• CLINICAL EXPERIENCE WITH RAS BLOCKING AGENTS
• CLINICAL EXPERIENCE WITH ACE INHIBITORS
• CLINICAL EXPERIENCE WITH ARBs
• DESIGN AND MAJOR RESULTS OF THE ONTARGET STUDY
• INSIGHT INTO THE RESULTS OF THE ONTARGET STUDY
• PRESPECIFIED ANALYSIS OF THE ONTARGET STUDY
• Renal Outcomes of the ONTARGET Study
• MAIN FINDINGS OF THE TRANSCEND STUDY
• INSIGHT INTO THE RESULTS OF THE TRANSCEND STUDY
• MAIN FINDINGS OF THE PRoFESS STUDY: COMMENTS AND CLINICAL IMPLICATIONS
• CONCLUSION
• REFERENCES

Development of effective therapeutic strategies aimed at reducing the incidence of cardiovascular (CV) morbidity and mortality represents a key priority for any prevention program, worldwide [1-4]. Among the different options available to prevent CV and renal diseases, the one that appears to be the best by far, is one based on identification and treatment of individuals at high risk. It is also the most cost-effective, as well as the most rewarding in terms of lives saved per patient treated [5]. In fact, both population strategies and single-risk-factor-based approaches have demonstrated significant drawbacks and do not seem to appropriately respond to current challenges (Table 1) [6], represented by the mounting tide of patients with a high CV risk profile. In 2020 the number of individuals estimated by World Health Organization (WHO) to be at high cardiovascular risk will double compared to today (Table 2) [7]. This major control of populations at high risk represents a major, affordable target for any intervention aimed at achieving effective CV disease prevention.

	TABLE 1. Effect of three preventive strategies on deaths from coronary heart disease over 10 years in Canadians aged 20-74 years  (Reprinted from Revisiting Rose: strategies for reducing coronary heart disease. Manuel DG, Lim J, Tanuseputro P, et al, 332(7542):659-662; Copyright © 2006, with permission from BMJ Publishing Group Ltd.)
	TABLE 2. Trends of CV Risk Factors in different world area

Over the last few years, the medical community has progressively focused attention on patients at high or very high CV risk [8,9]. This interest has been generated firstly by the growing population of patients surviving major CV events, mostly acute myocardial infarction and ischemic stroke, but also, if not predominantly, by a trend in interventional clinical studies enrolling populations of patients with high or very-high CV risk profiles [10]. This tendency is mostly justified by the need to achieve a sufficient number of events in a relatively short frame of time. Whatever the case, these studies have contributed to the identification of strategies that are able to effectively reduce the incidence of major CV events or CV death [11-14].
The major contribution of this kind of clinical trials, in fact, has been to validate the beneficial effects of drugs or classes of drugs, such as lipid-lowering agents, mainly statins [13,14], aspirin [15], Angiotensin-Converting Enzyme (ACE) inhibitors, and more recently Angiotensin II Receptor Blockers (ARBs) [16]. With regard to CV disease management, the large evidence in favor of ACE inhibitors, mostly ramipril, in these patients has been translated into a wide indication, and consequently, this antihypertensive drug class is increasingly used in a variety of clinical “high-risk” patients, such as those suffering myocardial infarction or those experiencing a stroke [16]. This type of indication for ACE inhibitors, however, clearly addresses patients with CV disease, rather than patients at “high CV risk”. In other words, this is a “secondary prevention” application of ACE inhibitor-based therapy that is secondary to clinical situations occurring in the advanced stages of the CV continuum. In any case, ACE inhibitors represent the “gold standard” today for treatment of CV patients [16].
The clinical availability of a newer class of antihypertensive agents, namely ARBs, which are able to counteract the deleterious effects of Renin-Angiotensin System (RAS) over-activation, has progressively raised the question as to which drug class may be more protective in CV and renal outcomes [17]. Clinical studies have been performed over the last two decades, substantially demonstrating that both monotherapies based on either ACE inhibitors or ARBs are effective in reducing blood pressure levels and improving blood pressure control [18,19], reducing progression or promoting regression of organ damage [20,21] and, thus, significantly reducing CV and renal morbidity and mortality [22]. Combination of ACE inhibitors and ARBs have, however, provided conflicting and confounding results [23].
In the present article, the main results of a large, international, randomized, controlled clinical trial program, based on the use of the ARB, telmisartan, and aimed at comparing the efficacy, safety and tolerability of an ACE inhibitor, an ARB and a combination of both drugs, will be reviewed and discussed, in order to explore whether the use of telmisartan may represent a new option for therapeutic management of patients at high or very high CV risk, and risk of renal diseases and diabetes mellitus.

CLINICAL EXPERIENCE WITH RAS BLOCKING AGENTS

The notion of the central physiological role of the RAS in maintaining fluid and electrolyte homeostasis, together with the established evidence of its involvement in the pathophysiology and natural history of several cardiovascular and renal conditions, have led to an unrelenting hunt during the last three decades for pharmacological compounds able to antagonize the effects of RAS activation, and in particular its biological effector, angiotensin II [17].
The development of ACE inhibitors has been associated with a revolutionary impact in the treatment of different clinical conditions, including high-risk hypertension [24-26], diabetes mellitus [27], stroke [28], coronary artery disease [29], left ventricular dysfunction [30,31], congestive heart failure [32-35], and renal disease [36-38]. Further studies have progressively highlighted, however, that the blockade of this system achievable with ACE inhibitors is far from complete, even when these agents are given at doses high enough to inhibit plasma ACE [39-41]. In fact, both angiotensin II and aldosterone tend to escape the blockade over time and angiotensin I may accumulate [42,43]. At the same time, the conversion of angiotensin I to angiotensin II via ACE is not an exclusive pathway for angiotensin II generation, especially in cardiovascular tissues [44]. Indeed, angiotensin II can be formed via a number of alternative pathways, involving cathepsin G, elastase, tissue plasminogen activator and, particularly in cardiovascular tissues, chymases [45]. According to this hypothesis, the latter pathway seems to be responsible for the vast majority of angiotensin II formation in human tissues, with the ACE-dependent pathway playing only a minor contributory role [46,47]. These considerations have been proposed to explain, at least in part, the relative failure of ACE inhibition to maintain the clinical benefits over time in some clinical conditions. As a consequence of this relatively poor specifi city of the mechanism of action of ACE inhibition, the observation of some relevant side effects of these compounds, mostly cough, but also first-dose hypotension and angioedema, is not surprising [48].
Because of these limitations of ACE inhibitors, research was focused on other potential therapeutic targets, mostly the AT1 subtype receptors, which are involved in the pathophysiologic responses to angiotensin II [49]. In fact, the AT1 subtype receptor is expressed in several human adult tissues and virtually mediates all known actions of angiotensin II in cardiovascular, renal, neuronal, endocrine and other target cells, as schematically shown in Figure 1 [50]. Altogether, under physiological conditions, these actions largely contribute to the homeostasis of arterial blood pressure, electrolyte and water balance, thirst, hormone secretion, renal function and cellular growth [51,52]. On the other hand, in pathological conditions, angiotensin II actions substantially contribute to development and maintenance of cardiac, vascular and renal abnormalities, leading to an increased cardiovascular risk and precipitating cardiovascular and renal events [51,52].

