, 1992;117:234–42.
    Crossref | PubMed
  33. Dykewicz MS, Cough and angioedema from angiotensinconverting enzyme inhibitors: new insights into mechanisms and management, Curr Opin Allergy Clin Immunol, 2004;4:267–70.
    Crossref | PubMed
  34. Weber MA, Messerli FH, Angiotensin-converting enzymeinhibitors and angioedema: estimating the risk, Hypertension, 2008;51:1465–7.
    Crossref | PubMed
  35. Battershill AJ, Scott LJ, Telmisartan: a review of its use in the management of hypertension, Drugs, 2006;66:51–83.
    Crossref | PubMed
  36. Deppe S, Böger RH, Weiss J, Benndorf RA, Telmisartan: a review of its pharmacodynamic and pharmacokinetic properties, Expert Opin Drug Metab Toxicol, 2010;6:863–71.
    Crossref | PubMed
  37. Sharpe M, Jarvis B, Goa KL, Telmisartan: a review of its use in hypertension, Drugs, 2001;61:1501–29.
    Crossref | PubMed
  38. Burnier M, Telmisartan: a different angiotensin II receptor blocker protecting a different population?, J Int Med Res, 2009;37:1662–79.
    Crossref | PubMed
  39. Redon J, The normal circadian pattern of blood pressure: implications for treatment, Int J Clin Pract Suppl, 2004;(145):3–8.
    Crossref | PubMed
  40. Weber MA, The 24-hour blood pressure pattern: does it have implications for morbidity and mortality?, Am J Cardiol, 2002;89(Suppl. 2A):27A–33A.
    Crossref | PubMed
  41. Neutel J, Smith DH, Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database, J Clin Hypertens (Greenwich), 2003;5:58–63.
    Crossref | PubMed
  42. Ding PY, Chu KM, Chiang HT, Shu KH, A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients, Int J Clin Pract Suppl, 2004;(145):16–22.
    Crossref | PubMed
  43. Mallion J, Siche J, Lacourciere Y, ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patientswith mild-to-moderate hypertension, J Hum Hypertens, 1999;13:657–64.
    Crossref | PubMed
  44. Smith DH, Cramer MJ, Neutel JM, et al., Comparison of telmisartan versus losartan: meta-analysis of titration-toresponsestudies, Blood Press Monit, 2003;8:111–7.
    Crossref | PubMed
  45. Bakris G, Comparison of telmisartan vs. valsartan in the treatment of mild to moderate hypertension using ambulatory blood pressure monitoring, J Clin Hypertens (Greenwich), 2002;4:26–31.
    Crossref | PubMed
  46. White WB, Lacourciere Y, Davidai G, Effects of the angiotensin II receptor blockers telmisartan versus valsartan
    Crossref | PubMed
  47. Lacourciere Y, Krzesinski JM, White WB, et al., Sustained antihypertensive activity of telmisartan compared with valsartan, Blood Press Monit, 2004;9:203–10.
    Crossref | PubMed
  48. Nixon RM, Muller E, Lowy A, Falvey H, Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach, Int J Clin Pract,2009;63:766–75.
    Crossref | PubMed
  49. Williams B, Gosse P, Lowe L, Harper R, The prospective, randomized investigation of the safety and efficacy of telmisartan versus ramipril using ambulatory blood pressure monitoring (PRISMA I), J Hypertens, 2006;24:193–200.
    Crossref | PubMed
  50. Alcocer L, Fernandez-Bonetti P, Campos E, et al., Clinical efficacy and safety of telmisartan 80 mg once daily compared with enalapril 20 mg once daily in patients with mild-to-moderate hypertension: results of a multicentre study, Int J Clin Pract Suppl, 2004;(145):23–8.
    Crossref | PubMed
  51. Nalbantgil I, Nalbantgil S, Ozerkan F, et al., The efficacy of telmisartan compared with perindopril in patients with mild-tomoderate hypertension, Int J Clin Pract Suppl, 2004;(145):50–4.
    Crossref | PubMed
  52. Stergiou GS, Efstathiou SP, Roussias LG, Mountokalakis TD, Blood pressure- and pulse pressure-lowering effects, trough:peak ratio and smoothness index of telmisartan compared with lisinopril, J Cardiovasc Pharmacol, 2003; 42:491–6.
    Crossref | PubMed
  53. Wilson PWF, D’Agostino RB, Parise H, et al., Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus, Circulation, 2005;112:3066–72.
