Summary Background Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, ...but harm for other outcomes. Methods In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2 . These trials were registered with ClinicalTrials.gov , number NCT00153101. Findings Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio HR 1·14, 95% CI 1·03–1·26), cardiovascular death (1·29, 1·12–1·49), and all deaths (1·28, 1·15–1·42) were increased compared with those in whom SBP was 120–140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110–120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20–1·42), myocardial infarction (1·55, 1·33–1·80), hospital admission for heart failure (1·59, 1·36–1·86) and all-cause death (1·16, 1·06–1·28) than a DBP 70–80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk. Interpretation Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality. Funding Boehringer Ingelheim.
Summary Background Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either ...treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. Methods The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00153101. Findings 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 13·4%) and ramipril (1150 13·5%; hazard ratio HR 1·00, 95% CI 0·92–1·09), but was increased with combination therapy (1233 14.5%; HR 1·09, 1·01–1·18, p=0·037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 2·21%) and ramipril (174 2·03%; HR 1·09, 0·89–1·34) and more frequent with combination therapy (212 2·49%: HR 1·24, 1·01–1·51, p=0·038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (−2·82 SD 17·2 mL/min/1·73 m2 vs −4·12 17·4, p<0·0001) or combination therapy (−6·11 17·9, p<0·0001). The increase in urinary albumin excretion was less with telmisartan (p=0·004) or with combination therapy (p=0·001) than with ramipril. Interpretation In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes. Funding Boehringer-Ingelheim.
Summary Background Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical ...arterial properties and reduce blood pressure in patients with uncontrolled hypertension. Methods We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov , number NCT01642498. Findings 83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting. Interpretation Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension. Funding ROX Medical.
Renin-angiotensin system and cardiovascular risk Schmieder, Roland E, Prof; Hilgers, Karl F, Prof; Schlaich, Markus P, MD ...
The Lancet (British edition),
04/2007, Volume:
369, Issue:
9568
Journal Article
Peer reviewed
Summary The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Basic research has revealed exciting new aspects, which could lead to novel or modified ...therapeutic approaches. Renin-angiotensin system blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system—ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first-line treatments for hypertensive target organ damage and progressive renal disease. Their effects are greater than expected by their ability to lower blood pressure alone. Angiotensin receptor blockers reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients. Thus, blockade of this system will remain a cornerstone of our strategies to reduce cardiovascular risk.