Figure 1. Schematic representation of the rennin-angiotensin system and sites of possible therapeutic interactions at different levels of the cascade. (Data taken from Volpe M, Tocci G, Pagannone E. [Activation of the renin-angiotensin-aldosterone system in heart failure]. Ital Heart J 2005;6 Suppl 1:16S-23S)

CLINICAL EXPERIENCE WITH ACE INHIBITORS

The role of the RAS in the pathophysiology of several clinical conditions, such as arterial hypertension, myocardial infarction, stroke, heart failure, diabetes and renal failure, has led in the last two decades to the development of pharmacological agents able to antagonize the effects of RAS activation, and most of all the effects of angiotensin II (Figure 1) [51,52]. As the result of a process of “inverse translational science”, a more thorough knowledge of the organization and pathophysiology of the RAS has been derived from the development and use of drugs inhibiting the RAS [53,54]. For instance, the impressive beneficial effects of ACE inhibitors in CV patients or in patients with renal disease strongly support the pathophysiologic role of the RAS and hence form the rational for the use of RAS blocking agents in reducing CV morbidity and mortality.
As previously discussed, the development of ACE inhibitors has been associated with a revolutionary impact in the treatment of different clinical conditions. At the same time, however, evidence is available demonstrating that the blockade of RAS achievable with ACE inhibitors is far from being complete. In addition, recent long-term analyses of “historical” clinical trials, performed in the early 1990’s, have demonstrated that even in the most established indication of ACE inhibition (i.e., congestive heart failure), the benefits on CV endpoints tend to fade over time, as observed in the prolonged observation of patients treated in the COoperative North Scandinavian ENalapril Survival Study (CONSENSUS) [55] and in the eXtension-Studies Of Left Ventricular Dysfunction (X-SOLVD) [56]. In the extended observation of Heart Outcomes Prevention Evaluation (HOPE)-TOO [57] in patients at high CV risk, the benefit is somehow preserved, but the residual risk remains very high. Together with these limitations, some of which are relevant, frequent side effects (e.g., cough and first-dose hypotension) of ACE inhibitors have prompted the need for different approaches to inhibit RAS activity [58-60].
Thus, research was focused on AT1 subtype receptors, which mediate most of the biological response to angiotensin II [51]. These actions largely contribute notoriously to the homeostasis of arterial blood pressure, maintenance of electrolyte and water balance, thirst, hormone secretion, and renal function, but also to the modulation of vasconstriction, aldosterone production and oxidative processes, cellular growth, apoptosis and tissue remodelling processes, mainly fibrosis [51]. Even in this case, the development of the ARBs has corroborated the postulated pathophysiologic relevance of AT1 receptors.

CLINICAL EXPERIENCE WITH ARBs

Clinical experience with ARBs is increasing with approximately two hundred thousand patients involved in completed or ongoing controlled, randomized, multicenter clinical trials. It has indeed been shown that blocking the RAS with ARBs can reduce CV and renal events in different settings, including hypertensive patients at high-risk or subjects with left ventricular hypertrophy [61-63], stroke [64,65], acute myocardial infarction and coronary artery disease [66,67], congestive heart failure with left ventricular dysfunction [68-74], type 2 diabetes and diabetic renal disease [75-79] (Figure 2). In particular, antihypertensive strategy based on ARBs has been shown to provide beneficial effects across the whole renal and CV continuum, both preventing the progression from microalbuminuria to proteinuria [20] or left ventricular dysfunction or hypertrophy [21] and even promoting the regression from microalbuminuria to normoalbuminuria [20] and from left ventricular hypertrophy to normal left ventricular geometry [21] (Table 3).

	Figure 2. Schematic representation of the cardiovascular and renal continuum. (Data taken from 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;121:1244-1263)
	TABLE 3. Recent randomised clinical trials performed with ARBs

Comparison of the effectiveness of different therapies in CV and renal protection has classically required the evaluation of the so-called “hard” endpoints, including fatal and non-fatal myocardial infarction, stroke, heart failure and end-stage renal disease [10]. In view of the long natural history of hypertension and CV and renal diseases, however, it appears very useful to postulate that modifications in measurable intermediate endpoints may permit prediction of the efficacy of a given treatment in preventing or modifying the course of organ damage, rather than variation in the future risk for development of hard endpoints associated with hypertension [16]. This is a valuable approach in clinical practice and can be easily undertaken by physicians to evaluate the status of a patient, the prognosis and the effectiveness of a treatment [16]. In addition, such an approach will permit better stratifi cation of absolute CV risk in individual patients, resulting in a more strict and cost-effective control of blood pressure levels [16].
While lowering blood pressure remains a key priority in the treatment of hypertensive patients [1], evidence derived from international clinical trials on hypertension have demonstrated that antihypertensive strategy based on those pharmacological agents that counteract RAS may confer additional benefit in terms of CV and renal protection, beyond their blood pressure lowering properties [80,81]. In these populations, for comparable reductions in blood pressure levels, antihypertensive strategies based on RAS blocking agents, including ACE inhibitors and ARBs, have been shown to be more effective than beta-blockers or calcium channel blockers on major CV and renal endpoints [80,81]. Of relevance, in recent clinical trials involving patients with hypertension or high-risk profile, ARB-based therapy has been demonstrated to prevent development, delay progression or even promote regression of clinical signs of CV and renal organ damage, including left ventricular hypertrophy and dysfunction [21], microalbuminuria, proteinuria and impairment of glomerular filtration rate [20,81], atherosclerosis [46,82] new onset diabetes [58] and atrial fibrillation [83]. Head-to-head comparisons between ACE Inhibitors and ARBs have, however, revealed conflicting results, supporting the need for large, international, randomized, controlled clinical trials with significant power to detect differences or similarities [23,24].
The vast clinical investigation program undertaken to define the clinical profile of efficacy and tolerability of telmisartan in patients at high CV risk has definitely accomplished this task throughout three major studies, including the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) [84], the Telmisartan Randomized Assessment Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND) [85], and the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) [86] trials. Altogether, the results of the these trials have challenged this substantially exclusive indication of the ACE inhibitor, ramipril, the drug used in the landmark HOPE study [24], at the dosage of 10 mg/day orally in patients with high CV risk.

DESIGN AND MAJOR RESULTS OF THE ONTARGET STUDY

The ONTARGET study [84] was designed to test the non-inferiority of the ARB telmisartan, at the dosage of 80 mg/day orally as compared with 10 mg of ramipril daily, and the hypothesis of a superiority of the combination of ramipril plus telmisartan as compared to monotherapy with ramipril alone on hard endpoints. As per protocol, the ONTARGET study [84] enrolled patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage:

The ONTARGET Trial Program (31,546 patients)

• ONTARGET – the principal trial (25,620 patients) Substudies: ABPM (n = 1000), Cardiac MRI (n = 350), Erectile dysfunction (n = 1500), Health economics (n = 7000), Blood markers (n = 12,000).
• TRANSCEND – the parallel trial (5926 patients) Substudies: see ONTARGET substudies; Arterial stiffness (n = 284), OGTT (n = 4000).