    Crossref | PubMed
  54. Alberti KGMM, Eckel RH, Grundy SM, et al., Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity, Circulation, 2009;120:1640–5.
    Crossref | PubMed
  55. Ichikawa Y, Comparative effects of telmisartan and valsartan on insulin resistance in hypertensive patients with metabolic syndrome, Intern Med, 2007;46:1331–6.
    Crossref | PubMed
  56. Vitale C, Mercuro G, Castiglioni C, et al., Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome, Cardiovasc Diabetol, 2005;4:6.
    Crossref | PubMed
  57. Derosa G, Fogari E, D’Angelo A, et al., Metabolic effects of telmisartan and irbesartan in type 2 diabetic patients with metabolic syndrome treated with rosiglitazone, J Clin Pharm Ther, 2007;32:261–8.
    Crossref | PubMed
  58. Negro R, Formoso G, Hassan H, The effects of irbesartan and telmisartan on metabolic parameters and blood pressure in obese, insulin resistant, hypertensive patients, J Endocrinol Invest, 2006;29:957–61.
    Crossref | PubMed
  59. Kurtz TW, Klein U, Next generation multifunctional angiotensin receptor blockers, Hypertens Res, 2009;32:826–34.
    Crossref | PubMed
  60. Verdecchia P, Sleight P, Mancia G, et al., Effects of telmisartan, ramipril, and their combination on left ventricular hypertrophy in individuals at high vascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease, Circulation, 2009;120:1380–9.
    Crossref | PubMed
  61. Cowan BR, Young AA, Anderson C, et al., Left ventricular mass and volume with telmisartan, ramipril, or combination in patients with previous atherosclerotic events or with diabetes mellitus (from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial [ONTARGET]), Am J Cardiol, 2009;104:1484–9.
    Crossref | PubMed
  62. Galzerano D, Tammaro P, Cerciello A, et al., Freehand threedimensional echocardiographic evaluation of the effect of telmisartan compared with hydrochlorothiazide on left ventricular mass in hypertensive patients with mild-tomoderate hypertension: a multicentre study, J Hum Hypertens, 2004;18:53–9.
    Crossref | PubMed
  63. Galzerano D, Tammaro P, del Viscovo L, et al., Threedimensional echocardiographic and magnetic resonance assessment of the effect of telmisartan compared with carvedilol on left ventricular mass a multicenter, randomized, longitudinal study, Am J Hypertens, 2005;18(12 Pt 1):1563–9.
    Crossref | PubMed
  64. Mann JF, Schmieder RE, McQueen M, et al., Renal outcomes with telmisartan, ramipril, or both, in people at high vascularrisk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial, Lancet, 2008;372:547–53.
    Crossref | PubMed
  65. Tobe SW, Clase CM, Gao P, et al., Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies, Circulation, 2011;123:1098–1107.
    Crossref | PubMed
  66. Makino H, Haneda M, Babazono T, et al., Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes, Diabetes Care, 2007;30:1577–8.
    Crossref | PubMed
  67. Makino H, Haneda M, Babazono T, et al., Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post-hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION)study, Hypertens Res, 2008;31:657–64.
    Crossref | PubMed
  68. Barnett AH, Bain SC, Bouter P, et al., Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy, N Engl J Med, 2004;351:1952–61.
    Crossref | PubMed
  69. Bakris G, Burgess E, Weir M, et al., Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy, Kidney Int, 2008;74:364–9.
    Crossref | PubMed
  70. Galle J, Schwedhelm E, Pinnetti S, et al., Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy, Nephrol Dial Transplant, 2008;23:3174–83.
    Crossref | PubMed
  71. Galzerano D, Conforti G, Breglio R, et al., Abstract 2521: A Multicentre Randomized Study comparing Efficacy Of Telmisartan versus Carvedilol In Preventing Atrial Fibrillation Recurrence In Hypertensive Patients, Circulation, 2007;116(Suppl. II):556–7.
  72. Fogari R, Mugellini A, Zoppi A, et al., Effect of Telmisartan and Ramipril on Atrial Fibrillation Recurrence and Severity in Hypertensive Patients With Metabolic Syndrome and Recurrent Symptomatic Paroxysmal and Persistent Atrial Fibrillation, J Cardiovasc Pharmacol Ther, 2011, 18 February [Epub ahead of print].
