title: A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. Effect of nebivolol vs. hydrochlorothiazide on the walking capacity in hypertensive patients with intermittent claudication PLACEBO-CONTROLLED COMPARISON OF CAPTOPRIL, ATENOLOL, LABETALOL, AND PINDOLOL IN HYPERTENSION COMPLICATED BY INTERMITTENT CLAUDICATION Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial Effects of captopril and ticlopidine, alone or in combination, in hypertensive patients with intermittent claudication. Brief Communication: Ramipril Markedly Improves Walking Ability in Patients with Peripheral Arterial Disease The effects of tertatolol on lipid profile. &bgr;-Blockers in Patients With Intermittent Claudication and Arterial Hypertension: Results From the Nebivolol or Metoprolol in Arterial Occlusive Disease Trial Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension. Lack of influence of propranolol and metoprolol on walking distance in patients with chronic intermittent claudication. [Are beta-blockers generally contraindicated in patients with peripheral arterial occlusive disease?]. Intensive Blood Pressure Control Reduces the Risk of Cardiovascular Events in Patients With Peripheral Arterial Disease and Type 2 Diabetes Telmisartan, ramipril, or both in patients at high risk for vascular events. Outcomes Among Hypertensive Patients With Concomitant Peripheral and Coronary Artery Disease: Findings From the INternational VErapamil-SR/Trandolapril STudy Walking capacity of patients with intermittent claudication during chronic antihypertensive treatment with metoprolol and methyldopa. Reduced arterial stiffness may contribute to angiotensin-converting enzyme inhibitor induced improvements in walking time in peripheral arterial disease patients Cardioprotective medication is associated with improved survival in patients with peripheral arterial disease. Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease Ramipril Reduces Large-Artery Stiffness in Peripheral Arterial Disease and Promotes Elastogenic Remodeling in Cell Culture Effect of beta-adrenergic blockers on the peripheral circulation in patients with peripheral vascular disease. [Comparative studies of the effect of a cardioselective and a noncardioselective beta-blocker on peripheral circulation in patients with arterial occlusive disease]. Beta-blockers and nitrates in patients with peripheral arterial occlusive disease: long-term findings. Morbidity, mortality, and antihypertensive treatment effects by extent of atherosclerosis in older adults with isolated systolic hypertension. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Int Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hypercholesterolaemia (the DAPHNE study). Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: an analysis of findings from the VALUE trial Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. The HOPE study investigators. A dose-effect study of beraprost sodium in intermittent claudication. Predictors of adverse outcome among patients with hypertension and coronary artery disease. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Design of the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial. Verapamil-sustained release-based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovascular events in patients with prior myocardial infarction: an INternational VErapamil SR-Trandolapril (INVEST) substudy. Left ventricular mass and volume with telmisartan, ramipril, or combination in patients with previous atherosclerotic events or with diabetes mellitus (from the ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]). The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. Effect of high dose verapamil on restenosis after peripheral angioplasty. Vitamin E supplementation and cardiovascular events in high-risk patients. Effects of ketanserin on blood pressure, peripheral circulation and haemocoagulative parameters in essential hypertensives with or without arteriosclerosis obliterans of the lower limbs. [Behavior of blood pressure and peripheral hemodynamics in interval therapy in untreated and propranolol-treated patients with arterial circulatory disorders of the lower extremities]. Effects of chronic administration of selective betablockers on peripheral circulation of the lower limbs in patients with essential hypertension. Global differences in blood pressure control and clinical outcomes in the INternational VErapamil SR‐Trandolapril Study (INVEST) beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Mortality over a period of 10 years in patients with peripheral arterial disease. Chronic effects of labetalol, pindolol, and propranolol on calf blood flow in intermittent claudication Clinical Efficacy of Picotamide in Long-Term Treatment of Intermittent Claudication Relation between risk factors and cardiovascular complications in patients with peripheral vascular disease. Results from the A.D.E.P. study. The effects of acebutolol and metoprolol on walking distances and distal blood pressure in hypertensive patients with intermittent claudication. [Hemodynamic effects of chronic treatment by cilazapril in normotensive patients with obliterative arterial diseases of the lower limbs]. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled tri Invasive hemodynamic evaluation of sublingual captopril and nifedipine in patients with arterial hypertension after abdominal aortic surgery. Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial. Beta blockade and intermittent claudication. Telmisartan, ramipril, or both in high-risk Chinese patients: analysis of ONTARGET China data. A new trial of the efficacy, tolerability, and safety of angiotensin-converting enzyme inhibition in mild systemic hypertension with concomitant diseases and therapies. Perindopril Therapeutic Safety Study Group (PUTS). Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial The influence of chronic treatment with betablockade and angiotensin converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication. A comparative cross-over trial. Baseline characteristics of participants in the Appropriate Blood Pressure Control in Diabetes trial. Effect of long-term beta-adrenergic-blockade on calf blood flow in hypertensive patients. Assessment of Captopril and Nicardipine Effects on Chronic Occlusive Arterial Disease of the Lower Extremity Using Doppler Ultrasound Different vasodilating mechanisms--different peripheral effects? ACE-inhibition with perindopril in essential hypertensive patients with concomitant diseases. The Perindopril Therapeutic Safety Collaborative Research Group. Double-Blind Comparison of Captopril with Nifedipine in Hypertension Complicated by Intermittent Claudication Vascular wall thickness in hypertension: the Perindopril Regression of Vascular Thickening European Community Trial (PROTECT). [Double-blind randomized controlled trial of ifenprodil tartrate versus placebo in chronic arterial occlusive disease of the legs at stage II of the Leriche and Fontaine classification]. Effect of Felodipine on Regional Blood Supply and Collateral Vascular Resistance in Patients with Peripheral Arterial Occlusive Disease Study population and treatment titration in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-IN Controlled trial of propranolol in intermittent claudication Erectile Dysfunction Predicts Cardiovascular Events in High-Risk Patients Receiving Telmisartan, Ramipril, or Both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONT
abstract: CONTEXT Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients , safety and efficacy of antihypertensive agents for coronary artery disease ( CAD ) have been discerned only from subgroup analyses in large trials . OBJECTIVE To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy ( CAS ) or a non-calcium antagonist strategy ( NCAS ) .  DESIGN , SETTING , AND PARTICIPANTS R and omized , open label , blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older , which was conducted September 1997 to February 2003 at 862 sites in 14 countries . INTERVENTIONS Patients were r and omly assigned to either CAS ( verapamil sustained release ) or NCAS ( atenolol ) . Strategies specified dose and additional drug regimens . Tr and olapril and /or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) of less than 140 mm Hg ( systolic ) and less than 90 mm Hg ( diastolic ) ; and less than 130 mm Hg ( systolic ) and less than 85 mm Hg ( diastolic ) if diabetes or renal impairment was present . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . MAIN OUTCOME MEASURES Primary : first occurrence of death ( all cause ) , nonfatal myocardial infa rct ion , or nonfatal stroke ; other : cardiovascular death , angina , adverse experiences , hospitalizations , and blood pressure control at 24 months . RESULTS At 24 months , in the CAS group , 6391 patients ( 81.5 % ) were taking verapamil sustained release ; 4934 ( 62.9 % ) were taking tr and olapril ; and 3430 ( 43.7 % ) were taking hydrochlorothiazide . In the NCAS group , 6083 patients ( 77.5 % ) were taking atenolol ; 4733 ( 60.3 % ) were taking hydrochlorothiazide ; and 4113 ( 52.4 % ) were taking tr and olapril . After a follow-up of 61 835 patient-years ( mean , 2.7 years per patient ) , 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies ( 9.93 % in CAS and 10.17 % in NCAS ; relative risk [ RR ] , 0.98 ; 95 % confidence interval [ CI ] , 0.90 - 1.06 ) . Two-year blood pressure control was similar between groups . The JNC VI blood pressure goals were achieved by 65.0 % ( systolic ) and 88.5 % ( diastolic ) of CAS and 64.0 % ( systolic ) and 88.1 % ( diastolic ) of NCAS patients . A total of 71.7 % of CAS and 70.7 % of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg . CONCLUSION The verapamil-tr and olapril-based strategy was as clinical ly effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients Aims Whereas product labels of beta blockers list peripheral arterial disease ( PAD ) as a contraindication , current PAD guidelines state otherwise . We aim ed to evaluate the clinical efficacy and safety of the ß1 selective blocker nebivolol in hypertensive patients with PAD . Methods and results This multicentre , prospect i ve , double-blind , active controlled , parallel-group study compared once-daily treatment with nebivolol ( Neb ) 5 mg vs. hydrochlorothiazide ( HCTZ ) 25 mg , in hypertensive patients with Fontaine stage II ( intermittent claudication ) . The primary endpoint was the initial claudication distance ( ICD ) during treadmill exercise after 24-week treatment in the per protocol population , using a noninferiority statistical approach . A total of 177 patients ( mean age was 66.3 ± 9.2 years , 76.7 % men ) were r and omized to study treatment and 127 completed the study ; the intent-to-treat ( ITT ) analysis was performed on 163 patients , the per protocol analysis on 127 patients . Both drugs lowered blood pressure significantly . After 24-week treatment , ICD increased in the Neb group in the ITT population by 28.3 % ( 95 % CI 15.6–41.0 ) vs. in the HCTZ group by 26.5 % ( 14.4–38.5 ) , and in the per protocol population in the Neb group by 26.4 % ( 13.4–39.4 ) vs. in the HCTZ group by 32.1 % ( 18.4–45.7 ) . Thus , noninferiority of Neb could neither be confirmed nor rejected . An increase of absolute claudication distance ( ACD , mean percentage increase after 24 weeks on Neb 15.8 ± 33.2 vs. on HCTZ 20.2 ± 46.6 ) was observed without statistical differences between groups . Ankle-brachial index ( ABI ) increased slightly in both groups . Generally , both treatments were well tolerated . Conclusion The increases in ICD , ACD and ABI with nebivolol suggest that this medication does not have negative effects on hypertensive patients with symptomatic PAD , and can be used for treatment of hypertension in these patients at high cardiovascular risk without reducing the walking ability In a six month placebo-controlled cross-over trial twenty patients with hypertension and peripheral arterial disease were r and omised to captopril 25 mg twice daily , atenolol 100 mg once daily , labetalol 200 mg twice daily , or pindolol 10 mg twice daily for one month . Although all treatments were equally effective at lowering blood pressure , pain-free and maximum walking distances on a treadmill were decreased by  atenolol , labetalol , and  pindolol  , but not by captopril .  Post-exercise calf blood flow availability was impaired by  atenolol , labetalol , and  pindolol  , but not by captopril . Despite ancillary characteristics of cardioselectivity , intrinsic sympathomimetic activity , or combination with alpha-blockade , beta-blockers seem to impair the lower limb circulation in such patients , whereas captopril seems to preserve it , possibly by maintaining the collateral blood supply BACKGROUND Trials of beta blockers in patients undergoing non-cardiac surgery have reported conflicting results . This r and omised controlled trial , done in 190 hospitals in 23 countries , was design ed to investigate the effects of perioperative beta blockers . METHODS We r and omly assigned 8351 patients with , or at risk of , atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate ( n=4174 ) or placebo ( n=4177 ) , by a computerised r and omisation phone service . Study treatment was started 2 - 4 h before surgery and continued for 30 days . Patients , health-care providers , data collectors , and outcome adjudicators were masked to treatment allocation . The primary endpoint was a composite of cardiovascular death , non-fatal myocardial infa rct ion , and non-fatal cardiac arrest . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00182039 . FINDINGS All 8351 patients were included in analyses ; 8331 ( 99.8 % ) patients completed the 30-day follow-up . Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint ( 244 [ 5.8 % ] patients in the metoprolol group vs 290 [ 6.9 % ] in the placebo group ; hazard ratio 0.84 , 95 % CI 0.70 - 0.99 ; p=0.0399 ) . Fewer patients in the metoprolol group than in the placebo group had a myocardial infa rct ion ( 176 [ 4.2 % ] vs 239 [ 5.7 % ] patients ; 0.73 , 0.60 - 0.89 ; p=0.0017 ) . However , there were more deaths in the metoprolol group than in the placebo group ( 129 [ 3.1 % ] vs 97 [ 2.3 % ] patients ; 1.33 , 1.03 - 1.74 ; p=0.0317 ) . More patients in the metoprolol group than in the placebo group had a stroke ( 41 [ 1.0 % ] vs 19 [ 0.5 % ] patients ; 2.17 , 1.26 - 3.74 ; p=0.0053 ) . INTERPRETATION Our results highlight the risk in assuming a perioperative beta-blocker regimen has benefit without substantial harm , and the importance and need for large r and omised trials in the perioperative setting . Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol Twenty four male hypertensive patients suffering also from peripheral obstructive arterial disease were r and omly subdivided in two groups and after a period of farmacological wash-out of one month Group I was treated with Captopril ( C 50 mg bid ) or Ticlopidine ( T 250 mg bid ) for three months and then with the association C plus T for three months again . After placebo administration for one month , patients were further treated with C plus T at low doses ( 25 mg bid and respectively 250 mg daily ) . In the first part of the study , patients of Group II received an inverse sequence of the drugs ( before Ticlopidine 250 mg bid and then Captopril 50 bid ) . In both groups of patients C induced a significant decrease of blood pressure and an increase of PFWD , TWD , and WI . T did not modify blood pressure but slightly increased PFWD , TWD , and WI . The improvement was more evident during administration of C plus T , whereas placebo administration induced a trend toward baseline values . Finally , the chronic administration of C plus T for twelve months induced a further improvement of all considered parameters . In conclusion , chronic administration of C plus T may be useful in the treatment of hypertensive patients suffering from intermittent claudication  , improving significantly PFWD and TWD Context Few therapies substantially reduce symptoms and improve exercise performance in patients with peripheral arterial disease ( PAD ) . Contribution In this double-blind trial , investigators r and omly assigned 40 older adults without diabetes and with symptomatic PAD to receive either ramipril or placebo , 10 mg once daily for 24 weeks . Compared with placebo , ramipril increased maximum and pain-free walking time and walking speed and distance . Caution s The trial was small and involved selected patients with limited mobility and exercise tolerance . Implication s Ramipril may improve symptoms in some patients with PAD . The Editors This article has been retracted . See Notice of Retraction . Peripheral arterial disease ( PAD ) is a common disorder , with 12 % of adults older than 50 years of age having an anklebrachial index ( ABI ) that is diagnostic of PAD ( < 0.9 ) ( 1 ) . Approximately one third of these patients experience intermittent claudication during walking , limiting normal activities . Medical treatments to improve walking distance are limited . The angiotensin-converting enzyme ( ACE ) inhibitor ramipril reduced cardiovascular morbidity and mortality compared with placebo in patients with established atherosclerotic disease , including PAD , in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) . This effect seemed to be independent of blood pressure reduction ( 3 ) and may relate to the known benefits of ACE inhibitors on both coronary and brachial endothelial function ( 4 ) . No previous controlled studies have investigated the effect of ACE inhibitors on symptoms of intermittent claudication . Given the positive effects of ramipril in the HOPE trial and its convenient once-daily dosing formulation , we hypothesized that therapy with ramipril would improve intermittent claudication symptoms . We aim ed to examine the effect of 6-month ramipril therapy on walking distance and claudication pain in a defined group of patients with claudication due to infrainguinal PAD by using a double-blind , r and omized , placebo-controlled design . Methods This article has been retracted . See Notice of Retraction . We screened 152 patients with PAD from general practice clinics in the Melbourne , Australia , metropolitan area ( Figure 1 ) . Of them , 40 patients ( mean age , 66 years [ SD , 4 ] ) were recruited and completed the trial . All patients gave written informed consent to participate in the study . The Ethics Committee of the Alfred Hospital , Melbourne , Australia , approved the study , and we performed the study in accordance with the Declaration of Helsinki 2000 . All participants had an ABI less than 0.9 at rest in at least 1 leg ; had a history of intermittent claudication ( unilateral or bilateral ) , which was stable for 6 months ; had evidence of superficial femoral artery stenosis or occlusion on duplex ultrasonography ; had blood pressure of 160/90 mm Hg or less ; had a stable medication regimen for at least 6 months ; and had not previously been treated with ACE inhibitors . We excluded patients with limiting coronary artery disease , renal failure , history of hypertension , or type 2 diabetes mellitus . Figure 1 . Flow of patients through the study . Computer-generated numbers specified the allocation sequence . A tamper-proof r and omization process generated by the hospital research center r and omly assigned participants into blocks of 10 to receive either ramipril ( Tritace , Aventis Pharma Pty . Ltd. , Macquarie Park , Australia , 10 mg once daily for 24 weeks ) or placebo ( 10 mg once daily for 24 weeks ) in a parallel-group , double-blind design . Both investigators and patients were blinded to drug assignment . Furthermore , investigators did not have access to baseline data when they performed follow-up measurements and patients were not asked which treatment they thought they were receiving . No patient assigned to placebo crossed over to ramipril during the trial or vice versa . We advised participants to maintain all aspects of their lifestyle throughout the trial and requested them to refrain from exercise , smoking , and caffeine for 24 hours before all testing . On the morning of testing , patients rested in a supine position for 15 minutes in a quiet room before the measurements . We assessed blood pressure , ABI , walking distance , duplex ultrasounds of leg arteries , and the Walking Impairment Question naire ( WIQ ) scores before and after both interventions . We advised patients about potential side effects and requested that they report any adverse event to the study coordinator . All patients performed a treadmill exercise test at a speed of 3.2 km/h and a grade of 12 % ( 5 ) , and we recorded pain-free walking time ( time to onset of claudication pain ) and maximum walking time . In our study , all patients reached a maximal level of claudication pain that limited exercise during the grade d treadmill test . The WIQ was developed and vali date d against treadmill walking and is used to evaluate limitations in community-based walking ability ( 6 ) . The WIQ assessed walking distance , speed , and stair-climbing ability , using a weighted st and ardized formula and returning a summary score between 0 % and 100 % ( 6 , 7 ) . Statistical Analyses All analysts were blinded to treatment assignment , and an independent investigator double-checked all measurement calculations and data base entries . The study was powered to detect a 180-second change in maximum walking time with ramipril , assuming a st and ard deviation of 250 seconds ( = 0.05 [ 2-sided ] ; power , 86 % ) . We compared 24-week changes from baseline in pain-free walking time , maximum walking time , and WIQ scores between treatments by using an analysis of covariance model with terms for treatment and baseline value as the analysis end points . We log-transformed the WIQ data to achieve a normal distribution before analysis . We conducted all statistical analyses by using Stata software , version 8.2 ( Stata Corp. , College Station , Texas ) . We expressed normally distributed data as means ( SDs ) or 95 % CIs and non-normally distributed data as medians ( ranges ) . A P value less 0.05 was deemed to be significant . No data were missing for any clinical variable measured in our study . Role of the Funding Sources This work was funded by the National Health and Medical Research Council of Australia . Aventis Pharma Pty . Ltd. provided ramipril ( Tritace ) and matching placebo capsules but provided no other funding for the study or to the investigators . The funding sources had no role in the design , conduct , or reporting of the study or in the decision to su bmi t the manuscript for publication . Results This article has been retracted . See Notice of Retraction . The ramipril and placebo groups were similar in age , other cardiovascular risk factors , medication use , and PAD severity , as evidence d by clinical symptoms ( walking times ) , WIQ scores , and resting ABI ( Table ) . No patient was taking cilostazol or pentoxifylline . On duplex ultrasonography , 6 of 40 patients had a superficial femoral artery occlusion ( 2 placebo patients and 4 ramipril patients ) , and the remaining patients had stenotic disease in the superficial femoral artery . Only 25 % of patients were taking antiplatelet or lipid-lowering therapy . No adverse events were reported . Table . Baseline Characteristics AnkleBrachial Index Ramipril  significantly increased ABI both at rest ( change with placebo , 0.05 mm Hg [ SD , 0.04 ] ; change with ramipril , 0.07 mm Hg [ SD , 0.08 ] ; P < 0.001 ) and after exercise ( change with placebo , 0.04 mm Hg [ SD , 0.05 ] ; change with ramipril , 0.08 mm Hg [ SD , 0.14 ] ; P < 0.001 ) . At rest , this increase was due to reduction in brachial systolic blood pressure with ramipril treatment ( 0.85 mm Hg [ SD , 1.57 ] vs. 5.05 mm Hg [ SD , 2.33 ] ; P < 0.001 ) rather than an increase in limiting leg pressure ( 0.75 mm Hg [ SD , 1.71 ] vs. 0.15 mm Hg [ SD , 1.27 ] ; P= 0.26 ) . After exercise , both a reduction in brachial pressure ( change with placebo , 0.30 mm Hg [ SD , 2.45 ] ; change with ramipril , 6.80 mm Hg [ SD , 6.07 ] ; P < 0.001 ) and an increase in limiting leg pressure ( change with placebo , 5.40 mm Hg [ SD , 7.56 ] ; change with ramipril , 7.10 mm Hg [ SD , 4.59 ] ; P < 0.001 ) contributed to the increase in ABI . Treadmill Test After adjustment for the baseline pain-free walking time , mean pain-free walking time after ramipril treatment was 227 seconds ( 95 % CI , 175 seconds to 278 seconds ; P < 0.001 ) longer than after placebo treatment ( Figure 2 ) . Similarly , maximum walking time significantly improved over the 24-week treatment period by 451 seconds ( CI , 367 seconds to 536 seconds ; P < 0.001 ) in the ramipril group after adjustment for baseline values ( Figure 2 ) . The lack of change observed over the 24-week treatment period in the placebo group ( change in mean walking time , 10 seconds [ SD , 9 ] [ CI , 14 seconds to 6 seconds ] ; P < 0.001 ) may reflect both the advanced age of participants and the fact that they all had limiting infrainguinal disease , which would probably give more reproducible treadmill data than aortoiliac disease . In addition , we asked patients to maintain all aspects of their lifestyle throughout the trial . Figure 2 . Effect of ramipril on maximum treadmill walking times . Walking Impairment Question naire Ramipril improved WIQ median distance score from 5 % ( range , 1 % to 39 % ) to 21 % ( range , 12 % to 58 % ) ( P < 0.001 ) , speed score from 3 % ( range , 3 % to 39 % ) to 18 % ( range , 8 % to 50 % ) ( P < 0.001 ) , and stair-climbing score from 17 % ( range , 4 % to 80 % ) to 67 % ( range , 38 % to 88 % ) ( P < 0.001 ) . Duplex Ultrasonography Volume flow was unaltered in the limiting leg at the stenotic site . However , ramipril significantly increased volume flow in the common femoral artery proximal to the site of stenosis in both the limiting leg ( change with placebo , 0.014 L/min [ SD , 0.022 ] ; change with ramipril , 0.017 L/min [ SD , 0.034 ] ; P= 0.008 ) and the nonlimiting leg ( change with placebo , 0.006 L/min [ SD , 0.041 ] ; change with ramipril , 0.019 L/min [ SD , 0.019 ] ; P= 0.035 ) . Discussion This article has been retracted . See Notice of Retraction . Our study shows that Tertatolol is a noncardioselective beta-blocker without intrinsic sympathomimetic activity . In a preliminary 3-month open study , it was shown that T was devoid of any atherogenic effect since HDL-cholesterol ( HDL-C ) and apoprotein levels did not change for 3 months of therapy . To investigate the long-term effects of tertatolol on the lipid profile and its safety in hypertensive patients with peripheral arterial disease ( PAD ) , a 9-month , r and omized , double-blind , parallel group study was carried out in 40 patients .  Tertatolol 5 mg once daily was compared with metoprolol 200 mg once daily . If BP was not controlled after 2 months , a vasodilatator agent , dihydralazine , was added at the lowest dose required to control BP ( diastolic BP < 90 mm Hg ) . Lipoprotein fractions and apoproteins were assayed before ( M0 ) and after 2 , 6 and 9 months of therapy . At the same occasions , peripheral arterial disease ( PAD ) was evaluated on exercise tests carried out on a treadmill and on the regional blood flow measured in the ankle arteries by the Doppler technique . Four patients were not eligible for analysis . In the tertatolol group , 1 patient with a normal BP , and 2 patients who dropped out , 1 because of persistent nausea and 1 because of personal reasons . In the metoprolol group , 1 patient refused to take dihydralazine . In the 35 fully documented patients , BP control was achieved in both groups . The mean reductions in supine systolic/diastolic BP were 31.4/14.6 and 34.7/17.1 mm Hg in the tertatolol and metoprolol groups , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS The use of & bgr;-receptor blockers in peripheral arterial disease is controversial for their impact on vasomotor tone . The & bgr;-blocker nebivolol possesses vasodilating , endothelium-dependent , NO-releasing properties that might be beneficial in peripheral arterial disease . The aim of the study was to evaluate the effects and tolerability of nebivolol in comparison with metoprolol in these patients . A total of 128 patients with intermittent claudication and essential hypertension were included and double-blind r and omized to receive 5 mg of nebivolol ( N=65 ) or 95 mg of metoprolol ( N=63 ) once daily . End points were changes in ankle-brachial index , initial and absolute claudication distance , endothelial function assessed by flow-mediated dilatation of the brachial artery , blood pressure , and quality of life using the claudication scale question naire . End point analysis was possible in 109 patients ( 85.2 % ) . After the 48-week treatment period , ankle-brachial index and absolute claudication distance improved significantly in both patient groups ( P<0.05 for both ) , with no difference across treatments . A significant increase of initial claudication distance was found in the nebivolol group . Adjusted mean change of initial claudication distance was 33.9 % after nebivolol ( P=0.003 ) and 16.6 % after metoprolol ( P=0.12 ) treatment . Quality of life was not influenced by either treatment , and there was no relevant change in flow-mediated dilatation in patients treated with nebivolol or metoprolol ( P=0.16 ) . Both drugs were equally effective in lowering blood pressure . In conclusion , & bgr;-blocker therapy was well tolerated in patients with intermittent claudication and arterial hypertension during a treatment period of ≈1 year . In the direct comparison , there was no significant difference between nebivolol and metoprolol OBJECTIVES The primary objective of the International Verapamil SR/Tr and olapril Study ( INVEST ) is to compare the risk for adverse outcomes ( all-cause mortality , nonfatal myocardial infa rct ion [ MI ] or nonfatal stroke ) in hypertensive patients with coronary artery disease ( CAD ) treated with either a calcium antagonist-based or a noncalcium antagonist-based strategy .  BACKGROUND Treatment recommendations for hypertension include initial therapy with a diuretic or beta-adrenergic blocking agent , for which reductions in morbidity and mortality are documented from r and omized trials but are less than expected from epidemiologic data . For this reason , recent attention has focused on calcium antagonists or angiotensin-converting enzyme inhibitors . While these agents reduce blood pressure , outcome data from large r and omized trials are lacking , but some case-control data , dominated by short-acting dihydropyridines , suggest an increased risk of cardiovascular events . These studies had method ologic limitations and did not differentiate among calcium antagonist types and formulations . Several studies differentiating among calcium antagonist types and an overview of published r and omized trials show no increased risk with verapamil and suggestion for benefit in CAD patients . METHODS A total of 27,000 CAD patients with hypertension will be r and omized at 1,500 primary care sites to receive either a calcium antagonist-based ( verapamil ) or beta-blocker/diuretic-based ( atenolol/hydrochlorothiazide ) antihypertensive care strategy . The study uses a novel , electronic " paper-less " system for direct on-screen data entry , r and omization and drug distribution from a mail pharmacy linked to the coordination center via the Internet . RESULTS Contract negotiations with the United States and international sites are ongoing . Patients being enrolled are predominantly elderly ( 72 % aged 60 years or older ) men ( 54 % ) , with either an abnormal coronary angiogram or prior MI ( 71 % ) . In addition to hypertension , CAD and elderly age , most patients ( 89 % ) have one or more associated conditions ( diabetes , dyslipidemia , smoking , cerebral or peripheral vascular disease , etc . ) contributing to increased risk for adverse outcome . While 26 % have diabetes , most of these are noninsulin dependent . Using the protocol strategies , target blood pressures ( according to JNC VI ) have been reached in 58 % at the fourth visit , and as expected most ( 89 % ) are requiring multiple antihypertensive drugs . CONCLUSION The design and baseline characteristics of the initial patients recruited for a prospect i ve , r and omized , international , multicenter study comparing two therapeutic strategies to control hypertension in CAD patients are described Ten patients with chronic intermittent claudication were included in a double-blind , r and omized cross-over study of placebo , propranolol 80 mg b.i.d . and metoprolol 100 mg b.i.d . , each given for two months . At the end of each treatment period , the patients were tested on a treadmill and the time to first claudication pain and to intolerable claudication pain was noted . There was no decrease in time to first claudication pain or to intolerable pain with either propranolol or metoprolol as compared to placebo Ninety patients with chronic ischemic heart disease and stage IIb peripheral arterial occlusive disease were investigated to determine the effect of celiprolol , atenolol and isosorbide dinitrate on peripheral arterial blood flow . Walking distance and the resistance index in the femoral artery were measured before and after 3 months medication and compared with the findings in controls ( 30 patients with chronic ischemic heart disease and stage IIb peripheral arterial occlusive disease ) who received placebo . Patients