Patients who could not tolerate ACE inhibitors were randomly assigned to receive either telmisartan or placebo in a parallel trial, the TRANSCEND study. If the non-inferiority of telmisartan was demonstrated, the superiority of telmisartan over ramipril would be tested. In addition, the study was powered to determine whether the combination of the two drugs was more effective than ramipril alone in reducing the composite outcome of death from CV causes, myocardial infarction, stroke, or hospitalization for heart failure. This composite outcome was chosen to test the primary hypothesis of the study. The main secondary outcome was a composite of death from CV causes, myocardial infarction, or stroke, which coincided with the primary outcome in the HOPE trial, performed with ramipril versus placebo in patients at high CV risk. Other secondary outcomes were new development of heart failure, diabetes mellitus, atrial fibrillation, dementia or cognitive decline, nephropathy, and revascularization procedures. Other outcomes were death from any cause or from non-CV causes, angina, transient ischemic attack, development of left ventricular hypertrophy, microvascular complications of diabetes, changes in blood pressure or in the ankle-to-arm ratio of blood pressure, and new cancers.
National coordinators and clinical monitors supervised the recruitment of patients at 733 centers in 40 countries. The trial was coordinated and data were gathered and analyzed by the Population Health Research Institute at McMaster University and Hamilton Health Sciences. The steering committee designed and oversaw the trial. All main study outcomes (including death due to any cause, myocardial infarction, stroke, and hospitalization for heart failure) were adjudicated by a central committee whose members were unaware of study-group assignments, using standard criteria. All serious adverse events were reviewed by an independent data and safety monitoring board. All of this speaks to the fact that this impressively large clinical trial was also designed and performed in a very rigorous manner.
At the beginning of the study, patients entered a single-blind run-in period in which they received 2.5 mg of ramipril once daily for 3 days, followed by 40 mg of telmisartan and 2.5 mg of ramipril once daily for 7 days and then 5 mg of ramipril plus 40 mg of telmisartan for 11 to 18 days. Of the 29,019 patients who entered the run-in period, 3399 (11.7%) were excluded from the study: 1123 (3.9%) had poor compliance, 597 (2.1%) withdrew from the study, 492 (1.7%) had symptomatic hypotension, 223 (0.8%) had an elevated potassium level, 64 (0.2%) had an elevated creatinine level, 872 (3.0%) had other reasons for exclusion, and 27 (0.1%) died. At the end of the run-in period, a total of 25,620 patients underwent randomization and were stratified according to site with the use of permuted blocks through a central automated telephone service. For the first 2 weeks after randomization, 8542 patients were assigned to receive 80 mg of telmisartan once daily, 8576 were assigned to receive 5 mg of ramipril once daily, and 8502 were assigned to receive the combination therapy. After 2 weeks, the dose of ramipril was increased to 10 mg per day. Follow-up visits occurred at 6 weeks, 6 months, and then every 6 months until the last scheduled visit.
Main characteristics of the 25,620 patients who underwent randomization were similar in the three study groups and are reported in Figure 3 and Table 4. In the overall population, 27% were women, 85% had CV disease, 69% had hypertension, and 38% had diabetes. As illustrated in Table 5, a high proportion of patients had previously received proven therapies, including statins (61.6% at baseline, increasing to 70.6% by the end of the study), antiplatelet therapy (80.9% and 77.5%, respectively), beta-blockers (56.9% and 56.9%), and diuretics (28.0% and 32.5%). Before the run-in period, the mean blood pressure was 141.8/82.1 mmHg. Patients in the telmisartan group and the combination-therapy group had slightly lower blood-pressure levels throughout the study period (average reductions 0.9/0.6 mm Hg and 2.4/ 1.4 mmHg, respectively) than did patients in the ramipril group (Table 4).

	Figure 3. Diagnosis at study entry for patients in ONTARGET, TRANSCEND and HOPE trials. (Derived from Sleight P. The ONTARGET/TRANSCEND Trial Programme: baseline data. Acta Diabetol 2005;42 Suppl 1:S50-S56)
	TABLE 4. Baseline clinical characteristics for patients in ONTARGET trial (Data taken from 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(15):1547-1559)
	TABLE 5. Baseline medications for patients in ONTARGET, TRANSCEND and HOPE trials (Reproduced with permission from Sleight P. The ONTARGET/TRANSCEND Trial Programme: baseline data. Acta Diabetol 2005;42 Suppl 1:S50-S56)

A total of 25,577 patients (99.8%) were followed until a primary event occurred or until the end of the study (median, 56 months). The primary outcome occurred in 1412 patients (16.5%) in the ramipril group, in 1423 patients (16.7%) in the telmisartan group, and in 1386 patients (16.3%) in the combination-therapy group (Figure 4). The upper boundary of 1.09 of the confidence interval (CI) for the relative risk (RR) of the primary outcome in the telmisartan group as compared with the ramipril group was significantly lower than the predefined non-inferiority boundary of 1.13 (p = .004). The lower boundary of the CI indicates that telmisartan was not superior to ramipril (Table 6). As illustrated in Table 7, the secondary outcome, including death from CV causes, myocardial infarction or stroke occurred in 1210 patients (14.1%) in the ramipril group and in 1190 patients (13.9%) in the telmisartan group (RR 0.99; 95% CI: 0.91-1.07; p = .001 for non-inferiority). The results were substantially consistent for all components of the primary outcome (Table 6 and Table 7) and for all pre-specified subgroups.

	Figure 4. Kaplan-Meier curves for the incidence of the primary composite outcome of the ONTARGET study. (Reprinted with permission from 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(15):1547-1559. Copyright © 2008 Massachusetts Medical Society. All rights reserved)
	TABLE 6. Incidence of the primary endpoints in ONTARGET trial  (Reprinted with permission from 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(15):1547-1559 Copyright © 2008 Massachusetts Medical Society. All rights reserved)
	TABLE 7. Incidence of the secondary endpoints in ONTARGET trial (Reprinted with permission from 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(15):1547-1559. Copyright © 2008 Massachusetts Medical Society. All rights reserved)

Combination therapy was not significantly better than ramipril alone (relative risk, 0.99; 95% CI, 0.92 to 1.07) (Figure 4). Adjustments for the small differences in blood pressure did not alter the results for the primary outcome (RR for telmisartan vs. ramipril, 1.02; 95% CI: 0.95-1.10; RR for combination therapy vs. ramipril, 1.00; 95% CI: 0.93-1.07). As reported in Table 6, there was no significant difference in the total number of deaths between the ramipril and the telmisartan group (1014 deaths and 989 deaths, respectively; RR 0.98; 95% CI: 0.90-1.07); the number of deaths was higher in the combination-therapy group than in the ramipril group (1065 deaths vs. 1014 deaths; RR 1.07; 95% CI: 0.98-1.16), but the difference did not achieve statistical significance. Also, there were no significant differences in the rates of secondary outcomes (Table 7), except for renal dysfunction, which occurred in 871 patients (10.2%) in the ramipril group, 906 patients (10.6%) in the telmisartan group, and 1148 patients (13.5%) in the combination therapy group. It should also be noted that as compared with the ramipril group, the telmisartan group had a similar incidence of renal impairment, whereas the combination therapy group had a significant increase in the incidence of this clinical outcome.
The number of patients who had a doubling of the creatinine level was similar in the three groups (159 in the ramipril group, 170 in the telmisartan group, and 180 in the combination therapy group). The number of patients who had an increase in the potassium level (as defined by more than 5.5 mmol per liter) was similar in the ramipril group (283 patients) and the telmisartan group (287 patients), but the number was significantly higher in the combination therapy group (480 patients, p <.001 for the comparison between the combination therapy group and the ramipril group). The rate of renal dialysis was the same in the ramipril group and the telmisartan group, with 48 patients (0.6%) and 52 patients (0.6%) respectively undergoing dialysis, whereas the rate was increased in the combination therapy group, with 65 patients (0.8%) undergoing dialysis (p = .10 for comparison with the ramipril group).
With regard to the tolerability profile, the proportion of patients receiving the full dose of ramipril at 2 years was 81.7% in the ramipril group and 75.3% in the combination therapy group. The proportion of patients receiving the full dose of telmisartan at 2 years was 88.6% in the telmisartan group and 84.3% in the combination therapy group. The study drug was discontinued by 2029 patients (23.7%) in the ramipril group and 1796 (21.0%) in the telmisartan group. In the combination-therapy group, 1929 patients (22.7%) discontinued both drugs, and an additional 566 (6.7%) stopped taking one drug. More patients discontinued ramipril (either as monotherapy or as combination therapy) than telmisartan alone, mostly because of cough or angioedema. In the combination therapy group, an increased number of patients stopped taking a study drug because of hypotensive symptoms, syncope, diarrhea, or renal impairment, as compared with the ramipril group.

