The attitude to modern antihypertensive treatment differs from that which prevailed only a few years ago in several important aspects. First, conclusive evidence is now available demonstrating that, since a substantial fraction of the benefit associated with antihypertensive treatment depends on blood-pressure lowering per se,1 reducing elevated blood pressure to <140/90mmHg is beneficial no matter how these values are achieved.2 Second, the results of several trials suggest that in patients at high cardiovascular risk the benefit can be greater if a blood-pressure reduction to <130/80mmHg is pursued; these should obviously be the goals of antihypertensive treatment strategy utilised in individuals whose blood pressure is above this target value.2 Third, there is a consensus that in a substantial fraction of the hypertensive population these more aggressive blood-pressure targets cannot be attained by monotherapy: a combination of at least two drugs offers a much greater chance of success.3
The TALENT (a mulTicenter study evALuating the Efficacy of Nifedipine GITS–Telmisartan combination in blood pressure control and beyond) study was designed to provide more information on the potential of combination treatments for the successful management of hypertension (see Figure 1). Some of the key goals and features of this study will be highlighted in this article.
Angiotensin Receptor Antagonist–Calcium Antagonist Combination
The recent guidelines on hypertension from the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC), besides taking a clear stand in favour of the greater effectiveness of a two- or three-drug versus a one drug-treatment strategy in terms of reducing blood pressure, emphasise the fact that physicians have at their disposal several two-drug combinations that can achieve an effective blood-pressure reduction.2
There is no question, however, that recent data appear to be in favour of a combination of a blocker of the renin–angiotensin system and a calcium antagonist. For example, in the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR),4 a combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium antagonist was associated with a lower rate of new-onset diabetes (a condition that increases long-term cardiovascular risk)5 compared with the classic ACE inhibitor–thiazide diuretic combination.
Furthermore, in the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) study6 on a large number of hypertensive patients, both an ACE inhibitor–calcium antagonist and an ACE inhibitor–diuretic combination reduced blood pressure to a remarkably effective degree (about 130mmHg systolic). However, in patients receiving the ACE inhibitor–calcium antagonist combination the incidence of cardiovascular events was significantly lower. Finally, there is also evidence that a remarkable reduction in blood pressure can be obtained when a calcium antagonist is combined with an angiotensin receptor antagonist, with the amlodipine–valsartan and the nifedipine gastrointestinal therapeutic system (GITS)–losartan combinations providing the best results.7,8
The TALENT study is investigating the blood-pressure-lowering potential of combining nifedipine GITS with telmisartan in about 400 patients at high cardiovascular risk because of the presence of diabetes, sub-clinical damage (microalbuminuria or left ventricular hypertrophy) or a metabolic syndrome. Nifedipine GITS can effectively control 24-hour blood pressure with once-a-day administration, and its use in a large randomised trial (International Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment [INSIGHT]) has proved its ability to protect hypertensive patients from the occurrence of cardiovascular events, as well as to exert a clear-cut antiatherogenic effect compared with traditional diuretic treatment.
Furthermore, Telmisartan is an angiotensin receptor antagonist that has a much longer half-life and potential for sustained 24-hour blood pressure control than other angiotensin receptor antagonists.9 This has been proved by measuring 24-hour ambulatory blood pressure – a more sensitive predictor of cardiovascular risk than office blood pressure10 – in all patients; this also allows the effect of treatment on other phenomena of prognostic relevance to be determined, such as night-time blood pressure, morning blood-pressure surge and blood-pressure variability.11,12
Angiotensin Antagonist–Calcium Antagonist Combination as First-choice Treatment
Until a few years ago, guidelines on hypertension invariably recommended starting treatment with a monotherapy, with other drugs being added only if needed to effectively reduce blood pressure. However, more recently this position has changed and physicians are presented with two options: either to start treatment with one drug or to use two drugs from the beginning if a patient can be classified as being at high cardiovascular risk.2,13 This has originated from the evidence that:
- in a high-risk individual the chance of a morbid or fatal cardiovascular event within a short time period is not negligible;
- blood-pressure control has been shown to reduce the event rate as early as a few months after the beginning of treatment; and
- in the VALUE study, patients in whom blood-pressure control was achieved early (within one month) had fewer events compared with those in whom it was achieved later.14
One other potential advantage of initiating treatment with two drugs has emerged more recently: the rate of blood-pressure control is improved compared with that obtained when treatment starts with a single drug and moves to combination only at a later time. The TALENT study allows this specific issue to be addressed, as:
- in one group treatment is started with nifedipine GITS 20mg plus telmisartan 80mg, a regimen that is maintained unchanged throughout the 16 weeks of the study; and
- in the other two groups treatment starts with telmisartan 80mg or nifedipine GITS 20mg, and the two drugs are administered in combination only after eight weeks, i.e. halfway through the study.
In both groups the goal of treatment is to reduce blood pressure to <130/80mmHg, as required by the high-risk conditions of the recruited patients.
The importance of strategies that improve the rate of blood-pressure control cannot be overemphasised. Evidence from all available data indicates that worldwide only a limited number of hypertensive patients have their blood pressure reduced to <140/90mmHg,2 and that only a minute fraction of high-risk individuals achieve the more aggressive goal recommended by guidelines (<130/80mmHg).15 This is presumably the reason why hypertension still stands as the number one cause of death worldwide.16
It is generally agreed that the poor rate of blood-pressure control in the hypertensive population results from the interplay of several complex factors, including insufficient use of combination treatment. As mentioned by the ESH/ESC guidelines (see Figure 2),2 however, an additional reason can be the frustration experienced following an initial unsuccessful monotherapy (particularly if followed by other monotherapy attempts), which can demotivate the patient and favour the clinical inertia of the physician. The demonstration in TALENT that initiating treatment with a combination of drugs leads to a greater rate of blood-pressure control would thus be a result of general importance.
Other Goals
The TALENT study also has other interesting goals. One of them is to look for a number of efficacy parameters based on ambulatory blood-pressure monitoring data, among them the smoothness index. This can determine more effectively than the classical trough-to-peak ratio how homogeneous the blood pressure fall induced by treatment is over 24 hours, with consequences for blood-pressure variability and for the protection of the organs exposed to the damage induced by a blood-pressure elevation.17
Another goal is to measure the antiproteinuric effect of the combination of nifedipine GITS and telmisartan compared with the two combination components as monotherapy. This has important clinical implications because both microalbuminuria and proteinuria predict the incidence of cardiovascular events, their reduction in turn being associated with a better prognosis in both diabetic and non-diabetic individuals.18,19
Finally, the TALENT study includes the measurement of inflammatory markers. This is an emerging area of interest in hypertension due to evidence that inflammation is a component of atherosclerosis and that inflammatory markers may therefore be important predictors of the outcome of patients.20 Improvement of these markers by treatment may thus become a future goal, in light also of the importance given by the ESH/ESC guidelines2 to the effect of treatment on precursors of events such as risk factors, organ damage and new-onset high-risk conditions.