Journal of hypertension. Supplement : official journal of the International Society of Hypertension最新文献

Clinical evaluation of cardiovascular risk in patients with hypertension is evolving from independently assessing well-known, traditional risk factors (e.g. hypertension, hypercholesterolemia, obesity, diabetes mellitus, smoking) towards an integrated, multidisciplinary clinical approach, aimed at determining the global (or total) cardiovascular risk profile in each individual patient for planning early and effective strategies for cardiovascular prevention. A paradigmatic example is provided by hypertension, in which new clinical behaviour implies a shift from focusing only on high blood pressure levels towards a more integrated approach, aimed at identifying and reducing global cardiovascular risk, as is highlighted in the European Guidelines. This approach arises from the acknowledgement that a cluster of cardiovascular risk factors is the rule, rather than the exception in hypertension. In addition, major cardiovascular diseases often develop from a subclinical level, which can be discovered at an early stage, thus providing the opportunity promptly to intercept and treat high-risk patients early. Identification of organ damage and assessment of hypertension-related clinical conditions can further contribute to a more precise definition of an individual total cardiovascular risk profile, and to the decision on when, how and how much to treat patients with hypertension. Implementing a clinical behaviour based on global cardiovascular risk assessment will help to target global cardiovascular risk reduction, while maintaining specific therapeutic goals for individual risk factors. This synergistic approach holds the best promise for treating total cardiovascular risk and reducing the mounting global burden of cardiovascular disease associated with hypertension.

Activation of the AT1 angiotensin II (Ang II) receptors has various effects including vasoconstriction, hypertrophy, and possibly hyperplasia of vascular smooth muscle cells and cardiomyocytes and increase in extracellular collagen matrix synthesis. These actions lead to the development of cardiovascular hypertrophy and fibrosis, as well as arterial stiffness, which are some key factors in the development of the cardiovascular and renal complications. In clinical studies, it has been shown that renin-angiotensin blockade has direct and specific implications in the evolution of heart failure, coronary disease, stroke, and hypertensive and diabetic renal disease. The beneficial cardiovascular and renal effects of blocking the renin-angiotensin-aldosterone system reported in numerous clinical trials may be at least partially related to the actions of these drugs on cardiovascular and renal fibrosis, and arterial stiffness. These effects are now well-established and lead the international medical societies to propose the use of the renin-angiotensin system (RAS) blockers as initial treatment (both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) in several cardiovascular, metabolic, and renal disorders such as hypertension, heart failure, and proteinuria.

Hypertension is one of the most important causes of cardiovascular morbidity and mortality and its treatment is a major focus of primary and secondary disease prevention strategies. The treatment of hypertension continues to evolve and the need for guidance on the use of newer screening tools, techniques for blood pressure measurement and different classes of drug therapies led to the first European guidelines for the management of arterial hypertension being issued in 2003 by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). The first update of these guidelines in 2007 crystallized much of the modern thinking about the evaluation and treatment of patients with hypertension with a sharp focus on detailed assessment of subclinical organ damage and cardiovascular disease risk, as well as differential blood pressure treatment targets and thresholds for those at different levels of risk. This review focuses on the 2007 ESH/ESC Guidelines, highlighting the evolution of treatment strategies in order to meet the challenge of improving blood pressure control in Europe. In particular, development of patient-centred treatment strategies, the benefits of blood pressure lowering, drug-specific influences over clinical outcomes, recommendations for the pharmacological treatment of hypertension and the role of combination therapies are discussed.

Stroke is the second most frequent cause of death in the world and is responsible for about 5 million deaths each year. Several trials have raised the possibility that blocking the renin-angiotensin system (RAS) may be beneficial in patients with stroke. The recently reported Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study evaluated the effect of lowering blood pressure with the angiotensin receptor blocker (ARB), telmisartan, initiated early after stroke. A total of 80 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke, a nonsignificant 5% relative risk reduction in the telmisartan group. Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and in 1463 patients (14.4%) in the placebo group, a 6% nonsignificant relative risk reduction. The mean follow-up in the PRoFESS study was only 2.5 years, which was too short to assess the impact of treatment on atherosclerotic disease. Stroke prevention aimed at the atherosclerotic process has repercussions on the entire cardiovascular system. The Kaplan-Meier curve of the incidence of major cardiovascular events in PRoFESS has a striking similarity with the Kaplan-Meier curves of Heart Outcomes Prevention Evaluation (HOPE), EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trials for a similar endpoint. It is highly probable that with a longer follow-up, the difference between telmisartan-treated and placebo-treated patients would become significant. In 2008, patients with cardiovascular disease are considerably better treated than 10 years ago. By omitting one class of drugs from the cocktail used for prevention in these high-risk patients (statins, beta-blockers, antiplatelet drugs and angiotensin-converting enzyme inhibitors or ARBs), part of the benefit obtained by the complete treatment will be lost. PRoFESS seems to be a negative trial at first sight, but if considered together with the available data from other clinical trials, it clearly shows that it would be a mistake to withhold drugs that counteract the effect of angiotensin II in patients with stroke or other atherosclerotic disease.