INSIGHT INTO THE RESULTS OF THE ONTARGET STUDY

Different and conflicting comments were generated after publication of the study, and these controversial reactions generated some confusion among physicians, even those with the widest experience with both ACE inhibitors and ARBs. Therefore, some comments on the controversial aspects of the clinical program may help in the interpretation of the trial.
A first critical aspect is that ONTARGET investigators, based on the numerous strict inclusion and exclusion criteria, selected a population mostly characterized by previous cardiovascular (predominantly coronary) events and thus at very high cardiovascular risk, even though the study recruitment plan was, indeed, addressed to high risk individuals [87]. Out of the 25,620 patients enrolled, a significant proportion, 19,162 (74.8%), had established and advanced coronary artery disease, as shown in Table 4 [84]. A total of 12,549 (49.0%) had, in fact, a history of myocardial infarction and 3817 (14.9%) had a history of unstable angina [84]. An exceptionally high proportion of patients (5675, 22.1%) had undergone coronary artery bypass grafting and 7437 (29.0%) had undergone percutaneous angioplasty [84]. Finally, 5342 (20.5%) patients had a documented history of cerebrovascular disease [84]. These features of the ONTARGET [84] population classify the study patients as “CV patients”, with most of the patients actually at “very high CV risk”; only a marginal minority had no previous CV event.
Thus, in view of the results of the study, and especially in view of the quite comparable effect of ramipril and telmisartan on the primary composite CV outcome and on its individual components, one may conclude that the ARB telmisartan is as effective as the current standard therapy with the ACE inhibitor ramipril in patients with established CV disease [88]. Therefore, also taking into account the results of TRANSCEND [85], these findings may support a new clinical indication that represents a novel therapeutic option besides ACE inhibitors to treat patients with coronary heart disease [88] or stroke [89].
A second important aspect is that ONTARGET [84] cannot be defined as a “hypertension trial”, since the characteristics of the population described above in no way fit the characteristics of a general hypertensive population. In spite of the fact that a vast proportion of patients included in the study were diagnosed with hypertension, they do not represent the general hypertensive population in any way because of their high cardiovascular risk. In any case, entry blood pressure levels of patients in this trial were on average slightly above 140 mmHg for systolic and around 82 mmHg for diastolic blood pressure levels [84]. In such a context, it is hard to draw conclusions that can be transferred to hypertension management or guidelines, with the exception of the implications for patients at “very high risk”. In this latter view, the available data from ONTARGET [84] do not seem to support the need for attaining systolic blood pressure levels below 130 mmHg. In fact, despite the signifi cantly greater reduction of systolic blood pressure levels obtained in the group of patients receiving a combination of ramipril and telmisartan (more than 2 mmHg), no additional benefi t was attained compared to the other two groups, which achieved systolic blood pressure levels of approximately 135 mmHg [84]. Actually, preliminary analysis seems to show that in the subgroups of patients in the lower quartile of initial blood pressure levels, a disadvantage with regard to events has been reported, especially in those who had the largest blood pressure reduction (Sleight P, oral presentation at European Society of Hypertension, Berlin 2008). This sort of “J-curve” [90-92] in high risk patients has been reported in other high risk groups in large clinical trials, such as the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) [93] and the International Verapamil SR-Trandolapril Study (INVEST) [94].
The ONTARGET trial [84] definitely confirms superior tolerability of the ARB, telmisartan, compared to ACE inhibitor, ramipril (Table 8). Analysis of side effects and drug related discontinuations in the ONTARGET trial [84], in fact, showed a slightly better tolerability of telmisartan compared to ramipril in this high risk population. In fact, according to exclusion criteria, those patients who showed intolerance to ACE inhibitors were excluded (about 6000 individuals, who shifted to TRANSCEND [85]) and thus, one may argue that the superior tolerability would have been definitely greater, if those patients had been enrolled in the trial [84]. In particular, exclusion of patients with first-dose hypotension due to ACE inhibitors may have accounted for the higher number of patients on ARBs who interrupted the study for hypotension related symptoms. Even considering this important aspect, total permanent discontinuations were 438 with telmisartan, 621 with ramipril and 978 with the combination of telmisartan plus ramipril [84]. These results highlight potential important implications with regard to therapy related cost, since the worse tolerability of ACE inhibitors may imply more visits, more laboratory tests and, of course, therapy adjustment or switch [88].

TABLE 8. Benefit versus tolerability of the combination therapy based on ACE inhibitors and ARBs in the Val-HeFT, VALIANT, CHARM-Added and ONTARGET trials  (Reprinted with permission from Volpe M. A New Option for Therapeutic Management of Patients with Cardiovascular Disease: A Closer Look at the ONTARGET Study. High Blood Press Cardiovasc Preven 2008;15(2):47-51)

Another aspect that deserves some discussion is the dosage of drug selected for the study. In ONTARGET [84], the highest dosage of ramipril commonly used in therapy (10 mg/day) was compared with telmisartan 80 mg. Considering that the best available results with ARBs have been obtained with the use of the higher available dosages, e.g., up to 100 mg of losartan in the Losartan Intervention For End-point reduction in hypertension (LIFE) [61] trial and the Reduction in End-points in patients with Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) [75] study, 32 mg of candesartan in the Candesartan cilexitil in Heart failure: Assessment of Reduction in morbidity and Mortality (CHARM) study [72] and 300 mg of irbesartan in the IRbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients (IRMA2) study [77], one cannot exclude that a higher dosage of telmisartan may have provided even better clinical performance than what has been achieved with 80 mg/day of telmisartan. On the other hand, in common clinical practice, the use of 2.5-5 mg/day of ramipril is definitely more frequent, whereas 10 mg/day is used in a much smaller proportion of patients [88].
The results of the ONTARGET trial [84] substantially confirm in a population mostly represented by coronary patients that ARBs do not produce more cases of acute myocardial infarction or acute coronary syndromes than those observed with ACE inhibitors. If further proof of the lack of difference in the incidence of acute myocardial infarction between ARBs and ACE inhibitors was still needed, the ONTARGET study [84] should definitely bury this old hypothesis. The narrative editorial article [95] that raised this issue and was followed by lively controversy in scientific journals concluded that “ONTARGET [84] would have clarified this aspect”. In this latter study, the proportion of fatal and non-fatal myocardial infarction events was 4.8% in the ramipril group and 5.2% in the telmisartan group (RR 1.01; 95% CI: 0.94-1.22; p = not significant), while worsening or new angina was 6.6% versus 6.3% (p = not significant), and revascularizations were 14.8% versus 15.1% (p = not significant) [84].
Finally, combination therapy of ARBs and ACE inhibitors does not add benefits, but adds side effects in CV patients [84]. This result is consistent with other large trials in CV patients, such as in the Valsartan in Acute myocardiaL InfArctioN Trial (VALIANT) [67]. Even in positive studies, such as the randomized trial of the angiotensin II receptor blocker VALsartan in congestive Heart Failure Trial (Val-HeFT) [68] and the CHARM-Added [73] trial, the benefit of the combination was “borderline” in the face of a consistently higher burden in terms of side effects, as reported in Table 8 [88].

PRESPECIFIED ANALYSIS OF THE ONTARGET STUDY

Following the publication of main findings of the ONTARGET study [84], some prespecified analyses have become available, in addition to the results of the TRANSCEND study [85]. General considerations on the results of these analyses are addressed in the following paragraphs.