with peripheral arterial occlusive disease who were treated with atenolol 50 mg/day demonstrated significant decreases in both pain-free and maximal walking distance . In contrast , the walking distances in those given celiprolol 200 mg/day and those who received isosorbide dinitrate 80 mg/day did not differ from the distances in control subjects . The Doppler flow through the femoral artery , as measured by color duplex sonography , showed a significant decrease in resistance index , both in patients given celiprolol and in those given isosorbide dinitrate . In patients treated with atenolol the resistance index rose significantly . The results of this study confirm that the beta-adrenoceptor blocker celiprolol exerts a supplementary vasodilatory action resembling that of nitrates and hence can be used in patients with chronic ischemic heart disease and impaired peripheral arterial perfusion Background —Peripheral arterial disease ( PAD ) and diabetes are both associated with a high risk of ischemic events , but the role of intensive blood pressure control in PAD has not been established . Methods and Results —The Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years ; 480 of the subjects were normotensive ( baseline diastolic blood pressure of 80 to 89 mm Hg ) . Patients r and omized to placebo ( moderate blood pressure control ) had a mean blood pressure of 137±0.7/81±0.3 mm Hg over the last 4 years of treatment . In contrast , patients r and omized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128±0.8/75±0.3 mm Hg ( P < 0.0001 compared with moderate control ) . PAD , which is defined as an ankle-brachial index < 0.90 at the baseline visit , was diagnosed in 53 patients . In patients with PAD , there were 3 cardiovascular events ( 13.6 % ) on intensive treatment compared with 12 events ( 38.7 % ) on moderate treatment ( P = 0.046 ) . After adjustment for multiple cardiovascular risk factors , an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment ( P = 0.009 ) , but not with intensive treatment ( P = 0.91 ) . Thus , with intensive blood pressure control , the risk of an event was not increased , even at the lowest ankle-brachial index values , and was the same as in a patient without PAD . Conclusions —In PAD patients with diabetes , intensive blood pressure lowering to a mean of 128/75 mm Hg result ed in a marked reduction in cardiovascular events BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P<0.001 ) and angioedema ( 0.1 % vs. 0.3 % , P=0.01 ) and a higher rate of hypotensive symptoms ( 2.6 % vs. 1.7 % , P<0.001 ) ; the rate of syncope was the same in the two groups ( 0.2 % ) . In the combination-therapy group , the primary outcome occurred in 1386 patients ( 16.3 % ; relative risk , 0.99 ; 95 % CI , 0.92 to 1.07 ) ; as compared with the ramipril group , there was an increased risk of hypotensive symptoms ( 4.8 % vs. 1.7 % , P<0.001 ) , syncope ( 0.3 % vs. 0.2 % , P=0.03 ) , and renal dysfunction ( 13.5 % vs. 10.2 % , P<0.001 ) . CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema . The combination of the two drugs was associated with more adverse events without an increase in benefit . ( Clinical Trials.gov number , NCT00153101 [ Clinical Trials.gov ] . ) Hypertension is a common risk factor for peripheral arterial disease ( PAD ) . Guidelines suggest treating PAD patients to a blood pressure < 130/80 mm Hg ; therefore , our objective was to explore whether attainment of this target blood pressure is associated with improved outcomes . We performed a post hoc analysis of the INternational VErapamil-SR/Tr and olapril STudy , a r and omized clinical trial , which included hypertensive patients with concomitant PAD and coronary artery disease . There were 2699 PAD patients followed for a mean of 2.7 years ( 60 970 patient-years ) . The primary outcome , all-cause death , nonfatal myocardial infa rct ion , or nonfatal stroke , occurred in 16.3 % of PAD patients versus 9.2 % without PAD ( adjusted hazard ratio : 1.26 [ 95 % CI : 1.13 to 1.40 ] ; P<0.0001 ) . The primary outcome occurred least frequently among PAD patients treated to an average systolic blood pressure of 135 to 145 mm Hg and an average diastolic blood pressure of 60 to 90 mm Hg . PAD patients displayed a J-shape relationship with systolic blood pressure and the primary outcome , although individuals without PAD did not . PAD patients may require a different target blood pressure than those without PAD In a placebo-controlled double-blind crossover trial , the effect of a 3-week course of treatment with metoprolol ( 100 - 200 mg daily ) and methyldopa ( 500 - 1000 mg daily ) on walking capacity on a treadmill with increasing work load was studied in 14 hypertensive patients with intermittent claudication . The walking capacity was not affected by the antihypertensive treatment Objective Claudication is a debilitating consequence of peripheral arterial disease . Evidence is accumulating to suggest that large artery stiffness may influence peripheral perfusion and walking time through effects on peripheral hemodynamics as well as microvascular structure and function . We have previously shown that the angiotensin-converting enzyme inhibitor ramipril increased systemic arterial compliance by 64 % , and increased maximum walking time by over 200 % in patients with peripheral arterial disease . In the current analysis in the same patient cohort , we hypothesized that this relationship may , in part , be causal . Methods Forty patients with peripheral arterial disease [ 66 ± 4 years ( mean ± SD ) ; n = 20 per group ] were r and omized to ramipril , 10 mg once daily , or placebo for 24 weeks in a double-blind study  . Maximum walking time was recorded during a st and ard treadmill test  . Indices of arterial stiffness were assessed globally by systemic arterial compliance and augmentation index and regionally via central pulse wave velocity . Results Ramipril  increased maximum walking time by 243 % and improved arterial stiffness parameters by between 17 and 64 % ( all P < 0.001 compared with placebo ) . There were moderately strong correlations between the pre/post intervention change in maximum walking time and the change in indices of arterial stiffness ( systemic arterial compliance , r = 0.65 , P < 0.001 ; central pulse wave velocity , r = −0.57 , P < 0.001 ; augmentation index , r = −0.79 , P < 0.001 ; time to pressure augmentation , r = 0.52 , P = 0.001 ) . Conclusion The present data support the hypothesis that the beneficial effects of ramipril on maximum walking time observed in our peripheral arterial disease population are , at least partly , a consequence of reduced arterial stiffness OBJECTIVES We sought to investigate the effect of cardiac medication on long-term mortality in patients with peripheral arterial disease ( PAD ) . BACKGROUND Peripheral arterial disease is associated with increased cardiovascular morbidity and mortality . Treatment guidelines recommend aggressive management of risk factors and lifestyle modifications . However , the potential benefit of cardiac medication in patients with PAD remains ill defined . METHODS In this prospect i ve observational cohort study , 2,420 consecutive patients ( age , 64 + /- 11 years , 72 % men ) with PAD ( ankle-brachial index < or = 0.90 ) were screened for clinical risk factors and cardiac medication . Follow-up end point was death from any cause . Propensity scores for statins , beta-blockers , aspirin , angiotensin-converting enzyme ( ACE ) inhibitors , calcium channel blockers , diuretics , nitrates , coumarins , and digoxin were calculated . Cox regression models were used to analyze the relation between cardiac medication and long-term mortality . RESULTS Medical history included diabetes mellitus in 436 patients ( 18 % ) , hypercholesterolemia in 581 ( 24 % ) , smoking in 837 ( 35 % ) , hypertension in 1,162 ( 48 % ) , coronary artery disease in 1,065 ( 44 % ) , and a history of heart failure in 214 ( 9 % ) . Mean ankle-brachial index was 0.58 ( + /-0.18 ) . During a median follow-up of eight years , 1,067 patients ( 44 % ) died . After adjustment for risk factors and propensity scores , statins ( hazard ratio [ HR ] 0.46 , 95 % confidence interval [ CI ] 0.36 to 0.58 ) , beta-blockers ( HR 0.68 , 95 % CI 0.58 to 0.80 ) , aspirins ( HR 0.72 , 95 % CI 0.61 to 0.84 ) , and ACE inhibitors ( HR 0.80 , 95 % CI 0.69 to 0.94 ) were significantly associated with a reduced risk of long-term mortality . CONCLUSIONS On the basis of this observational longitudinal study , statins , beta-blockers , aspirins , and ACE inhibitors are associated with a reduction in long-term mortality in patients with PAD Background Peripheral artery disease ( PAD ) is associated with high cardiovascular mortality and a poor quality of life . The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function . The aim of this study was to analyze the effects of telmisartan on absolute walking distance ( WD ) and endothelial function in patients with PAD . Methods In a single centre , single-blinded , prospect i ve study , 36 patients with PAD at stage Fontaine II or higher and mild to moderate arterial hypertension were treated with telmisartan 40/80 mg once daily or placebo for 12 months . Primary endpoint was the improvement of the absolute treadmill WD . Flow-mediated vasodilation ( FMD ) , carotid intima-media thickness ( IMT ) , ankle-brachial index ( ABI ) and disease-related quality of life ( DRQL ) were examined as well . Results After 12 months , maximum WD increased by 26 % in the telmisartan group ( P < 0.001 ) . However , in the placebo group it was comparable to baseline . FMD rose by 40 % in the telmisartan group while it deteriorated in the placebo group ( P < 0.001 ) . IMT and ABI were comparable in both groups at baseline and did not change considerably after 12 months . In non-diabetic patients ( 72.2 % ) , the ABI did not change in the placebo group , whereas it increased by 11 % in the telmisartan group ( P < 0.001 ) . While the DRQL remained stable in the telmisartan group , placebo treatment was associated with a marked deterioration ( P < 0.01 ) . Conclusion Telmisartan improves WD and endothelial function , the ABI in non-diabetic patients and it may prevent further loss of quality of life in patients with advanced PAD Ramipril improves cardiovascular outcome in patients with peripheral arterial disease ; however , the precise mechanisms of benefit remain to be eluci date d. The effect of ramipril on large-artery stiffness in patients with peripheral arterial disease was examined . In addition , we determined the effect of ramiprilat on extracellular matrix from human aortic smooth muscle cell culture . Forty patients with peripheral arterial disease were r and omized to receive ramipril , 10 mg once daily or placebo for 24 weeks . Arterial stiffness was assessed globally via systemic arterial compliance and augmentation index ( carotid tonometry and Doppler velocimetry ) , and regionally via carotid – femoral pulse wave velocity . Angiotensin-converting enzyme inhibition increased arterial compliance by 0.10±0.02 mL/mm Hg , ( P<0.001 , all probability values relative to placebo ) and reduced pulse wave velocity by 1.7±0.2 m/s ( P<0.001 ) , augmentation index by 4.1±0.3 % ( P<0.001 ) , and systolic blood pressure by 5±1 mm Hg ( P<0.001 ) . Ramipril did not reduce mean arterial pressure significantly compared with placebo ( P=0.59 ) . In cell culture , ramiprilat  decreased collagen deposition by > 50 % and increased elastin and fibrillin-1 deposition by > 3- and 4-fold respectively ( histochemistry and immunohistochemistry ) . Fibrillin-1 gene expression was increased 5-fold ( real-time reverse-transcriptase polymerase chain reaction ) . Ramiprilat also reduced gene and protein ( Western ) expression of both matrix metalloproteinase (MMP)-2 and MMP-3 . In conclusion , ramipril promoted an elastogenic matrix profile that may contribute to the observed clinical reduction in large-artery stiffness and carotid pressure augmentation , which occurred independently of mean arterial blood pressure reduction in patients with peripheral arterial disease Beta-Adrenergic blockers have not been widely used in patients with peripheral vascular disease because these drugs have been reported to worsen the symptoms of intermittent claudication . To test this assumption we studied the effects of a beta 1-selective and a nonselective beta-adrenergic blocker on postexercise calf blood flow and symptoms of claudication in 19 patients with mild-to-moderate peripheral vascular disease . Subjects received placebo for 3 weeks , and then were r and omized to 120 mg/day propranolol or 150 mg/day metoprolol with the use of a crossover design . Blood flow in the calf was measured by  strain-gauge plethysmography  at rest and immediately after exercise on a bicycle ergometer at a low and a high workload . The symptoms of claudication were monitored during bicycle exercise and by patient diaries maintained between visits . Maximal exercise heart rate was reduced an equivalent amount by metoprolol ( 19 beats/min ) and propranolol ( 16 beats/min ) . Mean arterial pressure was reduced by propranolol at rest and by both drugs with exercise . Calf blood flow was not affected by either drug compared with placebo at rest or at either workload . In addition , the symptoms of claudication were not worsened by either drug . We conclude that despite evidence of beta 1-adrenergic blockade and a lowering of arterial pressure , neither beta-adrenergic blocker adversely affected the peripheral circulation The effect of celiprolol at a daily dosage of 300 mg ( 19 patients ) was compared with that of propranolol at a daily dosage of 120 mg ( 14 patients ) on peripheral blood flow of the calf and foot in a r and omized double-blind trial . Altogether 33 patients ( 47 extremities ) suffering from arterial occlusive disease ( stage II according to Fontaine ) and hypertension , were treated for 25 days . Blood flow was measured by strain-gauge plethysmography .  Celiprolol led to a small , insignificant increase in resting blood flow of the muscle . Propranolol produced a small decrease in resting blood flow of the muscle , and a significant fall in resting blood flow of the skin of the foot . At the completion of treatment with celiprolol there was a small increase in the initial value of reactive hyperaemia of the calf . Propranolol led to a decrease in the initial , and in the maximum values of reactive hyperaemia of the calf and foot . Celiprolol and propranolol led to a comparable decrease in resting blood pressure METHODS The effect of 6 months ' administration of celiprolol , atenolol and isosorbide dinitrate on peripheral arterial occlusive disease ( PAOD ) , double-blind and placebo-controlled , was investigated in 56 patients with chronic ischaemic heart disease and stage IIb PAOD , using as criteria the walking distance and the change in resistance index in the femoral artery . The  placebo group consisted of 14 patients with chronic ischaemic heart disease and the same stage of PAOD . RESULTS Patients on 50 mg/day atenolol showed a significant reduction in both pain-free and maximal walking range compared with the controls . In contrast , those taking 200 mg/day celiprolol and those on 80 mg/day isosorbide dinitrate demonstrated significant increases in pain-free and maximal , walking distance compared with the control group . The colour duplex sonographically measured Doppler flow through the femoral artery showed a significant decrease both in the patients taking celiprolol and in those on isosorbide dinitrate , while in those receiving atenolol the resistance index increased significantly . CONCLUSIONS The study shows that the beta-adrenoceptor blocker celiprolol also possesses a nitrate-like vasodilatory property and can be used in patients with chronic ischaemic heart disease and impaired peripheral arterial blood flow BACKGROUND AND PURPOSE The Systolic Hypertension in the Elderly Program ( SHEP ) demonstrated a significant reduction in stroke and coronary event rates among participants r and omly assigned to active blood pressure treatment . Selected participants were evaluated for peripheral atherosclerosis and followed up for cardiovascular events beyond the end of the SHEP trial . Antihypertensive treatment effects were evaluated based on the presence or absence of clinical or sub clinical atherosclerosis . METHODS As an ancillary study to SHEP , 190 participants at the Pittsburgh center were evaluated for peripheral atherosclerosis , defined as either an internal carotid stenosis ( by duplex scan ) or lower extremity arterial disease ( identified by ankle blood pressure ) . Participants were subsequently followed up for cardiovascular events . RESULTS Estimates of 4-year mortality rates