  73. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA, The clinical implications of endothelial dysfunction, J Am Coll Cardiol, 2003;42:1149–60.
    Crossref | PubMed
  74. Tomiyama H, Yamada J, Koji Y, et al., Effect of telmisartan on forearm postischemic hyperemia and serum asymmetric dimethylarginine levels, Am J Hypertens, 2007;20:1305–11.
    Crossref | PubMed
  75. Schmieder RE, Delles C, Mimran A, et al., Impact of telmisartan versus ramipril on renal endothelial function in patients with hypertension and type 2 diabetes, Diabetes Care, 2007;30:1351–6.
    Crossref | PubMed
  76. Asmar R, Gosse P, Topouchian J, et al., Effects of telmisartan on arterial stiffness in Type 2 diabetes patients with essential hypertension, J Renin Angiotensin Aldosterone Syst, 2002;3:176–80.
    Crossref | PubMed
  77. Jacoby DS, Rader DJ, Renin-angiotensin system and atherothrombotic disease. From genes to treatment, Arch Intern Med, 2003;163:1155–64.
    Crossref | PubMed
  78. Koulouris S, Symeonides P, Triantafyllou K, et al., Comparison of the effects of ramipril versus telmisartan in reducing serum levels of high-sensitivity C-reactive protein and oxidized low-density lipoprotein cholesterol in patients with type 2 diabetes mellitus, Am J Cardiol, 2005;95:1386–8.
    Crossref | PubMed
  79. Yano Y, Hoshide S, Ishikawa J, et al., The differential effects of angiotensin II type 1 receptor blockers on microalbuminuria in relation to low-grade inflammation in metabolic hypertensive patients, Am J Hypertens, 2007;20:565–72.
    Crossref | PubMed
  80. Nakayama S, Watada H, Mita T, et al., Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetics with hypertension, Hypertens Res, 2008;31:7–13.
    Crossref | PubMed
  81. Tian Q, Miyazaki R, Ichiki T, et al., Inhibition of tumor necrosis factor-a-induced interleukin-6 expression by telmisartan through cross-talk of peroxisome proliferatoractivated receptor-g with nuclear factor kB and CCAAT/enhancer-binding protein-b, Hypertension, 2009;53:798–804.
    Crossref
  82. 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;362:759–66.
    Crossref | PubMed
  83. Teo K, Yusuf S, Sleight P, et al., Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials, Am Heart J, 2009;148:52–61.
    Crossref | PubMed
  84. Elliott HL, Focus on the ONTARGET results, J Hypertens Suppl, 2009;27:S8–S10.
    Crossref | PubMed
  85. Schumacher H, Mancia G, The safety profile of telmisartan as monotherapy or combined with hydrochlorothiazide: a retrospective analysis of 50 studies, Blood Press Suppl, 2008;1:32–40.
    Crossref | PubMed
  86. Michel MC, Bohner H, Koster J, et al., Safety of telmisartan in patients with arterial hypertension : an open-label observational study, Drug Saf, 2004;27:335–44.
    Crossref | PubMed
  87. Costa FV, Esposti LD, Cerra C, et al., Trends in Prescription and Determinants of Persistence to Antihypertensive Therapy: The PAPEETE Study, High Blood Press Cardiovasc Prev, 2009;16:167–76.
    Crossref | PubMed
  88. Sleight P, Redon J, Verdecchia P, et al., Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study, J Hypertens, 2009;27:1360–9.
    Crossref | PubMed
  89. NCT01435161, The Effect of Nifedipine Versus Telmisartan on Prevention of Atrial Fibrillation Recurrence in Hypertensive Patients With Paroxysmal Atrial Fibrillation by Intensive Lower Blood Pressure, 2011. Available at: http://clinicaltrials.gov/ct2/show/NCT01435161 (accessed 16 December 2011).
    Crossref | PubMed
  90. Thoene-Reineke C, Rumschüssel K, Schmerbach K, et al., Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models, PLoS One, 2011;6:e23646.
    Crossref | PubMed
  91. Yusuf S, Hawken S, Ounpuu S, et al., Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study, Lancet, 2004;364:937–52.
    Crossref | PubMed
  92. Ruilope LM, Telmisartan for the management of patients at high cardiovascular risk, Curr Med Res Opin, 2011;27:1673–82.
    Crossref | PubMed
Previous Volume Article Next Volume Article