Renal Outcomes of the ONTARGET Study

The prespecified analysis of the renal outcomes [96] with telmisartan, ramipril or both in the population at high CV risk in the ONTARGET study [84] has been surprising, not because of the lack of superiority of one treatment over the other, but rather because one of the “dogmas” of the last decade seems to be seriously challenged by the results of this study. In fact, the major conclusion of the authors of this subanalysis of the trial was that “although combination therapy reduces proteinuria to a greater extent than either monotherapy, overall it worsens major renal outcomes”, e.g., the primary renal endpoint, represented by a composite of dialysis, doubling of serum creatinine and death [96].
These results seem to show an inescapable dissociation from that observed in large, randomized, controlled clinical trials with the worsening of all hard endpoints but not proteinuria [75-79]. This can be clearly perceived as a definite drawback with respect to the established value in cardiorenal medicine of proteinuria as a mediator and marker of progressive loss of renal function [97]. Key aspects, however, need to be addressed. Again, the examination of renal outcomes in the ONTARGET study [84] was addressed through a prespecified analysis performed on a large population sample of patients (n = 25,620), greater than 55 years of age, who had a high or very high CV risk profile due to established vascular disease (mostly previous myocardial infarction or revascularization and stroke) and/or diabetes mellitus, including a vast proportion of hypertensive patients. About a third of the patients, however, were normotensive [84]. This aspect highlights the importance of blood pressure reduction observed with the different treatments and this issue should be addressed in order to properly interpret the results of the study.
Across the three arms of the study, in fact, blood pressure levels were reduced significantly, but to a greater extent in those patients receiving combination therapy with telmisartan and ramipril than ramipril alone, and the number of withdrawals from the study due to symptomatic hypotension was higher in those patients receiving the combination therapy than that observed in those patients randomized to receive telmisartan or ramipril alone [84]. These features of the study population are of key relevance for understanding the apparently controversial results.
The number of events for the renal composite primary endpoint were similar for telmisartan and ramipril (HR 1.00; 95% CI: 0.92-1.09) during the 5 years of follow-up [96]. The use of combination therapy, however, produced a borderline though significant increase in the primary outcome (HR 1.09; 95% CI: 1.01-1.18; p = .037) [96]. Also the secondary renal outcome, including dialysis and doubling of creatinine, was comparable with telmisartan and ramipril, but it was somewhat more frequent with the combination therapy (HR 1.24; 95% CI 1.01-1.51; p = .038) [96]. Ramipril produced less decline in estimated glomerular filtration rate (eGFR) than telmisartan and, more significantly, than combination therapy [96]. In sharp contrast with the trends of renal outcomes observed with the different therapies [75-79], the increase in urinary albumin was less with telmisartan (p = .004) and with combination therapy (p = .001) than with ramipril [96].
How can we explain these unanticipated discrepancies in the behavior of eGFR and proteinuria? The pioneering studies by Parving [98,99] and then by Lewis [100,101] using captopril in patients with diabetic nephropathy, together with a number of important papers with unequivocal results [102] have built a strong clinical position over time for the significance of proteinuria as a predictor of progressive renal disease, and for the importance of its reduction in delaying the progression of diabetic and non-diabetic nephropathies and CV events. A number of experiences with ACE inhibitors [36,37] or ARBs [75-79] have clearly substantiated the role of the RAS blocking agents in attenuating proteinuria. The results of renal outcomes in ONTARGET seem to conflict with this established view [96].
A closer look at the population features synthesized above permits, in our opinion, an explanation for a substantial proportion these findings and their apparent discrepancy with the former literature: 1) These patients had advanced vascular disease related to atherosclerosis, most likely multifocal, and therefore it is quite reasonable to postulate that these patients had impaired renal autoregulatory properties. 2) In this specific setting, the greater reduction in blood pressure, hypotension-related withdrawals, and presumable periods of hypotension observed in the population sample may account for the renal function deterioration as well as for the larger number of renal events. 3) The combined use of ACE inhibitors and ARBs together with other medications that these patients were taking (e.g., beta-blockers and antialdosteronic drugs, in particular) may have facilitated the occurrence of renal outcomes. 4) Finally, the patients recruited for the ONTARGET study [84] did not have advanced renal disease. These findings may be valid for patients with proteinuria levels lower than 1 gram per day, but this may be different in patients with more severe proteinuria and renal disease, where some reports obtained in specific populations have attributed a greater protection to the combination therapy.
In conclusion, renal diseases continue to represent a major medical problem that is on the uprise in patients with CV illness who are at high or very high CV risk. The protective role of the ARB telmisartan on the renal primary endpoint is comparable to that of ramipril in this high risk population. Taking into account that telmisartan was generally better tolerated than ramipril, this study represents an important stage in the exploration of the clinical indications of ARBs. Based on the results of this study, the combination of ACE inhibitors and ARBs in this population of vascular patients at high CV risk is not supported. Potential benefits in patients with more compromized renal function and more marked proteinuria need to be properly addressed through a specific prospective clinical study. Similarly, the predictive value of changes in proteinuria with regard to the progression of renal disease may need to be reassessed or reconsidered more carefully in patients with those clinical features. It should be considered, however, that the presence of vascular disease or the occurrence of hypotension may have heavily affected the apparent dichotomy between the renal results of ONTARGET [96] and previous literature with ACE inhibitors [36,37] or ARBs [75-79].
As schematically shown in Figure 3, the ONTARGET/ TRANSCEND trial program also encompasses a set of substudies and subanalyses [87] which will provide additional information on the beneficial effects of telmisartan as compared to ramipril in specific subgroups of patients [103,104]. In particular, analyses will be performed in those patients who underwent ambulatory blood pressure monitoring or cardiac magnetic resonance imaging [105] in order to evaluate the efficacy and safety of telmisartan, alone or in combination therapy as compared to ramipril in reducing 24-hour blood pressure levels and left ventricular hypertrophy. Other analysis will be available soon, addressing the predictive value of biomarkers in terms of risk of major cardiovascular and renal outcomes and the potential effect of antihypertensive therapy based on telmisartan on these clinical parameters. Of interest, among those patients with documented ACE inhibitor intolerance included in the TRANSCEND trial, the beneficial effects of the telmisartan based regimen as compared to placebo will be evaluated in terms of arterial stiffness and glucose tolerance. Finally, analyses will also be performed to evaluate the presence of erectile dysfunction [106] and the health and economic consequences of therapeutic strategy based on telmisartan, either alone or in combination therapy, as compared to ramipril or placebo will be evaluated.