were 4.8 % for participants with no atherosclerosis , 16.7 % for those with sub clinical atherosclerosis , and 23 % among those with clinical evidence of atherosclerosis ( P < .001 ) . Fatal plus nonfatal cardiovascular event rates were 10.9 % , 29.8 % , and 58.3 % for the three groups , respectively ( P < .001 ) . Differences remained significant after adjustment for age , sex , treatment assignment , smoking , and high-density lipoprotein cholesterol . Individuals assigned to placebo at the beginning of SHEP had higher cardiovascular event rates than individuals assigned to active treatment ( P = .011 ) , with the most striking difference 3 or more years after the end of the SHEP trial . When this analysis was stratified by the presence or absence of detectable atherosclerosis , the absolute treatment effect was largest among those with evidence of disease . CONCLUSIONS Individuals with systolic hypertension and evidence of peripheral atherosclerosis are at high risk for cardiovascular events . Targeting this group for antihypertensive therapy would result in the prevention of a large number of cardiovascular events BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors reduce mortality , myocardial infa rct ion , stroke , heart failure , need for revascularization , nephropathy , and diabetes and its complications . Although angiotensin-II receptor blockers ( ARBs ) have been less extensively evaluated , theoretically they may have " protective " effects similar to those of ACE inhibitors , but with better tolerability . Currently , there is uncertainty about the role of ARBs when used alone or in combination with an ACE inhibitor in high-risk population s with controlled hypertension . OBJECTIVES Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial ( ONTARGET ) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone , and if telmisartan is at least as effective as ramipril . The Telmisartan R and omized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease ( TRANSCEND ) will determine if telmisartan is superior to placebo in patients who are intolerant of ACE inhibitors . The primary outcome for both trials is the composite of cardiovascular death , myocardial infa rct ion , stroke , or hospitalization for heart failure . METHOD High-risk patients with coronary , peripheral , or cerebrovascular disease or diabetes with end-organ damage are being recruited and followed for 3.5 to 5.5 years in 2 parallel , r and omized , double-blind clinical trials . PROGRESS Recruitment from 730 centers in 40 countries for ONTARGET ( n = 25,620 ) was completed in July 2003 . For TRANSCEND , 5776 patients ( out of a projected total of 6000 ) have been recruited ( by May 10 , 2004 ) . Baseline patient characteristics are comparable to the Heart Outcomes Prevention Evaluation ( HOPE ) trial , the basis of the design of the current study , confirming that patients are at high-risk BACKGROUND Observational studies suggest a synergistic effect of hypertension and hyperlipidaemia on the progression of atherosclerosis . The alpha-blocker doxazosin has favourable effects on plasma lipids , insulin resistance and blood pressure , while the diuretic hydrochlorothiazide ( HCTZ ) principally affects blood pressure and increases insulin resistance . METHODS A r and omised double-blind study over 36 months was performed to compare the effects of doxazosin and HCTZ on fasting lipids and on progression of peripheral atherosclerosis .  Eighty males ( 45 to 70 years ) with peripheral atherosclerotic disease and increased cholesterol levels ( 5.2 - 8.0 mmol/l ) were treated for essential hypertension with either doxazosin ( n = 41 ) or HCTZ ( n = 39 ) . Main outcome measures were arterial intima-media thickness ( IMT ) of the carotid and femoral arteries and fasting lipid parameters . RESULTS In the doxazosin-treated group , significant changes were observed in the concentration of triglycerides ( -13.7 % , p < 0.01 ) , HDLc ( + 25.7 % , p < 0.05 ) and IDLc ( -30.1 % , P < 0.05 ) . In the HCTZ-treated group no significant changes in plasma lipid levels were observed . On follow-up visits systolic blood pressure in the doxazosin-treated group was 6 mm higher than in the HCTZ group . Nevertheless , the groups treated with doxazosin or HCTZ showed no differential effect on IMT after three years of treatment ( p = 0.8 ) . A significant reduction of the IMT of combined carotid and femoral arterial walls was shown in both treatment groups ( p < 0.005 ) . CONCLUSIONS Hypertension treatment with doxazosin or HCTZ result ed in a comparable change in arterial IMT after three years , in spite of differences in effect on plasma lipids . The study emphasises the importance of blood pressure control in patients with peripheral vascular disease and hypercholesterolaemia BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension . Left ventricular hypertrophy ( LVH ) is a strong independent indicator of risk of cardiovascular morbidity and death . We aim ed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and , consequently , reduces cardiovascular morbidity and death . METHODS We did a double-masked , r and omised , parallel-group trial in 9193 participants aged 55 - 80 years with essential hypertension ( sitting blood pressure 160 - 200/95 - 115 mm Hg ) and LVH ascertained by electrocardiography ( ECG ) . We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event ( death , myocardial infa rct ion , or stroke ) . We used Cox regression analysis to compare regimens . FINDINGS Blood pressure fell by 30.2/16.6 ( SD 18.5/10.1 ) and 29.1/16.8 mm Hg ( 19.2/10.1 ) in the losartan and atenolol groups , respectively . The primary composite endpoint occurred in 508 losartan ( 23.8 per 1000 patient-years ) and 588 atenolol patients ( 27.9 per 1000 patient-years ; relative risk 0.87 , 95 % CI 0.77 - 0.98 , p=0.021 ) . 204 losartan and 234 atenolol patients died from cardiovascular disease ( 0.89 , 0.73 - 1.07 , p=0.206 ) ; 232 and 309 , respectively , had fatal or non-fatal stroke ( 0.75 , 0.63 - 0.89 , p=0.001 ) ; and myocardial infa rct ion ( non-fatal and fatal ) occurred in 198 and 188 , respectively ( 1.07 , 0.88 - 1.31 , p=0.491 ) . New-onset diabetes was less frequent with losartan . Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated . Losartan seems to confer benefits beyond reduction in blood pressure Background In the Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial the primary outcome ( cardiac morbidity and mortality ) did not differ between valsartan and amlodipine-based treatment groups , although systolic blood pressure ( SBP ) and diastolic blood pressure reductions were significantly more pronounced with amlodipine . Stroke incidence was non-significantly , and myocardial infa rct ion was significantly lower in the amlodipine-based regimen , whereas cardiac failure was non-significantly lower on valsartan . Objectives The study protocol specified additional analyses of the primary endpoint according to : sex ; age ; race ; geographical region ; smoking status ; type 2 diabetes ; total cholesterol ; left ventricular hypertrophy ; proteinuria ; serum creatinine ; a history of coronary heart disease ; a history of stroke or transient ischemic attack ; and a history of peripheral artery disease . Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before r and omization . Methods The 15 245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics . Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model . Within each subgroup , treatment effects were assessed by hazard ratios and 95 % confidence intervals . Results For cardiac mortality and morbidity , the only significant subgroup by treatment interaction was of sex ( P = 0.016 ) , with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men , but SBP differences in favour of amlodipine were distinctly greater in women . No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments . For secondary endpoints , a sex-related significant interaction was found for heart failure ( P < 0.0001 ) , with men but not women having a lower incidence of heart failure with valsartan . Conclusion As in the whole VALUE cohort , in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments , despite a greater blood pressure decrease in the amlodipine group . The only exception was sex , in which the amlodipine-based regimen was more effective than valsartan in women , but not in men , whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial was design ed to test the hypothesis that for the same blood-pressure control , valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk . METHODS 15?245 patients , aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a r and omised , double-blind , parallel-group comparison of therapy based on valsartan or amlodipine . Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint , defined as a composite of cardiac mortality and morbidity .  Patients from 31 countries were followed up for a mean of 4.2 years . FINDINGS Blood pressure was reduced by both treatments , but the effects of the amlodipine-based regimen were more pronounced , especially in the early period ( blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month ; 1.5/1.3 mm Hg after 1 year ; p<0.001 between groups ) . The primary composite endpoint occurred in 810 patients in the valsartan group ( 10.6 % , 25.5 per 1000 patient-years ) and 789 in the amlodipine group ( 10.4 % , 24.7 per 1000 patient-years ; hazard ratio 1.04 , 95 % CI 0.94 - 1.15 , p=0.49 ) . INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups . Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes . The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk OBJECTIVE To describe the design of the HOPE ( Heart Outcomes Prevention Evaluation ) study . DESIGN Description of the key design features of HOPE , a large , simple r and omized trial of two widely applicable treatments -- ramipril , an angiotensin-converting enzyme inhibitor ; and vitamin E , a naturally occurring antioxidant vitamin -- in the prevention of myocardial infa rct ion , stroke or cardiovascular death . SETTING Two-hundred and sixty-seven hospitals , physician offices and clinics in Canada , the United States , Mexico , Europe and South America . PATIENTS Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infa rct ion and stroke were recruited over 18 months . INTERVENTIONS A 2X2 factorial design with ramipril and vitamin E with follow-up for up to four years . CONCLUSIONS HOPE will be one of the largest trials of two new interventions to prevent myocardial infa rct ion , stroke or cardiovascular death in high risk patients . The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice . Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease , inclusion of a substantial proportion of patients with diabetes ( 36 % ) and women ( 27 % ) , and detailed sub studies to provide data on mechanisms of benefit We compared the efficacy and safety of three doses of beraprost sodium , an epoprostenol analogue , with placebo in the treatment of intermittent claudication ( Fontaine 's stage II ) . One hundred sixty-four patients were r and omized to receive either placebo , 20 micrograms beraprost sodium ( BPS60 group ) , 40 micrograms beraprost sodium ( BPS120 group ) , or 60 micrograms beraprost sodium ( BPS180 group ) three times daily administered orally in a double-blind manner for 12 weeks . Treadmill exercise tests were performed twice during an initial selection phase ( D-28 and D0 ) at week 10 ( at trough beraprost concentration ) and week 12 ( at peak beraprost concentration ) of the treatment phase . At week 10 , all groups showed an increase in pain-free walking distance , and this distance was greatest in the BPS60 and BPS120 groups ( p = 0.055 ) . At week 12 , a similar pattern was observed , and the difference was significant between the groups ( p = 0.023 ) . The most frequent adverse events reported were gastrointestinal disorders , headaches , skin disorders , and flushes . Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance . Further studies are required to investigate why the highest dose used ( 180 micrograms daily ) showed lower efficacy . Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term , beraprost sodium is a promising drug for the treatment of intermittent claudication OBJECTIVES We sought to determine predictors for adverse outcomes in hypertensive patients with coronary artery disease ( CAD ) . BACKGROUND Factors leading to adverse outcomes in hypertensive patients with CAD are poorly understood . The INternational VErapamil-tr and olapril STudy ( INVEST ) compared outcomes in hypertensive patients with CAD that were assigned r and omly to either a verapamil sustained-release (SR)- or an atenolol-based strategy for blood pressure ( BP ) control . Tr and olapril and hydrochlorothiazide were used as added agents . During follow-up ( 61,835 patient-years ) , BP control and the primary outcome ( death , nonfatal myocardial infa rct ion , and nonfatal stroke ) were not different between strategies . METHODS We investigated risk for adverse outcome associated with baseline factors , follow-up BP , and drug treatments using Cox modeling . RESULTS Previous heart failure ( adjusted hazard ratio [ HR ] 1.96 ) , as well as diabetes ( HR 1.77 ) , increased age ( HR 1.63 ) , U.S. residency ( HR 1.61 ) , renal impairment ( HR 1.50 ) , stroke/transient ischemic attack ( HR 1.43 ) , smoking ( HR 1.41 ) , myocardial infa rct ion ( HR 1.34 ) , peripheral vascular disease ( HR 1.27 ) , and revascularization ( HR 1.15 ) predicted increased risk . Follow-up systolic BP < 140 mm Hg or diastolic BP < 90 mm Hg ( HRs 0.82 or 0.70 , respectively ) and tr and olapril with verapamil SR ( HRs 0.78 and 0.79 ) were associated with reduced risk . CONCLUSIONS In hypertensive patients with CAD , increased risk for adverse outcomes was associated with conditions related to the severity of CAD and diminished left ventricular function . Lower follow-up BP and addition of tr and olapril to verapamil SR each were associated with reduced risk BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive  ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity , largely due to a decreased incidence of stroke , whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies . Furthermore , treated hypertensive patients still have a higher cardiovascular complication rate , compared with matched normotensives . This is particularly evident in patients with left ventricular hypertrophy ( LVH ) , a major independent risk indicator for cardiovascular disease . In addition to elevating blood pressure , angiotensin II ( A-II ) exerts an important influence on cardiac structure and function , stimulating cell proliferation and growth . Thus , to further reduce morbidity and mortality when treating hypertensive patients , it may be important to effectively block the effects of A-II . This can be achieved directly at the A-II receptor level by losartan , the first of a new class of antihypertensive agents . It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy , and thus improves prognosis . The Losartan Intervention For Endpoint reduction ( LIFE ) in Hypertension study is a double-blind , prospect i ve , parallel group study design ed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients ( initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg ) with electrocardiographically documented LVH . The study , which will continue for at least 4 years and until 1,040 patients experience one primary endpoint , has been design ed with a statistical power that will detect a difference of at least 15 % between groups in the incidence of combined cardiovascular morbidity and mortality . It is also the first prospect i ve study with adequate power to link reversal of LVH to reduction in major cardiovascular events . The rationale of the study , which will involve more than 800 clinical centers in Sc and inavia , the United Kingdom , and the United States , is discussed , and the major features of its design and general organization are described . On April 30 , 1997 , when inclusion was stopped , 9,218 patients had been r and omized Essential hypertension is a major Public Health issue . Although the number of treated hypertensive patients has increased , only 25 % of treated patients have their blood pressure levels under control . The benefit of treating hypertension has been proven , but cardiovascular morbidity and mortality rates remain high . The ideal antihypertensive drug should not only normalize blood pressure levels , but also reduce the associated cardiovascular morbidity and mortality rates . The role of angiotensin II in systemic hypertension and its complications has been recently redefined . The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated , especially the role of angiotensin II in left ventricular hypertrophy , vascular hypertrophy , endothelial dysfunction , and congestive heart failure . Of all ongoing mortality and morbidity trials in systemic hypertension , VALUE ( Valsartan Antihypertensive Long-term Use Evaluation ) is the only one comparing an angiotensin II antagonist ( valsartan ) with a third-generation calcium channel blocker ( amlodipine ) . The main hypothesis of the VALUE trial is that , for an equivalent decrease in blood pressure , valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity . VALUE is a prospect i ve , multinational , multicentre , double-blind , r and omized , active-controlled , 2-arm parallel group comparison with a response-dependent dose titration scheme . VALUE involves 14,400 patients in over 30 countries , who will be followed for 4 years or until 1450 patients experience a primary endpoint . The population to be included in VALUE consists of hypertensive men and women , aged 50 years or older , and at a relatively high risk of sustaining a cardiovascular event . The high risk profile is defined taking into account age , gender , and a list of cardiovascular risk factors and disease factors . Risk factors are cigarette smoking , hypercholesterolaemia , diabetes mellitus , uncomplicated left ventricular hypertrophy , proteinuria , and high serum creatinine . Disease factors include documented history of myocardial infa rct ion , peripheral vascular disease , stroke or transient ischaemic attack , or the presence of left ventricular hypertrophy with strain on the ECG . A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients . The trial started on 10 September 1997 The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events ( OPERA ) trial is a large clinical trial of omapatrilat , a vasopeptidase inhibitor , in patients with stage 1 isolated systolic hypertension ( ISH ) . OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition . This 5-year multinational , r and omized , double-blind , parallel-group , placebo-controlled , forced-titration study will be conducted in approximately 12,600 subjects r and omized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years . The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat ( target dose 40 mg ) will reduce cardiovascular ( CV ) morbidity and mortality in older ( > or = 65 years ) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence -based requirement for treatment .  