Blockade of the renin-angiotensin system (RAS) has become an integral component of the treatment of patients at increased cardiovascular risk. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) studied 23 400 high-risk cardiovascular patients and compared the effectiveness of telmisartan with that of ramipril and showed that the two drugs were 'therapeutically equivalent'. Telmisartan is now the only angiotensin II blocker with clinical trial evidence of cardiovascular protection equivalent to that of ramipril, which is widely regarded as the 'reference' drug for RAS blockade in patients at increased cardiovascular risk. Despite the prior exclusion of patients intolerant of angiotensin-converting enzyme inhibitors drugs, there were fewer discontinuations in the telmisartan group, and so telmisartan had a superior overall efficacy/tolerability ratio.

Angiotensin-converting enzyme (ACE) inhibitors are useful drugs for preventing cardiovascular disease and death in patients at risk. However, a significant proportion of patients experience side effects, mainly cough or less frequently angioedema, when treated with ACE inhibitors. Angiotensin receptor blockers (ARBs) are also useful drugs for treatment of hypertension, diabetic nephropathy and patients with left ventricular dysfunction or cardiac failure who are intolerant to ACE inhibitors. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) study examined the effect of a long-acting ARB, telmisartan, on cardiovascular events in a group of patients at high-risk for cardiovascular disease who were intolerant to ACE inhibitors. Five thousand nine hundred twenty-six patients with known intolerance to ACE inhibitors were randomized to telmisartan or placebo added to current treatments. The primary composite endpoint, a sum of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to heart failure was nonsignificantly reduced in telmisartan-treated patients with respect to placebo (15.7 vs. 17%; relative risk reduction 8%). The key secondary endpoint (the primary endpoint excluding heart failure hospitalization) was reduced in telmisartan-treated patients by 13% (13 vs. 14.8%; P = 0.046). In conclusion, telmisartan reduces cardiovascular events in high-risk patients with the exception of heart failure hospitalization and can be considered as the first-line therapy in those intolerant to ACE inhibitors.

In patients with arterial hypertension and/or high cardiovascular risk, including patients with diabetes, chronic ischemic heart disease and kidney disease, the risk of heart failure decreases with blood pressure reduction and the use of drugs that inhibit the renin-angiotensin system (RAS) [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)]. The heart failure incidence seen in ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) is in line with this observation. In ONTARGET, telmisartan and ramipril were equally effective in heart failure prevention and with the same blood pressure reduction. The low event rate, including the low incidence of heart failure in TRANSCEND with the greater use of diuretics in the placebo arm, may help to explain the absence of significant differences between telmisartan and placebo.

One major element of novelty of the 2007 European guidelines on hypertension refers to the concept of risk categorization, with the aim of obtaining a more precise definition of the hypertensive patient. This has lead to identification of different categories of cardiovascular risk, from the low to the very high. Studies performed in the past few years have shown that the very high risk category is quite common and it is not unusually accompanied by poor blood pressure control. Results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACEI iNtolerant subjects with cardiovascular Disease (TRANSCEND) have allowed us to better define the therapeutic approach to high-risk patients showing the favorable effects of either ramipril or telmisartan on blood pressure control and risk profile. Additionally, these studies have shown that discontinuation of antihypertensive treatment is not a rare phenomenon, which can be at least in part minimized by the use of drugs with a high tolerability profile, such as angiotensin II receptor blockers (ARBs), and more specifically telmisartan. This review article examines in depth the results of the two above-mentioned trials as well as their impact on guidelines on antihypertensive treatment.

'Hard' primary endpoints from randomized clinical trials, such as cardiovascular morbidity and mortality data are usually considered as the backbone of evidence for clinical practice guidelines. However, 'intermediate' or 'surrogate' endpoints, for example, biological or imaging markers are increasingly being recognized for their importance in stratifying risk and determining treatment strategy in clinical practice. In hypertension, use of validated surrogate endpoints, notably left ventricular hypertrophy (LVH), microalbuminuria, arterial stiffness and carotid intima-media thickness are discussed. These variables are among those assessed in clinical practice, and are considered as predictors of cardiovascular risk. Moreover, some antihypertensive therapies can reverse these organ-damage abnormalities and improve cardiovascular prognosis partly independently from their blood pressure lowering effect. Recognizing the importance of identifying subclinical organ damage in the prediction of cardiovascular risk provides further support to physicians making decisions in their daily clinical practice and offers possibilities for prospective studies on cardiovascular prevention in populations of middle age with low cardiovascular risk. In this article we overview the advantages and disadvantages of morbidity/mortality trials and 'hard' versus 'soft' endpoints. We also considered the relevance of analyzing not only primary endpoints but also secondary endpoints.

The early detection of cardiac organ damage in clinical practice is primordial for cardiovascular risk profiling of patients with hypertension. In this respect the determination of microalbuminuria is very appealing because it increasingly appears to be the most cost-effective means to identify cardiovascular and renal complications. Considering the treatment of patients with target organ damage, blockers of the renin-angiotensin system have a key position as they are very effective in regressing left ventricular hypertrophy, lowering urinary albumin excretion and delaying the progression of nephropathy. In high-risk patients with atherosclerosis, the use of a blocker of the renin-angiotensin system is also appealing, and it appears increasingly judicious to combine such a blocker with a calcium antagonist whenever required to control blood pressure.