MAIN FINDINGS OF THE TRANSCEND STUDY

The design of the ONTARGET trial program has been previously described [84]. Briefly, patients intolerant to ACE inhibitors were enrolled in TRANSCEND [85] if they had established coronary artery, peripheral vascular or cerebrovascular disease, or diabetes with end-organ damage. Intolerance to ACE inhibitors was defined as previous discontinuation by a physician because of intolerance with a specific documented cause [87].
In TRANSCEND [85] the characteristics of the randomized patients were similar in both treatment groups. The mean age of the randomized patients was 66.9±7.3 years; 2547 (43.0%) were women, 4528 (76.4%) had hypertension, and 2118 (35.7%) had diabetes [85]. Mean blood pressure was 141.0±16.6/81.9±10.1 mmHg, fasting plasma glucose was 6.50±2.44 mmol/L, and total cholesterol was 5.09±1.16 mmol/L [85]. Many of the patients were on therapy. The median duration of follow-up was 56 months. During the study period, mean blood pressure was lower on telmisartan than it was with placebo by 6.2/3.6 mmHg at 6 weeks, by 4.7/2.4 mmHg at 1 year, by 4.2/2.3 mmHg at 2 years, and by 3.2/1.3 mmHg at study end [85]. In particular, the mean weighted difference between groups in blood pressure during the study was 4.0 (SD 19.8)/2.2 (SD 12.0) mmHg [85].
Fewer patients in the telmisartan group experienced the primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for heart failure than did patients in the placebo group, although the difference did not achieve statistical significance (HR 0.92; 95% CI 0.81–1.05, p = .216) (Figure 5) [85]. The HOPE study outcome of CV death, myocardial infarction, or stroke was significantly lower with telmisartan than with placebo (HR 0.87; 95% CI 0.76–1.00; p = .048) (Figure 6) [85]. When this value for significance was adjusted to account for the 87% overlap between primary and secondary outcomes and the multiplicity of comparisons, the p value obtained was not significant. In the first 18 months there was little benefit, but thereafter there were fewer events on telmisartan [85]. Adjustment for the changes in blood pressure did not alter the overall results for the primary (HR 0.92; 95% CI 0.81–1.05) or HOPE secondary outcomes (HR 0.87; 95% CI 0.76–1.00) [85].

Figure 5. Kaplan-Meier curves for the primary outcome of cardiovascular death, myocardial infarction, stroke or heart failure hospitalisation. (Reprinted from The Lancet, 372(9644), Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, 1174-1183. Copyright © 2008, with permission from Elsevier)

Figure 6. Kaplan-Meier curves for the secondary outcome of cardiovascular death, myocardial infarction, or stroke (HOPE Study outcome). (Reprinted from The Lancet, 372(9644), Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, 1174-1183. Copyright © 2008, with permission from Elsevier)

Subgroup analyses show that the effect of telmisartan on the primary and secondary outcomes was consistent in various subgroups of patients [85]. Of the components of the primary composite outcome, there were fewer myocardial infarctions and strokes in the telmisartan group than in the placebo group, although this was not significant; the number of CV deaths and hospitalizations for heart failure were similar between the two groups. Total mortality did not significantly differ in the two groups [85]. The combined outcome of macrovascular disease (CV death, myocardial infarction, or stroke) and microvascular disease (retinopathy, doubling of creatinine, new macroalbuminuria, or need for dialysis), which was the primary outcome of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study [27], occurred less frequently with telmisartan than with placebo (HR 0.89; 95% CI 0.79–1.00; p = .049) [85]. More patients in the telmisartan group than in the placebo group experienced the composite outcome of macrovascular and microvascular disease plus the development of microalbuminuria (HR 0.85, 95% CI 0.77–0.94; p = .001) [85].
Of the randomized population, the most common reason for intolerance to ACE inhibitors was cough, which was reported in 5225 participants (88.2%), followed by 244 (4.1%) patients with symptomatic hypotension, 75 (1.3%) with angioedema or anaphylaxis, 58 (1.0%) with renal dysfunction, and 492 (8.3%) with other conditions requiring discontinuation [85]. With regard to the tolerability profile, at the end of the run-in period, fewer patients permanently discontinued treatment with telmisartan than did those receiving placebo [85]. Syncope was rare, despite more minor symptoms of hypotension, such as dizziness with telmisartan [85]. Renal abnormalities (based on local clinical reports) occurred in 308 (10.4%) patients in the telmisartan group, and 241 (8.1%) in the placebo group, although only a few patients permanently discontinued study medications because of these abnormalities [85]. Doubling of serum creatinine was reported in 60 patients in the telmisartan group as compared to 42 in the placebo group, while hyperkalemia, as defined by potassium serum levels over 5.5 mmol/L, occurred more frequently with telmisartan than with placebo, with no significant difference in incident renal dialysis [85]. Among those with cough as the initial reason for intolerance to ACE inhibitors, the proportion stopping study medication for the same reason was similar and infrequent (14 in the telmisartan group vs. 15 in the placebo group) [85]. Among those with previous hypotension (n = 244), hypotension after randomization occurred in two (1.5%) patients in the telmisartan group and one (0.9%) in the placebo group; one case of angioedema occurred in the placebo group amongst the 75 patients with a history of such disease [85]. There was one case of renal dysfunction in each group in the 58 patients who had reported this as a reason for ACE intolerance.

INSIGHT INTO THE RESULTS OF THE TRANSCEND STUDY

The results of TRANSCEND [85] have raised an active debate in the medical scientific community. After the demonstration of non-inferiority of the ARB, telmisartan, compared to the ACE inhibitor, ramipril in ONTARGET [84], many would have expected a net benefit on the primary composite CV endpoint in the group treated with telmisartan versus placebo, on the basis of a mere translation of the results obtained with ramipril versus placebo observed in the HOPE study [24].
Indeed, although a statistically significant superiority versus placebo in the CV endpoint could not be demonstrated in the TRANSCEND study [85] in favour of telmisartan as compared to placebo (RR -8%; 95% CI: 0.81-1.105; p = .219), a borderline significant reduction in a pre-specified secondary endpoint, including CV death, myocardial infarction and stroke, corresponding to the primary endpoint of HOPE, was observed (RR -13%; 95% CI 0.76-1.00; p = .048) (Table 9) [85]. In addition, Table 10 illustrates the effects of telmisartan-based therapy on the incidence of secondary outcomes as compared to placebo [85].

TABLE 9. Incidence of the components of the primary endpoint in TRANSCEND trial (Reprinted from The Lancet, 372(9644), Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, 1174-1183. Copyright © 2008, with permission from Elsevier)

TABLE 10. Incidence of the components of the secondary endpoints in TRANSCEND trial (Reprinted from The Lancet, 372(9644), Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, 1174-1183. Copyright © 2008, with permission from Elsevier)