Blood pressure inclusion criteria are  systolic blood pressure ( SBP ) 140 to 159 mm Hg ( SBP 125 to 139 mm Hg in diabetic individuals ) and diastolic blood pressure ( DBP ) < 90 mm Hg . The primary end point is defined as the composite of fatal/nonfatal stroke , fatal/nonfatal myocardial infa rct ion , fatal/nonfatal heart failure , and other CV mortality . Secondary end points include the individual components of the primary end point , CV mortality , and major cardiovascular end points , as well as effects on cognitive function and initiation of treatment for diabetes . Additional analyses will be conducted in men and women , in diabetic patients , in different risk classes and according to prior evidence of vascular disease BACKGROUND In patients with prior myocardial infa rct ion ( MI ) , beta-blockers reduce mortality by 23 % to 40 % . However , despite this favorable effect , adverse effects limit compliance to this medication . The purpose of the study was to compare a beta-blocker-based strategy with a heart rate-lowering calcium antagonists-based strategy in patients with prior MI . METHODS We evaluated 7,218 patients with prior MI enrolled in the INternational VErapamil SR-Tr and olapril ( INVEST ) sub study r and omized to verapamil-sustained release (SR)- or atenolol-based strategies . Primary outcome was time to first occurrence of death ( all-cause ) , nonfatal MI , or nonfatal stroke . Secondary outcomes included death , total MI ( fatal and nonfatal ) , and total stroke ( fatal and nonfatal ) considered separately . RESULTS During the 2.8 + /- 1.0 years of follow-up , patients assigned to the verapamil-SR-based and atenolol-based strategies had comparable blood pressure control , and the incidence of the primary outcome was equivalent . There was no difference between the 2 strategies for the outcomes of either death or total MI . However , more patients reported excellent/good well-being ( 82.3 % vs 78.0 % , P = .02 ) at 24 months with a trend toward less incidence of angina pectoris ( 12.0 % vs 14.3 % , adjusted P = .07 ) , nonfatal stroke ( 1.4 % vs 2.0 % ; P = .06 ) , and total stroke ( 2.0 % vs 2.5 % , P = .18 ) in the verapamil-SR-based strategy group . CONCLUSIONS In hypertensive patients with prior MI , a verapamil-SR-based strategy was equivalent to a beta-blocker-based strategy for blood pressure control and prevention of cardiovascular events , with greater subjective feeling of well-being and a trend toward lower incidence of angina pectoris and stroke in the verapamil-SR-based group The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial ( ONTARGET ) showed that the angiotensin receptor blocker telmisartan 80 mg was not inferior to the angiotensin-converting enzyme inhibitor ramipril 10 mg , and the combination no more effective than ramipril alone , in decreasing morbidity and mortality in patients with cardiovascular disease or high-risk diabetes . Although therapy targeting angiotensin II is known to decrease left ventricular ( LV ) mass and volume , the relative influence of angiotensin-converting enzyme inhibitor inhibitors and angiotensin receptor blocker , and their combination , on the heart remains unclear in this population . Magnetic resonance imaging was performed in 287 patients enrolled in ONTARGET , across 8 centers in 6 countries , at r and omization and after 2-year treatment ( 90 , 100 , and 97 patients in the ramipril , telmisartan , and combination therapy groups , respectively ) . Baseline patient characteristics showed higher frequencies of coronary artery disease , Asian ethnicity , and use of statins and beta blockers than the main ONTARGET trial . LV mass decreased in all groups ( p < 0.0001 for each ) , but there were no significant differences in change in LV mass or volume among groups , except that LV mass index decreased more on combination versus telmisartan ( p = 0.04 ) . Key determinants of LV mass decrease were a history of hypertension ( p = 0.03 ) , baseline mass ( p < 0.0001 ) , and decrease in systolic blood pressure ( p < 0.0001 ) . The best magnetic resonance imaging predictor of composite events was end-systolic volume ( p < 0.0001 ) . In conclusion , telmisartan and ramipril had similar effects on LV mass and volume , and combination therapy was not more effective , in high-risk patients with cardiovascular disease . These results are consistent with the major outcome findings of the main ONTARGET study BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications . Because this issue remains controversial , we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were r and omly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study . METHODS The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve , r and omized , blinded trial comparing the effects of moderate control of blood pressure ( target diastolic pressure , 80 to 89 mm Hg ) with those of intensive control of blood pressure ( diastolic pressure , 75 mm Hg ) on the incidence and progression of complications of diabetes . The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes . In the current study , we analyzed data on a secondary end point ( the incidence of myocardial infa rct ion ) in the subgroup of patients in the ABCD Trial who had hypertension . RESULTS Analysis of the 470 patients in the trial who had hypertension ( base-line diastolic blood pressure , > or = 90 mm Hg ) showed similar control of blood pressure , blood glucose and lipid concentrations , and smoking behavior in the nisoldipine group ( 237 patients ) and the enalapril group ( 233 patients ) throughout five years of follow-up . Using a multiple logistic-regression model with adjustment for cardiac risk factors , we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infa rct ions ( a total of 24 ) than enalapril ( total , 4 ) ( risk ratio , 9.5 ; 95 percent confidence interval , 2.7 to 33.8 ) . CONCLUSIONS In this population of patients with diabetes and hypertension , we found a significantly higher incidence of fatal and nonfatal myocardial infa rct ion among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril . Since our findings are based on a secondary end point , they will require confirmation OBJECTIVES We sought to determine whether treatment with high dose verapamil prevents restenosis in patients at high risk for reoccurrence after successful percutaneous transluminal coronary angioplasty ( PTCA ) . BACKGROUND Restenosis is the major limitation of PTCA . Calcium antagonists have demonstrated some potential as inhibitors of this process . METHODS A total of 98 patients with peripheral occlusive arterial disease ( POAD ) , stable angina pectoris , mild hypertension and at least one additional risk factor increasing the likelihood of restenosis after angioplasty were selected for this placebo-controlled , double-blind , r and omized trial .  Verapamil ( 240 mg twice daily ) or placebo was taken for 6 months . Efficacy variables assessed before and after angioplasty and at 6 weeks and 6 months after PTCA included thickness of the intima/media complex degree of stenosis , interventricular septal thickness , crurobrachial pressure ratios of dorsalis pedis and posterior tibial arteries , distance to claudication and total vessel diameter . RESULTS No significant intergroup differences emerged before or immediately after PTCA . Six weeks after angioplasty , a significant thickening of the intima/media complex in the treated vascular segment of 14.3 % occurred in the placebo group versus 0 % among verapamil patients ( p < 0.01 ) . At 6 months , the intima/media thickness was 35.7 % greater in the placebo group but had decreased by 14.3 % in the verapamil group ( p < 0.001 ) . At 6 months , a marked reduction in septal thickness was observed in the verapamil group versus that in the placebo group ( p < 0.001 ) . The rate of restenosis was also significantly lower in the verapamil group ( p < 0.001 ) . Few minor side effects were reported . CONCLUSIONS In patients with POAD at increased risk for restenosis , the administration of high dose verapamil prevented recurrent stenosis for 6 months after successful peripheral angioplasty and was well tolerated BACKGROUND Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis . METHODS We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor . These patients were r and omly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor ( ramipril ) or matching placebo for a mean of 4.5 years ( the results of the comparison of ramipril and placebo are reported in a companion article ) . The primary outcome was a composite of myocardial infa rct ion , stroke , and death from cardiovascular causes . The secondary outcomes included unstable angina , congestive heart failure , revascularization or amputation , death from any cause , complications of diabetes , and cancer . RESULTS A total of 772 of the 4761 patients assigned to vitamin E ( 16.2 percent ) and 739 of the 4780 assigned to placebo ( 15.5 percent ) had a primary outcome event ( relative risk , 1.05 ; 95 percent confidence interval , 0.95 to 1.16 ; P=0.33 ) . There were no significant differences in the numbers of deaths from cardiovascular causes ( 342 of those assigned to vitamin E vs. 328 of those assigned to placebo ; relative risk , 1.05 ; 95 percent confidence interval , 0.90 to 1.22 ) , myocardial infa rct ion ( 532 vs. 524 ; relative risk , 1.02 ; 95 percent confidence interval , 0.90 to 1.15 ) , or stroke ( 209 vs. 180 ; relative risk , 1.17 ; 95 percent confidence interval , 0.95 to 1.42 ) . There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause . There were no significant adverse effects of vitamin E. CONCLUSIONS In patients at high risk for cardiovascular events , treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes Ketanserin is a new strong antiserotoninergic drug that , unlike the previous ones , is selective for 5-hydroxytryptamine receptors . This drug has been employed successfully in the treatment of arterial hypertension and of some peripheral vascular diseases . The authors are carrying out a trial on medium term treatment with ketanserin ( K ) or propranolol ( P ) in comparison with placebo , to evaluate their effects on blood pressure , haemocoagulative parameters and peripheral circulation . The trial is a double-blind cross-over r and om trial on subjects with mild or moderate hypertension . Until now 13 patients have ended the study ; six of them are suffering from arteriosclerosis obliterans of the lower limbs at 1st or 2nd stage according to Fontaine . Both propranolol and ketanserin significantly reduced the blood pressure , although the decrease in systolic blood pressure was more evident after propranolol .  Heart rate diminished significantly only after propranolol administration . The noninvasive , intermittent ( every 30 min ) monitoring of blood pressure showed a significant 24-hour reduction of blood pressure after administration of propranolol or ketanserin without significant changes of circadian behaviour of the blood pressure . After administration of ketanserin a slight improvement in peripheral circulation was demonstrated , evaluated by using strain-gauge plethysmography . As regards the results obtained for platelet function and other haemocoagulative parameters examined , adenosine diphosphate-induced platelet aggregation , adenosine diphosphate slope , collagen lag period , antithrombin III biological activity , and serum fibrinogen did not show noticeable modifications after treatment , while beta-thromboglobulin levels decreased slightly after ketanserin administration Search ing for a possibility of an effective therapy of disturbances of peripheral arterial blood supply ( stage I and II ) , the authors examined a medicamentously untreated group of patients as well as a comparable group of patients which was pretreated with propranolol .  The two groups of patients performed twice a week an interval run exercise . Under the three-month training therapy in the two groups significant systolic and diastolic blood pressure reductions as well as statistically ascertained shortenings of the xenon-133-half-value time under working conditions and enlargements of the average functional vascular cross section A appeared . The distance of the intermittent claudication and the st and ardized moving up and down test prolonged . An influence on the microcirculation caused by propranolol could not be proved . The results are discussed on the basis of literature This paper summarizes the results of two studies carried out to evaluate the effects of the cardioselective betablockers atenolol , acebutolol and metoprolol on peripheral circulation of the lower limbs . The 1st study was a double dummy double blind cross over placebo controlled trial carried out for 13 weeks to evaluate the effects of acebutolol ( 600 mg/die ) and metoprolol ( 300 mg/die ) , two cardioselective betablockers , on peripheral haemodynamics in patients suffering from mild to moderate hypertension . The 2nd study was a placebo controlled trial on the effects of atenolol ( 100 mg/day ) on haemodynamics at the calf carried out for 8 weeks in patients suffering from essential to severe moderate hypertension , part of which aged over 65 years and affected by arteriosclerosis obliterans of the lower limbs , stage I and II according to Fontaine 's classification .  