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

The benefits of blood pressure control on the risks of major cardiovascular events are well established. In clinical trials conducted in patients with mild-to-moderate hypertension, the angiotensin II receptor blocker (ARB) telmisartan has been shown to provide reduction of blood pressure throughout the 24-h dosing interval. Clinical trials have also demonstrated that ARBs are effective agents in reducing the risk of cardiovascular mortality, stroke, heart failure and new-onset atrial fibrillation. Recently, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study established that telmisartan reduces morbidity and mortality in a broad cross-section of patients at high risk for heart and vascular events, to an extent similar to that of the angiotensin-converting enzyme inhibitor ramipril. In addition, ONTARGET demonstrated that telmisartan is somewhat better tolerated than ramipril. Attributes such as effective blood pressure lowering, tolerability and convincing outcomes data mean that ARBs satisfy the requirements for first-line antihypertensive agents.

Impaired kidney function increases the risk of cardiovascular morbidity and mortality. Coexistence of hypertension and type 2 diabetes increases the risk of kidney damage, hypertension being an independent risk factor for kidney disease progression. Angiotensin II, through its inflammatory, proliferative, and thrombotic effects, adversely affects renal perfusion and increases oxidative stress, thus playing a pivotal role in kidney disease progression. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors improve markers of kidney disease and slow kidney disease progression in diabetic and nondiabetic patients; this kidney protection may be in addition to their antihypertensive activity in those with advanced proteinuric nephropathy. Key beneficial effects of ARBs and ACE inhibitors throughout the kidney disease continuum are primarily explained by blood pressure lowering effects and partially by their direct blockade of angiotensin II. Recent studies have shown that telmisartan, an ARB with high lipophilicity and the longest half-life compared with other ARBs, provides benefits on markers of cardiovascular risk, that is, microalbuminuria and slowing of early-stage nephropathy.

The Heart Outcomes Prevention Evaluation study established the angiotensin-converting enzyme inhibitor ramipril, versus placebo, for prevention of cardiovascular events in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was later conducted in similar high-risk patients using multifactorial treatment to control hypertension, platelet aggregation, and dyslipidemia, while comparing ramipril, telmisartan, or their combination, without placebo. In ONTARGET, the first angiotensin II receptor blocker-based study to be performed in a broader population of patients without congestive heart failure and/or left ventricular hypertrophy/dysfunction, telmisartan provided cardiovascular protection that was noninferior to ramipril. However, greater blockade of the renin-angiotensin system, using their combination, was not superior to ramipril alone. Telmisartan was better tolerated than ramipril in this high-risk population: notably, the incidence of cough and angioedema was significantly lower with telmisartan alone. Thus, telmisartan provides comparable efficacy to ramipril with less adverse events, which may encourage patient compliance.

It is well established that lowering blood pressure (BP) in patients with hypertension is associated with cardiovascular protection. Therefore, BP goals have been defined by international hypertension guidelines (<140/90 mmHg; <130/80 mmHg for patients with type 2 diabetes). However, the relationship of BP with prognosis is complex, and controlling office BP may not be enough to optimally manage total cardiovascular risk. It is becoming clear that out-of-office BP measurements have important prognostic value. In the observational Pressioni Arteriose Monitorate E Loro Associazioni study, the risk of cardiovascular death over 11 years was progressively higher with 10-mmHg increases in office, home, or ambulatory BPs. Smooth control of 24-h BP may be of even greater importance, as the early morning BP surge, nighttime BP, and BP variability are associated with significant risk. A further consideration in managing total cardiovascular risk is the need for multiple antihypertensive agents to control BP.

Angiotensin II has diverse effects on cardiovascular structure and function, and hence drugs that inhibit the formation or activity of this peptide have attained a central position in the prevention of morbidity and mortality from cardiovascular causes. The recent ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) has shown that, in patients with vascular disease or patients with diabetes who were at high risk of cardiovascular events, the angiotensin II receptor blocker telmisartan is noninferior to the angiotensin-converting enzyme inhibitor ramipril in preventing such events, despite the ONTARGET patients receiving better background preventive therapy than those enrolled in the earlier Heart Outcomes Prevention Evaluation (HOPE) study. In addition, telmisartan offers superior tolerability to that of ramipril. Moreover, the finding in this study that combination therapy with telmisartan and ramipril produced no further reduction in cardiovascular events than either drug alone, despite producing greater reductions in blood pressure, highlights the potential importance of endothelial effects of renin-angiotensin system blockade in cardiovascular protection.

Renin-angiotensin system blockers have been shown to reduce stroke risk, partly independent of their blood pressure-lowering effect. The PReventiOn regimen For Effectively avoiding Second Strokes (PRoFESS) trial, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease (TRANSCEND) recently showed potential benefits of the angiotensin II receptor blocker, telmisartan, in reducing secondary strokes. In PRoFESS, 20 332 ischemic stroke patients were randomized to telmisartan 80 mg versus placebo and to two antiplatelets in a 2 x 2 factorial design. After a mean exposure of 2 years, telmisartan showed a nonsignificant lower rate of recurrent stroke versus placebo [880 versus 934; hazard ratio 0.95; 95% confidence interval (CI) 0.86-1.04]. In a post-hoc analysis, from 6 months, telmisartan significantly reduced the number of strokes versus placebo (533 versus 608; hazard ratio 0.88; 95% CI 0.78-0.99; P = 0.042). In the stroke subgroup of ONTARGET, telmisartan 80 mg showed a trend toward reducing recurrent stroke versus ramipril 10 mg (hazard ratio 0.91; 95% CI 0.79-1.05). In the TRANSCEND study, 5926 patients who were intolerant to angiotensin-converting enzyme inhibitors were treated with 80 mg telmisartan or placebo. In a combined analysis of PRoFESS and TRANSCEND, the incidence of the composite of stroke, myocardial infarction, or vascular death was 12.8% for telmisartan versus 13.8% for placebo (hazard ratio 0.91; 95% CI 0.85-0.98; P = 0.013).

Angiotensin II plays an important role in the cardiovascular continuum starting with risk factors and progressing to atherosclerosis, target organ damage, and ultimately to heart failure, stroke, or death. Inhibiting the renin-angiotensin-aldosterone system (RAAS) represents a cornerstone for the treatment of hypertension and heart failure. In patients with heart failure, the single RAAS blockade with angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality, increase life expectancy, and preserve the renal function. AT1 receptor blockers (ARBs) are equally effective in reducing mortality and morbidity in patients with impaired left ventricular function. The combination of ACE inhibitors with ARBs leads to an additive blood pressure lowering effect, better reduction in proteinuria, and to additive benefits in heart failure and left ventricular hypertrophy. But combination therapy is also associated with more side effects. Further investigations evaluating the effect of dual RAAS blockade on fatal and nonfatal cardiovascular events are needed.

Hypertension control in populations, although improving, remains far from satisfactory, even though effective and inexpensive therapies are available. Among many factors responsible for this situation, poor adherence to treatment appears to be particularly important. Unfortunately, even if its causes have been quite well defined, this problem is still far from being solved in clinical practice. The present paper discusses the key issues related to treatment adherence, and discontinuation in hypertension, in the light of recent evidence coming from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease trial (TRANSCEND).