In relation to these findings, some educated comments were substantially negative towards these results and advocated the persistent leadership of ACE inhibitors for managing CV patients [107-109]. While on one side, the attitude reflected in these comments suggests a pragmatic interpretation of a large randomized controlled clinical trial, on the other hand it also reflects a tendency for a “black or white” judgement of clinical trials, which actually require a more thorough reading to analyze the complexity of the study within the framework of the specific historical period and application to clinical practice [89].
As a starting point for the discussion, we recently proposed an interesting exercise [89] comparing the historical clinical background in terms of guidelines, clinical attitudes and practice associated with TRANSCEND [85] with that of clinical studies in similar populations performed with ACE inhibitors, mainly the HOPE study with ramipril [24]. The study population sample of TRANSCEND [85], including about 6000 high CV risk patients 60 years of age, was somehow similar to that of the HOPE study [24], as it was probably the intention of the original project, but indeed differed in many aspects. The most important difference was that patients selected for this study were, by definition, ACE inhibitor intolerant. For this reason, it could be expected that the population of the TRANSCEND study would not tolerate or respond to another RAS blocking agent. However, half of this population was indeed treated successfully for 5 years with the ARB, telmisartan. This suggests that the ARB, telmisartan, is not only a viable alternative to ACE inhibitors for those who cannot tolerate ACE inhibitors, it may also represent another therapeutic option in and of itself for patients who have proven intolerance to ACE inhibitors.
As compared to the HOPE population [24], the TRANSCEND study [85] included more patients treated with statins (55% versus 28%), beta-blockers (58% versus 39%) and antiplatelet drugs (85% versus 75%). In addition, there is no record of the dosages of lipid-lowering agents or statins and beta-blockers, as well as the type of antiplatelet drugs, but it is quite reasonable to speculate that high doses of statins and beta-blockers and double antiplatelet treatment in a large proportion of the population were represented in the TRANSCEND study [85] as compared to HOPE [24], in view of the significant changes in CV guidelines and clinical practice that occurred between 2000 and 2008 [104]. Obviously, in the ADVANCE trial there was a much higher proportion of patients receiving antidiabetic drugs [27].
With regard to treatment, it should also be noted that in TRANSCEND [85], a significantly higher proportion of patients was treated with diuretics and calcium channel blockers in the placebo than in the telmisartan group. Other studies with ACE Inhibitors versus placebo, performed more recently than HOPE [24], failed to find a significant difference between active treatment and placebo, as in the Prevention of Events with ACE inhibition (PEACE) study [29], or were able to produce a significant advantage only when a much more marked reduction in blood pressure levels were obtained. In this latter regard, the mean weighted blood pressure differences in the TRANSCEND study [85] were 4/2 mmHg for the systolic and diastolic blood pressure levels, respectively. For a quite similar blood pressure reduction of 5/3 mmHg with perindopril versus placebo observed in the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) [28], there was no significant difference in the primary endpoint, while a significant beneficial effect on the primary outcome was observed only for a difference of blood pressure of 12/5 mmHg between arms which was achieved with perindopril plus indapamide. A similar trend was also observed in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) [110]. This time-related trend for the outcome of clinical studies performed in high CV risk patients reveals the difficulty of comparing clinical studies performed in different “historical” periods [89].
In spite of this limit in the analysis, the so-called “HOPE endpoint” (cumulative incidence of myocardial infarction, stroke and CV death) in the TRANSCEND study [85] was substantially achieved, since there was a -13% relative risk reduction in the CV endpoint, depurated of congestive heart failure, which was the same endpoint and the same proportion of benefit observed in the LIFE study [61], a clinical trial comparing the ARB losartan with the active comparator beta-blocker, atenolol. The interpretation of the lack of significance of the primary endpoint, including congestive heart failure, is difficult and may include the fact that investigators were too ambitious in powering the study at 94% to detect a 19% risk reduction. Another explanation that could be taken into account is that in the placebo arm of the TRANSCEND study [85] diuretics were used significantly more often than in the active arm (40% versus 33.7%, p <.0001), as well as beta-blockers and calcium channel blockers, both of which were used more often in the placebo arm.
As mentioned above, in addition to the way in which a large clinical trial is perceived, what really counts is how the findings can be translated into clinical practice. The prespecified secondary HOPE outcome was reduced by 13% (p = .048 unadjusted and p = .068 after adjustment for multiplicity of comparisons and overlap with primary outcome, an analysis that has not been performed in many popular clinical trials) [85], and this was perceived in some commentaries as not very convincing [107-109]. Just to cite a pragmatic and recent example, in the ADVANCE trial [27], a large study universally praised and perceived as “positive”, the relative risk reduction of the primary composite endpoint (microvascular and macrovascular disease, including CV death, non-fatal stroke or myocardial infarction, plus new or worsening diabetic renal or eye disease) was only 9% (HR 0.91, CI 0.83-1.00; p = .04) in the presence of a systolic blood pressure reduction of 5.6 mmHg in favor of the fixed combination therapy based on perindopril and indapamide versus placebo in type 2 diabetes mellitus. Thus, a first conclusion that can be transferred to clinicians is that based on comparative studies comparing ACE inhibitors with placebo in different populations, the CV protection displayed by telmisartan in the TRANSCEND trial [85] does not seem to be lesser than that achieved by ACE inhibitors (on the other hand, the head-to-head comparison in the ONTARGET study [84] strikingly confirms this point).
A second remarkable aspect is that the limited population size of the study may have led to an underestimation of protection properties. In order to address this issue and overcome the limits related to size, we performed a meta-analysis of the incidence of stroke as an endpoint in placebo controlled randomized clinical trials [89]. Figure 7 shows that ACE inhibitors and ARBs were all able to produce significant reduction of stroke versus placebo, ranging between 17 and 19%, with no significant difference between them [89]. Similarly, as reported in Figure 8, also the “HOPE” cumulative CV endpoint was significantly reduced by both ACE inhibitors and ARBs as compared to placebo (-16% ad -15%, respectively), with no significant differences between the two treatment strategies [89].

	Figure 7. Incidence of Stroke Endpoint in Placebo-Controlled Randomized Clinical Trials. (Reprinted with permission from Volpe M. TRANSCEND Aftermath: Angiotensin II Receptor Blockers at the clinical cross-road. High Blood Press Cardiovasc Preven 2009;16(1):1-6)
	Figure 8. Incidence of HOPE Endpoint in Placebo-Controlled Randomized Clinical Trials. (Reprinted with permission from Volpe M. TRANSCEND Aftermath: Angiotensin II Receptor Blockers at the clinical cross-road. High Blood Press Cardiovasc Preven 2009;16(1):1-6)

On the basis of this complementary analysis to TRANSCEND [85], one may conclude that ARBs are as effective as ACE inhibitors in affording CV protection. Unfortunately, due to the small number of major CV events, the TRANSCEND results were not helpful in the further understanding of whether ARBs are protective in terms of prevention of atrial fibrillation [85]. Similarly, prevention of new onset diabetes could not be properly addressed by TRANSCEND [85], given the elevated number of patients who already had diabetes at the time of recruitment (about 36%), as well as the elevated mean age of the study population (about 67 years).
Two final clinically relevant aspects are blood pressure reduction and tolerability. With regard to these aspects, a recent meta-analysis by Zou [111], considering 28 randomized clinical trials and 5127 patients, has reported that telmisartan provides superior blood pressure control over ACE inhibitors (specifically enalapril, ramipril and perindopril). Telmisartan also caused fewer drug-related adverse events than enalapril (RR 0.57, 95% CI: 0.44- 0.74), ramipril (RR 0.44, 95% CI: 0.26-0.75), lisinopril (RR 0.70, 95% CI: 0.56-0.89) and perindopril (RR 0.52, 95% CI: 0.28-0.98) [111].