Calf blood flow in basal condition ( R.F. ) and after ischemic stimulus ( P.F. ) was evaluated by strain gauge plethysmography ; basal ( B.V.R. ) and minimal ( M.V.R. ) vascular resistances at the calf by the ratio between M.B.P./R.F. and M.B.P./P.F. respectively , Windsor 's index ( W.I. ) by ultrasound . Neither the patients with hypertension only nor the elderly hypertensive suffering from arteriosclerosis obliterans of the lower limbs showed changes in R.F. and P.F. , in B.V.R. and M.V.R. and in W.I. after chronic treatment with cardioselective beta-blockers . Many patients --about 17 % of all patients , and 40 % of arteriopathics -- in the two trials had cold h and s and feet . These studies suggest that chronic administration of selective beta-blockers does not exert unfavourable effects on muscular blood flow at the calf in patients with hypertension with or without arteriosclerosis obliterans of the lower limbs at I and II stage . ( ABSTRACT TRUNCATED AT 250 WORDS Background : The INternational VErapamil SR‐Tr and olapril Study ( INVEST ) , a prospect i ve , r and omized , antihypertensive trial , found that two different medication regimens produced similar blood pressure ( BP ) control with equivalent cardiovascular ( CV ) outcomes ( death from any cause , nonfatal myocardial infa rct ion [ MI ] , or nonfatal stroke ) OBJECTIVE --To determine the effects of the beta 1 selective adrenoceptor blocker atenolol , the dihydropyridine calcium antagonist nifedipine , and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication . DESIGN --R and omised controlled double blind four way crossover trial . SETTING --Royal Hallamshire Hospital , Sheffield . SUBJECTS--49 patients ( 40 men ) aged 39 - 70 with chronic stable intermittent claudication . INTERVENTIONS --Atenolol 50 mg twice daily ; slow release nifedipine 20 mg twice daily ; atenolol 50 mg plus slow release nifedipine 20 mg twice daily ; placebo . Each treatment was given for four weeks with no washout interval between treatments . MAIN OUTCOME MEASURES --Claudication and walking distances on treadmill ; skin temperature of feet as measured by thermistor and probe ; blood pressure before and after exercise ; subjective assessment s of walking difficulty and foot coldness with visual analogue scales . RESULTS --Atenolol did not significantly alter claudication distance ( mean change -6 % ; 95 % confidence interval 1 % to -13 % ) , walking distance ( -2 % ; 4 % to -8 % ) , or foot temperature .  Nifedipine did not alter claudication distance ( -4 % ; 3 % to -11 % ) , walking distance ( -4 % ; 3 % to -10 % ) , or foot temperature .  Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance ( -9 % ; -3 % to -15 % ( p less than 0.003 ) ) and skin temperature of the more affected foot ( -1.1 degrees C ; 0 to -2.2 degrees C ( p = 0.05 ) ) . These effects on walking distance and foot temperature seemed unrelated to blood pressure changes . CONCLUSIONS --There was no evidence of adverse or beneficial effects of atenolol or nifedipine , when given singly , on peripheral vascular disease . The combined treatment , however , affected walking ability and foot temperature adversely . This may have been due to beta blockade plus reduced vascular resistance , which might also explain the reported adverse effects of pindolol and labetalol on claudication The aim was to determine if certain risk factors in the general population are more strongly related to peripheral arterial disease than to ischemic heart disease . Arterial disease in the lower limbs was measured by means of the World Health Organization question naire on intermittent claudication , the ankle brachial pressure index , and a reactive hyperemia test in 1,592 men and women aged 55 - 74 years selected r and omly in 1988 from the age-sex registers of 10 general practice s in Edinburgh , Scotl and . Peripheral arterial disease was strongly related to lifetime cigarette smoking , with additional risks in current and exsmokers of less than 5 years . Multiple regression of risk factors on measures of peripheral arterial disease showed associations with diabetes mellitus ( but not impaired glucose tolerance ) , systolic blood pressure , and serum cholesterol ; inverse association with high-density lipoprotein cholesterol ; and only univariate association with triglycerides . In multiple logistic regressions of risk factors on six separate indicators of cardiovascular disease , the only consistent difference was that smoking increased the risk of peripheral arterial disease ( range of odds ratios , 1.8 - 5.6 ) more than heart disease ( range of odds ratios , 1.1 - 1.6 ) . Diabetes mellitus was not a stronger risk factor for peripheral arterial disease BACKGROUND Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication , and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease , as diagnosed by noninvasive testing . In this study , we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease . METHODS We examined 565 men and women ( average age , 66 years ) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques -- measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound . We identified 67 subjects with the disease ( 11.9 percent ) , whom we followed prospect ively for 10 years . RESULTS Twenty-one of the 34 men ( 61.8 percent ) and 11 of the 33 women ( 33.3 percent ) with large-vessel peripheral arterial disease died during follow-up , as compared with 31 of the 183 men ( 16.9 percent ) and 26 of the 225 women ( 11.6 percent ) without evidence of peripheral arterial disease . After multivariate adjustment for age , sex , and other risk factors for cardiovascular disease , the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 ( 95 percent confidence interval , 1.9 to 4.9 ) for deaths from all causes , 5.9 ( 95 percent confidence interval , 3.0 to 11.4 ) for all deaths from cardiovascular disease , and 6.6 ( 95 percent confidence interval , 2.9 to 14.9 ) for deaths from coronary heart disease . The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease . After the exclusion of subjects who had a history of cardiovascular disease at base line , the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated . Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic . CONCLUSIONS Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes To evaluate the role of β‐adrenoceptor blockade on lower limb circulation in patients with peripheral arterial disease , heart rate , blood pressure , calf blood flow and vascular resistance were measured at rest and during reactive hyperemia in seven patients with hypertension and intermittent claudication . The study was performed as a placebo‐controlled , double‐blind , crossover trial of 10 days with doses of propranolol , 80 mg twice a day , pindolol , 5 mg twice a day , labetalol , 200 mg twice a day , and labetalol , 400 mg twice a day as active drug . Heart rate was lowest during propranolol dosing and blood pressure was lowest during labetalol dosing irrespective of the labetalol dose used . The degree of peripheral arterial disease modulated the effect of β‐blockade on limb circulation . In the less symptomatic limbs , reactive hyperemic flow was greater after pindolol than after the other drugs and did not differ from the level recorded after placebo . These differences were inconsistent and small in the more symptomatic limbs . Thus as the peripheral arterial disease became more severe and extensive , β‐blockade , irrespective of its type , lost its hemodynamic effect on lower limb circulation The clinical efficacy of picotamide was investigated in a r and omized , double- blind , placebo-controlled study in patients with peripheral occlusive arterial disease of the lower limbs at functional stage II of the Fontaine classification . Forty patients with a history of claudication for at least six months were admit ted to the study and were given either 3 x 300 mg tablets of picotamide ( 20 subjects ) or three identical placebo tablets ( 20 subjects ) for six months . The two groups of patients were similar in regard to clinical features and potential risk factors . At the end of treatment painfree walking distance and systolic ankle-arm pressure ratio improved more in the picotamide than in the placebo group ( p=0.05 ) . Systolic ankle pressure curves , determined before and after the six- month treatment , showed a positive trend to a higher postexercise ankle pres sure and a faster return to the preexercise levels in the picotamide group ; however , the difference was not statistically significant . Laboratory monitoring revealed a slight prolongation of bleeding time , a significant decrease in arachi donic acid-induced platelet aggregation , and an enhanced fibrinolysis with ab sence of interference with hemostasis in the picotamide group . One patient in the placebo group developed a major cardiovascular event ( angina pectoris ) during the study . These results indicate that picotamide is an effective drug that may modify the natural course of intermittent claudication and associated vascular prob lems The relationship between risk factors and the onset of cardiovascular events was analyzed in patients suffering from peripheral obstructive arterial disease . One thous and and eleven patients were recruited in 120 Italian centers and participated in a clinical trial on picotamide ( A.D.E.P. study ) , whose results have been previously reported . Patients were followed-up for 18 months and cardiovascular events were recorded . Hypertension ( 35 % ) , smoking ( 34 % ) , and diabetes ( 19 % ) were the most common risk factors at baseline . During the follow-up period , 246 patients ( 11.7 % ) had a cardiovascular event , mainly affecting cerebral , cardiac or peripheral circulation . Thirty-five of these events ( 14.2 % ) were fatal . A logistic regression analysis showed in general that hypertension ( odds ratio 1.48 ) , an ankle arm pressure ratio lower than 0.8 ( odds ratio 1.42 ) , smoking ( odds ratio 1.43 ) , previous vascular surgery ( odds ratio 1.35 ) , high white blood cell ( WBC ) count ( odds ratio 1.15 for a difference of 2.0 x 10(9 ) WBC/1 ) and plasma fibrinogen ( odds ratio 1.16 for a difference of 1.05 g/l ) were significantly associated with a higher incidence of cardiovascular events . In particular , deaths of any origin were more frequent in patients with an ankle/arm pressure ratio below 0.8 . High plasma fibrinogen increased the risk of cerebrovascular events , hypertension or coronary heart events and , to a less evident extent , peripheral vascular complications and cerebrovascular events . A history of vascular surgery increased the risk of peripheral vascular complications . Both smoking and a high WBC count showed to be borderline significant risk factors for coronary heart events and the former also for peripheral vascular complications . In male patients ( 84 % ) , ankle/arm pressure ratio lower than 0.8 , high fibrinogen and hypertension were the most important factors for cardiovascular events . This study helps to identify some categories at higher risk of cardiovascular events among patients with peripheral obstructive arterial disease ; this finding is useful to plan future trials to decrease the frequency of such complications The effects of acebutolol ( with intrinsic sympathomimetic activity ( ISA ] and metoprolol ( without ISA ) on arm blood pressure , ankle systolic blood pressure , claudication distances ( CD ) and maximal walking distances ( MWD ) were compared in patients with essential hypertension and intermittent claudication . Fourteen patients participated in a long-term , open , r and omized cross-over study . After r and omization the patients received either acebutolol , 200 mg b.i.d . , or metoprolol , 100 mg b.i.d . After eight weeks the drugs were shifted and after another eight weeks they were withdrawn . Arm and ankle blood pressure , CD and MWD were determined before r and omization and after 4 , 8 , 12 and 16 weeks , and again 4 - 6 weeks after withdrawal of the drugs . The arm blood pressure was reduced by 20/13 mmHg after acebutolol and by 22/21 mmHg after metoprolol . In spite of a significant decrease in arm blood pressure there were no significant changes in ankle blood pressure , CD or MWD after the two drugs . After withdrawal of the drugs and after the arm blood pressure had returned to the control value no significant changes were seen in CD , MWD or ankle blood pressure . It is concluded that beta-blockers have no deleterious effect on CD , MWD or ankle blood pressure in patients with hypertension and intermittent claudication . No effect of ISA was demonstrated OBJECTIVE To determine whether long-term treatment with cilazapril ( CIL ) may improve pulse pressure ( PP ) , arterial compliance and ankle-arm systolic index ( AAI ) in patients with lower-extremity arterial disease ( LEAD ) . Indeed , in both systolic hypertension and LEAD , the increase in pulse pressure has been attributed to a reduced compliance . DESIGN AND METHODS Thirteen patients ( age : 65 + /- 5 yrs ; AAI : 0.78 + /- 0.15 ; m + /- SD ) were included in a double-blind r and omized parallel study to compare the effects of a 6 month treatment with CIL ( 10 mg per day ; n = 6 ) to those of placebo ( PL ; n = 7 ) Blood pressure , AAI and arterial compliance were determined at baseline ( MO ) and after 3 ( M3 ) and 6 months ( M6 ) . Common carotid ( CC ) and common femoral ( CF ) artery compliances were noninvasively determined from pulsatile changes in arterial diameter ( Wall Track System , Hoeks et al. , 1990 ) and pressure ( PP ) . RESULTS Both groups were comparable at MO . Compared to PL , CIL significantly reduced PP ( -22 + /- 4 vs -2 + /- 9 mmHg ) and MAP ( -16 + /- 11 vs -4 + /- 7 mmHg ) and improved CC ( + 54 + /- 34 vs + 5 + /- 21 mm2.mmHg-1.10(-3 ) ) at M6 . Weaker effects were observed at M3 . No significant changes in AAI and CF compliance were observed . CONCLUSIONS A direct effect of CIL on the large artery wall was suggested by 1 ) a greater reduction in PP than in MAP and 2 ) a disproportionately greater improvement in CC compliance compared with the reduction in distending pressure ( MAP ) . These results indicate that long-term treatment with CIL may improve large artery function in patients with LEAD BACKGROUND The apparent shortfall in prevention of coronary heart disease ( CHD ) noted in early hypertension trials has been attributed to disadvantages of the diuretics and beta blockers used . For a given reduction in blood pressure , some suggested that newer agents would confer advantages over diuretics and beta blockers . Our aim , therefore , was to compare the effect on non-fatal myocardial infa rct ion and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril . METHODS We did a multicentre , prospect i ve , r and omised controlled trial in 19 257 patients with hypertension who were aged 40 - 79 years and had at least three other cardiovascular risk factors . Patients were assigned either amlodipine 5 - 10 mg adding perindopril 4 - 8 mg as required ( amlodipine-based regimen ; n=9639 ) or atenolol 50 - 100 mg adding bendroflumethiazide 1.25 - 2.5 mg and potassium as required ( atenolol-based regimen ; n=9618 ) . Our primary endpoint was non-fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) and fatal CHD . Analysis was by intention to treat . FINDINGS The study was stopped prematurely after 5.5 years ' median follow-up and accumulated in total 106 153 patient-years of observation . Though not significant , compared with the atenolol-based regimen , fewer individuals on the amlodipine-based regimen had a primary endpoint ( 429 vs 474 ; unadjusted HR 0.90 , 95 % CI 0.79 - 1.02 , p=0.1052 ) , fatal and non-fatal stroke ( 327 vs 422 ; 0.77 , 0.66 - 0.89 , p=0.0003 ) , total cardiovascular events and procedures ( 1362 vs 1602 ; 0.84 , 0.78 - 0.90 , p<0.0001 ) , and all-cause mortality ( 738 vs 820 ; 0.89 , 0.81 - 0.99 , p=0.025 ) . The incidence of developing diabetes was less on the amlodipine-based regimen ( 567 vs 799 ; 0.70 , 0.63 - 0.78 , p<0.0001 ) . INTERPRETATION The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen . On the basis of previous trial evidence , these effects might not be entirely explained by better control of blood pressure , and this issue is addressed in the accompanying article . Nevertheless , the results have implication s with respect to optimum combinations of antihypertensive agents OBJECTIVES To examine the central hemodynamic and blood gas responses to sublingual captopril and nifedipine administration in patients with arterial hypertension after abdominal aortic surgery . DESIGN Prospect i ve , r and omized , parallel-group clinical study . SETTING Twenty-nine-bed medical-surgical intensive care unit in a university hospital . PATIENTS Twenty patients with arterial hypertension ( mean arterial pressure of > or = 115 mm Hg ) the day after abdominal aortic surgery . Patients with bilateral renal artery stenoses , identified with the preoperative angiogram , were excluded . INTERVENTIONS Pressures were measured using intravascular catheters and cardiac output was determined by thermodilution for 2 hrs after captopril 25 mg ( n = 10 ) or nifedipine 10 mg ( n = 10 ) was administered by the sublingual route . MEASUREMENTS AND MAIN RESULTS Captopril administration and nifedipine administration decreased mean arterial pressure ( from 121 + /- 1 to 94 + /- 4 mm Hg and from 121 + /- 2 to 94 + /- 2 [ sem ] mm Hg , respectively ) , pulmonary arterial pressure , pulmonary artery occlusion pressure , and right atrial pressure ( p < .001 for all variables ) . Changes in heart rate and in cardiac output were not significant . PaO2 decreased after nifedipine , from 101 + /- 8 to 81 + /- 3 torr [ 13.5 + /- 1.1 to 10.8 + /- 0.4 kPa ] ( p < .01 ) , but not after captopril ( 104 + /- 9 to 100 + /- 7 torr [ 13.9 + /- 1.2 to 13.3 + /- 0.9 kPa ] ) . Excessive or symptomatic decreases in blood pressure were not observed , nor was deterioration in renal function observed . CONCLUSIONS Sublingual captopril and nifedipine were equally effective for the treatment of arterial hypertension after abdominal aortic surgery . Nifedipine , but not captopril , caused a deterioration in pulmonary gas exchange IMPORTANCE Approximately one-third of patients with peripheral artery disease experience intermittent claudication , with consequent loss of quality of life . OBJECTIVE To determine the efficacy of ramipril for improving walking ability , patient-perceived walking performance , and quality of life in patients with claudication . DESIGN , SETTING , AND PATIENTS R and omized , double-blind , placebo-controlled trial conducted among 212 patients with peripheral artery disease ( mean age , 65.5 [ SD , 6.2 ] years ) , initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia . INTERVENTION Patients were r and omized to receive 10 mg/d of ramipril ( n = 106 ) or matching placebo ( n = 106 ) for 24 weeks . MAIN OUTCOME MEASURES Maximum and pain-free walking times were recorded during a st and ard treadmill test . The Walking Impairment Question naire ( WIQ ) and Short-Form 36 Health Survey ( SF-36 ) were used to assess walking ability and quality of life , respectively . RESULTS At 6 months , relative to placebo , ramipril was associated with a 75-second ( 95 % CI , 60 - 89 seconds ) increase in mean pain-free walking time ( P < .001 ) and a 255-second ( 95 % CI , 215 - 295 seconds ) increase in maximum walking time ( P < .001 ) . Relative to placebo , ramipril improved the WIQ median distance score by 13.8 ( Hodges-Lehmann 95 % CI , 12.2 - 15.5 ) , speed score by 13.3 ( 95 % CI , 11.9 - 15.2 ) , and stair climbing score by 25.2 ( 95 % CI , 25.1 - 29.4 ) ( P < .001 for all ) . The overall SF-36 median Physical Component Summary score improved by 8.2 ( Hodges-Lehmann 95 % CI , 3.6 - 11.4 ; P = .02 ) in the ramipril group relative to placebo . Ramipril did not affect the overall SF-36 median Mental Component Summary score . CONCLUSIONS AND RELEVANCE Among patients with intermittent claudication , 24-week treatment with ramipril result ed in significant increases in pain-free and maximum treadmill walking times compared with placebo . This was associated with a significant increase in the physical functioning component of the SF-36 score . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00681226 The aim of the present study was to evaluate whether beta blockade presents a risk of intermittent claudication and how it affects the walking capacity and lower limb haemodynamics in patients with intermittent claudication . The study was divided into six parts : A case-control study with 55 pairs , cases with hypertension and intermittent claudication and controls with hypertension only , matched for age , sex , place of residence , and time of examination , all without coronary heart disease , which is a known confounding factor . An open controlled study on the effect of withdrawal of beta blockade on walking capacity of 28 patients with intermittent claudication . A placebo-controlled double-blind crossover study on the effect of antihypertensive treatment on the walking capacity of 14 patients with intermittent claudication . Three placebo-controlled double-blind crossover studies on the effect of propranolol , metoprolol , pindolol , labetalol , and /or methyldopa on calf blood flow in 34 hypertensive subjects without peripheral arterial disease and in altogether 21 patients with intermittent claudication .  Walking capacity was measured on a treadmill . Calf blood flow was measured with strain gauge plethysmography by the venous occlusion technique . The case-control comparison showed that beta blockers were used as often by patients with intermittent claudication as by controls . Walking capacity increased during the first month of the open controlled study irrespective of whether the beta blockade was withdrawn or continued . There was no difference in this respect between the various types of beta blockers . Antihypertensive treatment with metoprolol or methyldopa did not affect walking capacity . Resting calf blood flow was unaffected by propranolol or metoprolol , regardless of the presence or absence of peripheral arterial disease , as well as by pindolol , labetalol , or methyldopa in patients with intermittent claudication . During reactive hyperaemia , propranolol and metoprolol reduced flow in patients without peripheral arterial disease . Propranolol also reduced hyperaemic blood flow in the limb with less or no symptoms in patients with intermittent claudication . None of the active drugs decreased the hyperaemic flow consistently in the limb with the stronger symptoms . In a comparison of haemodynamic effects between the drugs , calf blood flow at rest was higher after pindolol than after propranolol and hyperaemic flow of the better limb was higher after pindolol than after propranolol and labetalol . ( ABSTRACT TRUNCATED AT 400 WORDS BACKGROUND The results from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial ( ONTARGET ) indicated that the angiotensin-receptor blocker telmisartan was not inferior to the angiotensin-converting-enzyme inhibitor ramipril in reducing the composite endpoint of cardiovascular death , myocardial infa rct ion , stroke or hospitalization for congestive heart failure in high-risk patients , and telmisartan was associated with slightly superior tolerability . The combination of the two drugs was associated with more adverse events without an increase in benefit . This study aim ed to analyze the data from ONTARGET obtained from a subgroup of patients enrolled in China and to evaluate the demographic and baseline characteristics , the compliance , efficacy , and safety of the different treatment strategies in r and omized patients in China . METHODS A total of 1159 high-risk patients were r and omized into three treatment groups : with 390 assigned to receive 80 mg of telmisartan , 385 assigned to receive 10 mg of ramipril and 384 assigned to receive both study medications . The median follow-up period was 4.3 years . RESULTS The mean age of Chinese patients was 65.6 years , 73.6 % of patients were male . The proportion of patients with stroke/transient ischemic attacks at baseline in China was two times more than the entire study population ( 47.7 % vs. 20.9 % ) . In Chinese patients the proportion of permanent discontinuation of study medication due to cough was 0.5 % in the telmisartan group , which was much less than that in the combination or the ramipril group . There were no significant differences in the incidence of primary outcome among three treatment groups of Chinese patients . More strokes occurred in Chinese patients than in the entire study population ( 8.5 % vs. 4.5 % ) . Greater systolic blood pressure reduction ( -9.8 mmHg ) , and more renal function failure were noted in the combination treatment group than in the ramipril or telmisartan group ( 2.6 % vs. 1.6 % and 1.0 % ) . CONCLUSIONS There was no evidence that the results of ONTARGET differed between Chinese patients and the entire study population with respect to the incidence of primary outcome , particularly safety . Compliance with study medications was good . The evidence from ONTARGET indicated that the treatment strategies in ONTARGET were applicable to patients in China A multicenter , double-blind , r and omized , and placebo-controlled trial , the Perindopril Therapeutic Safety Study ( PUTS ) , was design ed to assess the interaction between angiotensin-converting enzyme ( ACE ) inhibition and the diseases and therapies commonly found associated with mild hypertension . A total of 480 male and female patients aged 30 - 70 years with a diastolic pressure of 90 - 104 mm Hg were included after a 3-week placebo run-in if they satisfied st and ard criteria for any of the following : hyperlipidemia , type II diabetes , ischemic heart disease , cardiac arrhythmia , peripheral arterial occlusive disease , nephropathy with proteinuria , chronic obstructive lung disease or treatment with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . At the end of the placebo run-in period , patients were r and omly assigned to either placebo or perindopril 4 mg once daily . A total of 460 patients completed the 6-week double-blind phase , comprising 3 assessment s at 1 , 3 , and 6 weeks . In this report , the principal results obtained in 5 disease groups ( hyperlipidemia , type II diabetes , ischemic heart disease , nephropathy with proteinuria , and NSAID treatment ) will be reported . A total of 269 patients belonging to one of the aforementioned 5 disease groups completed the double-blind phase of the study and were included for statistical evaluation . In the perindopril group , systolic and diastolic blood pressures decreased significantly more than in the placebo group , and a sitting diastolic blood pressure of 90 mm Hg was achieved in 65 % of patients in the perindopril group and 30 % of patients in the placebo group . The incidence of symptoms spontaneously reported by the patients was low : 2 patients of the perindopril group complained of cough . ( ABSTRACT TRUNCATED AT 250 WORDS Objective To test the primary hypothesis that a newer antihypertensive treatment regimen ( calcium channel blocker ± an angiotensin converting enzyme inhibitor ) is more effective than an older regimen ( β-blocker ± a diuretic ) in the primary prevention of coronary heart disease ( CHD ) . To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol ⩽ 6.5 mmol/l . Design Prospect i ve , r and omized , open , blinded endpoint trial with a double-blinded 2 × 2 factorial component . Setting Patients were recruited mainly from general practice s. Patients Men and women aged 40–79 were eligible if their blood pressure was ⩾160 mmHg systolic or ⩾ 100 mmHg diastolic ( untreated ) or ⩾140 mmHg systolic or ⩾ 90 mmHg diastolic ( treated ) at r and omization . Interventions Patients received either amlodipine ( 5/10 mg ) ± perindopril ( 4/8 mg ) or atenolol ( 50/100 mg ) ± bendroflumethiazide ( 1.25/2.5 mg ) + K+ with further therapy as required to reach a blood pressure of ⩽140 mmHg systolic and 90 mmHg diastolic . Patients with a total cholesterol of ⩽ 6.5 mmol/l were further r and omized to receive either atorvastatin 10 mg or placebo daily . Main outcome measure Non-fatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) . Results 19 342 men and women were initially r and omized , of these 10 297 were also r and omized into the lipid-lowering limb . All patients had three or more additional cardiovascular risk factors . Conclusions The study has 80 % power ( at the 5 % level ) to detect a relative difference of 20 % in CHD endpoints between the calcium channel blocker-based regimen and the β-blocker-based regimen . The lipid-lowering limb of the study has 90 % power at the 1 % level to detect a relative difference of 30 % in CHD endpoints between groups In a comparative cross-over trial we examined the influence of the betablocker bisoprolol and the ACE-inhibitor lisinopril on the peripheral blood flow of 2 groups of hypertensive patients with and without concomitant intermittent claudication . In 11 patients with hypertension without peripheral arterial obstructive disease and 11 patients with hypertension and claudication we assessed the blood pressure , leg blood flow , vascular resistance , walking distance , transcutaneous oxygen consumption and Laser-Doppler flow after treatment of one month with 10 mg bisoprolol once daily or 20 mg lisinopril once daily . The walking distance of patients with claudication improved in all patients while participating in an exercise program . For both treatment groups this improvement was significant ( p < 0.05 ) compared to baseline , from 264 m at baseline to 313 m with bisoprolol and to 400 m with lisinopril . The difference was not significant between the both drugs . In patients without peripheral vascular obstructive disease we found a significant ( p < 0.05 ) reduction in blood flow for both drugs . The peripheral blood flow parameters of 38 legs showed no statistical significant effect of bisoprolol nor lisinopril on the local vascular resistance at rest , after occlusion or after exercise The ABCD ( Appropriate Blood Pressure Control in Diabetes ) trial is a large , prospect i ve , r and omized clinical trial design ed to compare the effects of intensive with moderate blood pressure control on the prevention and progression of diabetic nephropathy , retinopathy , cardiovascular disease , and neuropathy in non-insulin-dependent diabetes ( NIDDM ) . The secondary objective is to determine equivalency of the effects of a calcium channel blocker ( nisoldipine ) and of an angiotensin-converting enzyme inhibitor ( enalapril ) as a first-line antihypertensive agent in the prevention and /or progression of these diabetic vascular complications . The study consists of two study population s : a hypertensive one ( diastolic blood pressure of > or = 90.0 mm Hg at the time of r and omization ) and a normotensive one ( diastolic blood pressure of 80.0 - 89.0 mm Hg at the time of r and omization ) . A total of 950 men and women aged 40 - 74 years were r and omized and are being followed for 5 years at a single center . There were 470 r and omized participants in the hypertensive population and 480 r and omized participants in the normotensive population . This report summarizes the demographic , biochemical , and clinical characteristics of the r and omized patients at the time of entry into the trial and evaluates the balance between the treatment groups within each population The effect of a four-week treatment with propranolol and metoprolol on blood pressure and regional haemodynamics of the lower extremity at rest , after exercise and during reactive hyperaemia was studied in 34 patients with essential hypertension , but without peripheral arterial disease , in a r and omized placebo-controlled trial . No significant difference in side-effects recorded during the trial was observed between these two drugs . Treatment with beta-adrenergic blocking drugs reduced systemic blood pressure . Calf blood flow during vasodilatation was also decreased . The most marked changes were observed during reactive hyperaemia ; mean calf blood flow was reduced from about 250 ml/min/litre of tissue to 200 ml/min/litre of tissue ( P less than 0.01 ) by propranolol and to 214 ml/min/litre of tissue ( P less than 0.01 ) by metoprolol . Both drugs caused a significant increase in peripheral resistance above the initial level during reactive hyperaemia ( P less than 0.05 ) . No significant difference in peripheral resistance was observed , however , when the active drugs were compared with the placebo . There was no difference between propranolol and metoprolol in any of the parameters . Thus , the flow reduction can mainly be attributed to the diminished perfusion pressure due to the decreased cardiac output caused by beta-blockade of the heart The effects of two potent vasodilating drugs , captopril ( C ) ( 25 mg tid ) , nicar dipine ( N ) ( 20 mg tid ) , and placebo ( P ) were evaluated and compared , in 10 men ( mean age of sixty-five years ) with intermittent claudication from moderate to severe multilevel chronic occlusive arterial disease ( COAD ) of the lower extrem ity , by use of the Doppler ultrasonic method , at rest and after Carter 's exercise test . All the examined subjects were normotensive , without diabetes or cardio pathy ; all have been smokers . The eight-week total protocol consisted of an initial two-week placebo run-in period followed by two active drug phases and a two-week placebo phase , ac cording to a double-blind , r and omized , crossover design . At the end of each two-week period , ankle-arm index ( AAI ) and , following exercise , onset of lower extremity discomfort time ( ODT ) , duration of exercise ( ET ) , decrease of ankle systolic pressure after test ( APD ) , and recovery time ( RT ) were determined . Moreover , at rest , just after exercise , and after recovery , simultaneous common femoral artery velocity waves were recorded and analyzed by a quantitative approach to detect the peripheral vasomotor adjustments . None of the patients required the withdrawal of the active treatments . Com pared with P , C significantly reduced APD and RT , and N reduced RT and AAI ; furthermore N caused a significant decrease in ODT , whereas C showed a trend , although not statistically significant , to increase ODT . Neither active therapy modified ET . These results suggest that C and N have different short-term effects on pe ripheral circulation in COAD . During exercise , C induces hemodynamic i m provement in the ischemic lower extremity probably by inhibition of the sympathetic system and consequent reduction in collateral vessel vasoconstric tion Many factors , both local and systemic , are known to influence the caliber of peripheral vessels and regional blood flow . Methods of study ing limb blood flow and its alteration by disease and drugs present considerable problems . We compared the effects of a series of antihypertensive drugs on limb blood flow and their functional effects in patients with hypertension and peripheral vascular disease . Results from studies with new antihypertensive drugs such as carvedilol are awaited PURPOSE Many hypertensive patients have other , usually long-term diseases . Antihypertensive therapy may interfere with these diseases and their therapies . In the present study , the possible interactions of the ACE-inhibitor perindopril with several of the most common long-term diseases was evaluated . PATIENTS AND METHODS In a multicenter , double-blind , r and omized , placebo-controlled trial , the effect of perindopril was evaluated in 490 patients with mild essential hypertension and any one of the following concomitant diseases : hyperlipidemia , type II diabetes mellitus , ischemic heart disease , cardiac arrhythmia , peripheral arterial occlusive disease , nephropathy with proteinuria , chronic obstructive pulmonary disease , or degenerative joint disease treated with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . After a 3-week single-blind placebo run-in , the patients received either perindopril ( 4 mg/d ) or matching placebo for 6 weeks . RESULTS Blood pressure was effectively reduced by perindopril irrespective of the associated disease . The rate of spontaneously reported side effects was low . Treatment with perindopril was free from adverse interactions with the concomitant diseases and therapies . Moreover , favorable actions could be observed in patients with ischemic heart disease ( reduction of maximal ST-segment depression during peak exercise and decrease in the number of angina attacks ) , in patients with proteinuria ( decrease in albuminuria in patients with normal serum creatinine levels ) , and in patients with NSAID-treatment ( increase in prostagl and in E2 concentration in gastric mucosa suggesting gastric cytoprotection ) . CONCLUSION This trial shows that ACE-inhibition with perindopril represents a simple , safe , and effective short-term therapeutic option for the large proportion of patients with mild essential hypertension and concomitant diseases and therapies In a double-blind , crossover trial 12 patients with hypertension and peripheral arterial disease were r and omized to three months ' treatment with captopril 25 - 50 mg twice daily or nifedipine SR 20 - 40 mg twice daily . While both treatments were equally effective at lowering blood pressure , postexercise calf blood flow availability was greater during treatment with captopril ( P < 0.04 ) . This was not reflected in walking capacity assessed by treadmill exercise . The results sug gest that both captopril and nifedipine are appropriate antihypertensive agents in patients with peripheral arterial disease A high prevalence of increased intima/media thickness of the arterial wall has been documented in hypertension . These alterations in vascular wall structure may be potent determinants for the promotion of the development of atherosclerosis . Direct histologic data from animal models of hypertension , and indirect data from hypertensive patients , have demonstrated a marked regression of increased intima/media thickness by angiotensinconverting enzyme ( ACE ) inhibition . Long-term effects of ACE inhibition on structural wall changes in humans have not been examined . Therefore , a multicenter , r and omized , double-blind European trial was design ed to compare the effects of the ACE inhibitor perindopril and the diuretic hydrochlorothiazide in slowing or reversing progression of increased intima/media thickness of carotid and femoral arteries in hypertensive patients . A total of 800 patients at 17 clinical centers in 7 European countries , aged 35–65 years , with hypertension and ultrasonographically proven intima/media thickness ≥0.8 mm of the common carotid artery will be r and omly assigned to receive in a doubleblind fashion either perindopril or hydrochlorothiazide and will be followed for 24 months . High resolution duplex sonography will be used to quantify intima/media thickness at baseline and twice a year during follow-up . A change of 0.1 mm of intima/media thickness from baseline is considered to be detectable , and the st and ard deviations of the changes from baseline are expected not to be higher than 0.2 mm . The primary endpoint of the study is the comparison of changes in intima/media thickness of the common carotid artery . Secondary endpoints include comparison of the effectiveness of the two treatments on left ventricular mass , posterior wall thickness , intraventricular septal thickness , left ventricular end-diastolic diameter , and comparison of the 2 treatments on ultrasonographically determined thickness of the intima/media complex of the common femoral artery . Further analyses will assess the relation between intima/ media thickness changes and the changes of blood pressure , heart rate , low and high density lipoprotein cholesterol , triglycerides , and glucose . The study is design ed to assess the impact of antihypertensive therapy on early pathological vascular wall changes and to clarify whether this is due to a drug-specific action or only dependent on the blood pressure lowering effect Authors report results on a comparative multicenter double blind trial carried out to assess the efficacy of Ifenprodil tartrate ( * ) ( 60 mg a.d . ) versus placebo in symptomatic treatment of stable peripheral arterial occlusive disease ( Fontaine stage II ) . Ninety four patients were included in this six months , two parallel group study ( 2 homogeneous groups ) which shows a statistically significant functional improvement in the treatment group versus the placebo group . After six months of treatment , the maximum walking distance (MWD)--main assessment criteria --was 126.0 + /- 18.5 meters in the Ifenprodil group versus 46.4 + /- 20.2 meters in the placebo group ( p = 0.005 ) . This represents an improvement of 62.1 % in the Ifenprodil group versus 21.0 % in the placebo group . An improvement of at least 50 % in MWD was observed in 41.3 % of patients treated by Ifenprodil and in only 12.5 % of patients receiving placebo ( p = 0.002 ) . The evolution of ankle/brachial systolic post exercise index from JO to J180 was not significantly different in the two groups . Clinical and biological tolerance of Ifenprodil tartrate was excellent This double-blinded , r and omized , placebo-controlled study was design ed to investigate the acute effect of felodipine on regional blood supply and collateral vascular resistance in patients with peripheral arterial occlusive disease ( PAOD ) . Thirty men with PAOD were treated with a single dose of 5 mg felodipine or placebo .  Systolic blood pressure ( SBP ) , Doppler ankle pressure ( DAP ) , calf blood flow ( CBF ) by venous occlusion plethysmography and calf transcutaneous oxygen tension ( tcpO2 ) were measured during a cycle ergometry . Felodipine reduced SBP significantly ( from 149 to 136 mmHg , p < 0.05 ) , while placebo did not . DAP increased slightly but not significantly in both groups . The pressure gradient between SBP and DAP fell significantly in the felodipine group ( 60 vs 39 mmHg , p < 0.01 ) but not in the placebo group ( 59 vs 56 mmHg ) . There was a trend for lower velocity in tcpO2 decrease during the stress test and higher velocity of tcpO2 increase during recovery from exercise in the felodipine group although the differences between both groups were not significant . In the felodipine group , CBF increased by 35.6 % ( p < 0.05 ) whereas it did not change in the placebo group . In conclusion , while lowering SBP , felodipine increased slightly , or at least maintained , the blood supply to the calves in PAOD patients , which probably results from reducing collateral vascular resistance OBJECTIVES To ascertain the baseline characteristics of the high-risk hypertensive patients entering the International Nifedipine GITS Study : Intervention as a Goal in Hypertension Treatment ( INSIGHT ) . To determine the success of single and combination therapy in achieving target blood pressures in such a population . DESIGN INSIGHT is a double-blind , prospect i ve outcome trial comparing the efficacy of the calcium channel blocker , nifedipine GITS , and the thiazide , co-amilozide , in preventing myocardial infa rct ion and stroke . We recruited 2996 men and 3454 women , aged 55 - 80 years , with blood pressure during placebo run-in > 150/95 mmHg or isolated systolic blood pressure > 160 mmHg from nine countries . Treatment allocation to nifedipine GITS 30 mg daily or co-amilozide ( hydrochlorothiazide 25 mg/amiloride 5 mg ) once daily was performed by minimization rather than r and omization to balance additional risk factors . This was followed by four optional increases in treatment : dose-doubling of the primary drug , addition of atenolol 25/50 mg or enalapril 5/10 mg , and then any other hypotensive drug excluding calcium blockers or diuretics . Target blood pressure was 140/90 mmHg or a fall > or = 20/10 mmHg . RESULTS Blood pressure at r and omization was 172+/-15 / 99+/-9 mmHg . Thirteen per cent of the patients were previously untreated . The proportions of each additional risk factors were : smoking > 10/day , 29 % ; cholesterol > 6.43 mmol/l , 52 % ; family history of premature myocardial infa rct ion or stroke , 21 % ; diabetes mellitus 20 % ; left ventricular hypertrophy , 10 % ; previous myocardial infa rct ion , other presentations of coronary heart disease , and peripheral vascular disease , each 6 % ; proteinuria , 3 % . Fifty-five per cent of patients had one additional risk factor , whereas 33 % , 9 % and 3 % had two , three or more additional risk factors , respectively . The blood pressure ( and falls in blood pressure ) at the end of titration and at 1 year after minimization was 139+/-12 / 82+/-7 mmHg ( 33+/-15 / 17+/-9 ) in the 5226 patients still on r and omized treatment The numbers requiring the four treatment increments were , respectively , 1591 , 780 , 597 and 294 , meaning that almost 70 % of patients on r and omized treatment in INSIGHT are receiving only the primary drug . At one year , 69 % of patients had a blood pressure < or = 140/90 mmHg . CONCLUSION INSIGHT is one of the first double-blind comparisons of active antihypertensive treatments , requiring high-risk patients to achieve sufficient power . Despite this requirement , it is possible to achieve good blood pressure control in most patients without the addition of multiple additional treatments that may dilute any differences between the primary agents BACKGROUND Erectile dysfunction ( ED ) is a common disorder in middle-aged men and is significantly influenced by cardiovascular risk factors ( CVRFs ) and cardiovascular disease . The sub study of the ONTARGET/TRANSCEND trials evaluates the relationship of erectile function to baseline characteristics and current treatment in cardiovascular high-risk patients who have been enrolled in these trials . The effects of treatment with telmisartan and ramipril , alone or in combination , including a telmisartan versus placebo arm will be determined prospect ively during a follow-up of 4 years . METHODS One thous and three hundred fifty-seven patients were evaluated in 13 countries at baseline , 2 years , and 4 years , with ED determined using the ED score of the Cologne Male Survey ( Kölner [ Cologne ] Evaluation of Erectile Dysfunction ) and the 5-item International Index of Erectile Function . Erectile dysfunction scores were related to CVRF and the use of cardiovascular drugs . RESULTS Prevalence of ED was 50.7 % ( Kölner [ Cologne ] Evaluation of Erectile Dysfunction ) and 54.3 % ( 5-item International Index of Erectile Function ) , respectively , with a decline of sexual activity after the diagnosis of cardiovascular disease . In multivariate analysis , diabetes mellitus ( P < .00001 ) , stroke ( P = .00026 ) , pelvic surgery ( P = .025 ) , and age of > 65 years ( P < .00001 ) correlated with the degree of ED . No significant associations were observed for cholesterol levels , hypertension , and smoking status as well as current treatment with angiotensin-converting enzyme inhibitors , angiotensin I antagonists , diuretics , beta-blockers , or calcium-channel blockers . CONCLUSIONS The ONTARGET/TRANSCEND-ED sub study shows a significant influence of cardiovascular disease on erectile function . In contrast to prior smaller studies , drug therapy and CVRF seem to play a minor role in cardiovascular high-risk patients . Follow-up data will provide information whether angiotensin-converting enzyme inhibitors , angiotensin I antagonists , or a combination thereof are able to improve erectile function Seven patients ( 5 with arteriosclerosis obliterans and 2 with Buerger 's disease ) completed a two‐phase double‐blind crossover trial of  propranolol in intermittent claudication . Performance was measured on a moving treadmill . In the initial phase , the patients were hospitalized in order to determine an “ effective ” dose of propranolol . Improvement was noted in all : after 1,600 mg in 5 and after 240 mg and 600 mg in the others . The controlled phase was carried out on an outpatient basis over 8 weeks , the patients receiving propranolol and placebo in a r and om manner , each for two 2‐week periods . Comparison of matched periods of drug and placebo revealed no advantage  for propranolol . Patients ’ performances deteriorated with time . None of the patients evidence d deterioration of occlusive peripheral arterial disease that could be attributed to propranolol , in spite of the high doses used Background — Although erectile dysfunction ( ED ) is associated with cardiovascular risk factors and atherosclerosis , it is not known whether the presence of ED is predictive of future events in individuals with cardiovascular disease . We evaluated whether ED is predictive of mortality and cardiovascular outcomes , and because inhibition of the renin-angiotensin system in high-risk patients reduces cardiovascular events , we also tested the effects on ED of r and omized treatments with telmisartan , ramipril , and the combination of the 2 drugs ( ONTARGET ) , as well as with telmisartan or placebo in patients who were intolerant of angiotensin-converting enzyme inhibitors ( TRANSCEND ) . Methods and Results — In a prespecified sub study , 1549 patients underwent double-blind r and omization , with 400 participants assigned to receive ramipril , 395 telmisartan , and 381 the combination thereof ( ONTARGET ) , as well as 171 participants assigned to receive telmisartan and 202 placebo ( TRANSCEND ) . ED was evaluated at baseline , at 2-year follow-up , and at the penultimate visit before closeout . ED was predictive of all-cause death ( hazard ratio [ HR ] 1.84 , 95 % confidence interval [ CI ] 1.21 to 2.81 , P=0.005 ) and the composite primary outcome ( HR 1.42 , 95 % CI 1.04 to 1.94 , P=0.029 ) , which consisted of cardiovascular death ( HR 1.93 , 95 % CI 1.13 to 3.29 , P=0.016 ) , myocardial infa rct ion ( HR 2.02 , 95 % CI 1.13 to 3.58 , P=0.017 ) , hospitalization for heart failure ( HR 1.2 , 95 % CI 0.64 to 2.26 , P=0.563 ) , and stroke ( HR 1.1 , 95 % CI 0.64 to 1.9 , P=0.742 ) . The study medications did not influence the course or development of ED . Conclusions — ED is a potent predictor of all-cause death and the composite of cardiovascular death , myocardial infa rct ion , stroke , and heart failure in men with cardiovascular disease . Trial treatment did not significantly improve or worsen ED . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT 00153101
target: However , lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure
background: BACKGROUND Peripheral arterial disease ( PAD ) causes considerable morbidity and mortality .
  Hypertension is a risk factor for PAD .
  Treatment for hypertension must be compatible with the symptoms of PAD .
  Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers .
  Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD .
  This is the second up date of a Cochrane review first published in 2003 .
  OBJECTIVES To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death , symptoms of claudication and critical leg ischaemia , and progression of atherosclerotic PAD as measured by ankle brachial index ( ABI ) changes and the need for revascularisation ( reconstructive surgery or angioplasty ) or amputation .