MAIN FINDINGS OF THE PRoFESS STUDY: COMMENTS AND CLINICAL IMPLICATIONS

As a major cause of morbidity and mortality, ischemic stroke currently represents the third most common cause of death in developed countries after coronary artery disease and cancer, and it is expected to dramatically increase over the next two decades. The risk of a recurrent stroke or transient ischemic attack (TIA) ranges between 5% and 15% per year in the general population, and it increases progressively with age and following a first ischemic episode [112]. Effective prevention of recurrent stroke still represents a major challenge for physicians [113]. Recent surveys have documented that physicians considered stroke prevention as the most important outcome in the clinical management of hypertensive patients, both at the primary care and the cardiologist levels [114]. In this setting, the use of low-dose aspirin is supported by a number of clinical studies [115-117] and is consistently recommended by international guidelines [1]. On the other hand, while effective and tight blood pressure control is primarily recommended for reducing stroke risk in both primary and secondary prevention [1], it is still unclear whether specific drug classes should be preferred.
Among effective antihypertensive strategies, ACE inhibition is reported to decrease stroke recurrence. In the PROGRESS trial [28], for example, use of an ACE inhibitor-based therapy reduced stroke recurrence by 28% versus placebo. This beneficial effect, however, achieved statistical significance only when the diuretic indapamide was used in association with perindopril, whereas perindopril alone had practically no effect on stroke recurrence [28]. In addition, the benefits, when presented, were associated with significant blood pressure reductions compared to placebo [28]. Similarly, in the high-risk population of the HOPE study [24], antihypertensive strategy based on the ACE inhibitor ramipril significantly reduced cerebrovascular events compared to placebo. Whether the greater reduction in blood pressure observed with ACE inhibitor played a determinant role is still being debated.
In this view, it has been postulated that the use of a more selective blockade of RAS, such as that provided by ARB-based therapy, may confer specific benefits in terms of stroke prevention, even for similar blood pressure lowering efficacy. This hypothesis has been supported by the results of the LIFE trial [61] for primary prevention of stroke in hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy, and, more recently, by the MOrbidity and mortality after Stroke, Eprosartan compared with nitrendipine for Secondary prevention (MOSES) study [64] in patients with previous stroke. This latter study has demonstrated that while the ARB eprosartan produced similar BP reductions to the dihydropiridinic calcium channel blocker nitrendipine, the primary endpoint (e.g. recurrent cerebrovascular accidents) was significantly lower in the ARB arm than in the calcium channel blocker arm.
On the basis of these considerations, the PRoFESS trial [86] was designed to expand this hypothesis in a 2 x 2 factorial, comparing the combination of aspirin/extended-release dipyridamole to clopidogrel and the effect of adding the ARB telmisartan to conventional treatment for reducing the risk of subsequent stroke. Patients were 50 years or older and had to have had an ischemic stroke within the past 120 days. The primary endpoint was time to first recurrent stroke of any type over the course of the study, and the primary hypothesis of the PRoFESS trial [86] was that the ARB telmisartan would be superior to placebo in reducing recurrent stroke and secondarily, that telmisartan was superior to placebo in reducing the composite outcome of recurrent stroke, myocardial infarction, vascular death, or new or worsening heart failure.
In this large-scale, international, randomized trial involving 695 sites in 35 countries, 20,332 patients were randomized to telmisartan (n = 10,146) or placebo (n = 10,186) and followed for 3.5 years [86]. In addition to study medications, 20% to 35% of patients were also taking blood pressure lowering drugs, including diuretics, ACE inhibitors, beta-blockers or calcium channel blockers during the trial [86]. At all time points measured, telmisartan produced a reduction in both systolic and diastolic blood pressure levels versus placebo [86]. Although the primary endpoint of recurrent stroke was reduced in the telmisartan group, the overall effect was not significantly different from placebo (8.7% vs. 9.2%; p = .231) (Figure 9) [86]. The incidence of major cardiovascular events was slightly, but not statistically significantly lower in those patients treated with telmisartan as compared with those treated with placebo (Figure 10) [86]. In particular, more patients in the telmisartan group experienced recurrent strokes in the first 6 months of the study, but after that time point, the placebo group had more strokes until the end of the study, which was significant for the interaction (p = .042) (Table 11) [86]. The same trend was observed for substantially all pre-specified subgroup analyses of the study (Figure 11 and Figure 12) [86].

	Figure 9. Kaplan-Meier curves for the incidence of the primary composite endpoint and of major CV events. (Reprinted with permission from Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359(12):1225-1237. Copyright © 2008 Massachusetts Medical Society. All rights reserved)
	Figure 10. Kaplan-Meier curves for the incidence of major CV events. (Reprinted with permission from Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359(12):1225- 1237. Copyright © 2008 Massachusetts Medical Society. All rights reserved)
	TABLE 11. Combined analysis of the results of TRANSCEND and PROFESS comparing telmisartan versus placebo (Reprinted from The Lancet, 372(9644), Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, 1174-1183. Copyright © 2008, with permission from Elsevier)
	Figure 11. Effect of Telmisartan on the Risk of Stroke in Pre-specified Subgroups. (Reprinted with permission from Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359(12):1225- 1237. Copyright © 2008 Massachusetts Medical Society. All rights reserved)
	Figure 12. Effect of Telmisartan on the Risk of Major Cardiovascular Events in Pre-specified Subgroups. (Reprinted with permission from Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359(12):1225-1237, Copyright © 2008 Massachusetts Medical Society. All rights reserved)

The reasons for this divergent trend cannot be clarified at this moment. It is likely, however, that the large blood pressure reduction observed in the telmisartan group as compared to placebo may have played a detrimental role in high-risk patients experiencing a recent stroke [118]. According to the study protocol, treatment could have, in fact, been started immediately after stroke [86]. On the other hand, given the lesser number of stroke recurrences in the telmisartan arm in the last three years of the study, it is reasonable to speculate that a longer observation (e.g., 5 years) could have led to a significant difference between the two Kaplan-Meier curves [86]. Other hypotheses that have been raised cannot be excluded: for instance, that angiotensin II could play a protective role in the ischemic area of the brain in the acute phase of stroke, or that stimulation of AT2 receptors by unbound angiotensin II may antagonize new angiogenesis in the ischemic or penumbra area [118]. In these latter two hypotheses, obviously selective blockade of the AT1 subtype receptors on top of the conventional therapy would not help. On the other hand, they are made unlikely by the design of the study, especially if one considers the very high proportion of patients in the two arms already receiving a blockade of the RAS by ACE inhibition (28.4% vs. 33.9%). The evidence from the entire clinical program with telmisartan seems to speak against such a strategy.
The placebo group also experienced more secondary outcome events, including stroke, myocardial infarction, vascular death, and heart failure [86]. However, the difference was only significant for the interaction with regard to time, which paralleled the primary outcome in that more telmisartan patients had a secondary outcome event in the first 6 months but the placebo group had more events in the following three years (p = .004) [86]. Finally, significantly more patients randomized to receive telmisartan discontinued taking their medication (p <.001) [86], primarily due to hypotensive symptoms, as also observed in the ONTARGET [84]. Altogether, the interesting results of this study reopen the question as to whether it is recommended and safe to aggressively lower blood pressure levels in the early stages after an acute stroke.
Although the use of telmisartan did not prove to be superior to placebo in secondary stroke prevention, the study analysis suggests that a potential later benefit specifically related to the addition of telmisartan to standard best treatment becomes evident over time following stroke. These benefits that begin to appear after 6 months are consistent with those seen in previous clinical trials with ARBs and are supported by recent meta-analyses focused on the benefits of RAS blocking agents in stroke prevention.

CONCLUSION

The ONTARGET/TRANSCEND/PRoFESS clinical trial program [84-86] has confirmed the clinical efficacy of telmisartan in preventing CV outcomes in patients at high CV risk, confirming a substantial clinical equivalence to the ACE inhibitor ramipril. When evaluated along with the results of other recent randomized clinical trials performed with ARBs, these new data reinforce the clinical position of the antihypertensive class of ARBs in clinical practice. Furthermore, they support an indication for the ARB telmisartan in reducing CV morbidity and mortality in patients with a high CV risk profile. In particular, the effectiveness and long-term safety in a population intolerant to ACE inhibitors at high or very high CV risk, support a new solution for an emerging clinical crossroad: whether to use an ARB as a new option and not only as an alternative to ACE inhibitors for CV patients. Besides its superior antihypertensive efficacy and documented tolerability in this vast clinical program, telmisartan has been shown to be a “CV drug” as powerful as the ACE inhibitor ramipril, and able to prevent major events in CV patients. In addition, telmisartan has confirmed tolerability superior to that of ramipril, which can be translated into superior treatment persistence.
A close look into the ONTARGET/TRANSCEND/ PRoFESS clinical trial program [84-86] reveals many interesting aspects that have relevance for clinical practice. Altogether, the results of the study significantly contribute to offering a new therapeutic option based on the use of telmisartan, in addition to the current standard represented by ACE inhibitors for the treatment of patients with CV disease at very-high risk. The ongoing substudies and subanalyses of the ONTARGET/TRANSCEND trial program [87] will provide additional important information.

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