human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Therapeutic strategies in resistant hypertension include adding another drug or changing drugs in search for a better synergic combination . Most patients , however , receive all of their drugs in a single morning dose . We have evaluated the impact on the circadian pattern of blood pressure on modifying the time of treatment without increasing the number of prescribed drugs . We studied 250 hypertensive patients who were receiving 3 antihypertensive drugs in a single morning dose .  Patients were r and omly assigned to 1 of 2 groups according to the modification in their treatment strategy : changing 1 of the drugs but keeping all 3 in the morning or the same approach but administering the new drug at bedtime .  Blood pressure was measured for 48 hours before and after 12 weeks of treatment . There was no effect on ambulatory blood pressure when all of the drugs were taken on awakening . The baseline prevalence of nondipping ( 79 % ) was slightly increased after treatment ( 86 % ; P=0.131 ) . The ambulatory blood pressure reduction was statistically significant ( 9.4/6.0 mm Hg for systolic/diastolic blood pressure ; P<0.001 ) with 1 drug at bedtime . This reduction was larger in the nocturnal than in the diurnal mean of blood pressure . Thus , whereas only 16 % of the patients in this group were dippers at baseline , 57 % were dippers after therapy ( P<0.001 ) . Results indicate that , in resistant hypertension , time of treatment may be more important for blood pressure control and for the proper modeling of the circadian blood pressure pattern than just changing the drug combination Several previous studies found that too great a reduction of clinic blood pressure ( BP ) by treatment increased cardiovascular disease ( CVD ) risk , whereas moderate reduction decreased it . Thus , it has been suggested that the relationship between BP and CVD events is J-shaped , with CVD risk decreasing as BP is lowered , and then rising as BP is further decreased . Correlation between BP level and CVD risk , however , is stronger for ambulatory BP monitoring ( ABPM ) than clinical BP measurements . We previously established that the hypertension treatment-time regimen , upon awakening versus at bedtime , exerts differential effect on BP control during the day and nighttime , which translates into a differential degree of CVD risk prevention . We , therefore , investigated the role of hypertension treatment-time scheme on the nature of the relationship between achieved clinic and ambulatory BP and CVD risk in the MAPEC ( Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares , i.e. , Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events ) study , a prospect i ve , open-label , blinded-endpoint trial on 2156 hypertensive patients ( 1044 men/1112 women ) , 55.6 ± 13.6 ( mean ± SD ) yrs of age , r and omized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime  . Ambulatory BP was measured for 48-h at baseline and annually thereafter , and more frequently ( quarterly ) when adjustment of treatment was necessary . After a median follow-up of 5.6 yrs , a J-shaped relationship was detected between total CVD events and clinic as well as awake BP mean , but only for the group of patients ingesting all medications upon awakening . The relationship was different in the group of patients who ingested ≥1 medications at bedtime ; the risk of CVD events progressively diminished in a linear , rather than J-shaped , manner with treatment-induced decrease in awake BP mean . The adjusted hazard ratio of CVD events was significantly lower with the progressive reduction in the asleep BP mean , independent of the hypertension treatment-time regimen . There was no single major event , i.e. , CVD death , myocardial infa rct ion , or stroke , in patients who achieved an asleep systolic BP mean < 103 mm Hg . Our findings indicate that bedtime hypertension treatment is not associated with a J-shaped relationship between achieved BP and CVD risk . The decreased CVD risk associated with the progressive reduction in asleep BP , more feasible by bedtime than morning hypertension treatment , has clinical implication s , in particular , the need to consider the proper timing of hypertension medications , in conjunction with ABPM for proper assessment of BP control , as an improved and potentially safer means of reducing CVD risk of hypertensive patients . ( Author correspondence : rhermida@uvigo.es CONTEXT Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk , but the benefit compared with other drug classes is controversial . OBJECTIVE To determine whether initial therapy with controlled-onset extended-release ( COER ) verapamil is equivalent to a physician 's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized clinical trial conducted at 661 centers in 15 countries . A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31 , 2000 . After a mean of 3 years of follow-up , the sponsor closed the study before unblinding the results . INTERVENTION Initially , 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide . Other drugs ( eg , diuretic , beta-blocker , or an angiotensin-converting enzyme inhibitor ) could be added in specified sequence if needed . MAIN OUTCOME MEASURES First occurrence of stroke , myocardial infa rct ion , or cardiovascular disease-related death . RESULTS Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group . There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group ( hazard ratio [ HR ] , 1.02 ; 95 % confidence interval [ CI ] , 0.88 - 1.18 ; P = .77 ) . For fatal or nonfatal stroke , the HR was 1.15 ( 95 % CI , 0.90 - 1.48 ) ; for fatal or nonfatal myocardial infa rct ion , 0.82 ( 95 % CI , 0.65 - 1.03 ) ; and for cardiovascular disease-related death , 1.09 ( 95 % CI , 0.87 - 1.37 ) . The HR was 1.05 ( 95 % CI , 0.95 - 1.16 ) for any prespecified cardiovascular disease-related event and 1.08 ( 95 % CI , 0.93 - 1.26 ) for all-cause mortality . Nonstroke hemorrhage was more common with participants in the COER-verapamil group ( n = 118 ) compared with the atenolol or hydrochlorothiazide group ( n = 79 ) ( HR , 1.54 [ 95 % CI , 1.16 - 2.04 ] ; P = .003 ) . More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil ( 99/277 ) and atenolol or hydrochlorothiazide ( 88/274 ) groups ; HR , 1.15 ( 95 % CI , 0.86 - 1.53 ) . CONCLUSIONS The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker . When considered in the context of other trials of calcium antagonists , these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment OBJECTIVE ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism . The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events R and omized Trial ( FACET ) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension . Prospect ively defined cardiovascular events were assessed as secondary outcomes . RESEARCH DESIGN AND METHODS Inclusion criteria included a diagnosis of NIDDM and hypertension ( systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg ) . Exclusion criteria included a history of coronary heart disease or stroke , serum creatinine > 1.5 mg/dl , albuminuria > 40 μg/min , and use of lipid-lowering drugs , aspirin , or antihypertensive agents other than beta-blockers or diuretics . A total of 380 hypertensive diabetics were r and omly assigned to open-label fosinopril ( 20 mg/day ) or amlodipine ( 10 mg/day ) and followed for up to 3.5 years . If blood pressure was not controlled , the other study drug was added . RESULTS Both treatments were effective in lowering blood pressure . At the end of followup , between the two groups there was no significant difference in total serum cholesterol , HDL cholesterol , HbA1c , fasting serum glucose , or plasma insulin . The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infa rct ion , stroke , or hospitalized angina than those receiving amlodipine ( 14/189 vs. 27/191 ; hazards ratio = 0.49 , 95 % CI = 0.26–0.95 ) . CONCLUSIONS Fosinopril and amlodipine had similar effects on biochemical measures , but the patients r and omized to fosinopril had a significantly lower risk of major vascular events , compared with the patients r and omized to amlodipine In the HOPE-trial , the ACE inhibitor ramipril significantly reduced cardiovascular morbidity and mortality in patients at high risk for cardiovascular events . The benefit could only partly be attributed to the modest mean reduction of office blood pressure ( OBP ) during the study period ( 3/2 mm Hg ) . However , because according to the HOPE protocol ramipril was given once daily at bedtime and blood pressure was measured during the day , the 24-hour reduction of blood pressure may be underestimated based on OBP . Thirty-eight patients with peripheral arterial disease enrolled in the HOPE study underwent  24-hour ambulatory blood pressure ( ABP ) measurement  before r and omization and after 1 year . OBP was measured in the sitting position immediately before fitting the ABP measuring equipment to the patients . Ramipril did not significantly reduce OBP ( 8/2 mm Hg , P = NS ) or day ABP ( 6/2 mm Hg , P = NS ) after 1 year . Twenty-four – hour ABP was significantly reduced ( 10/4 mm Hg , P = 0.03 ) , mainly because of a more pronounced blood pressure lowering effect during nighttime ( 17/8 mm Hg , P < 0.001 ) . The night/day ratio was also significantly lowered in the ramipril  group . ABP shows greater falls , especially at night , than OBP during treatment with ramipril given once daily at bedtime . Although , OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies , the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may , to a larger extent than previously ascribed , relate to effects on blood pressure patterns over the 24-hour period 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 
    Output:
    
agent
Nighttime blood pressure strongly predicts cardiovascular events ( CVEs ) .
Further , a preliminary trial has shown decreased CVEs from evening vs morning dosing of antihypertensive therapy .
Unlike other EDTs , the Heart Outcomes Prevention Evaluation ( HOPE ) study administered its entire antihypertensive dose prior to sleep and gave the greatest risk reduction .
This study provides a third type of evidence suggesting a beneficial effect from evening dosing of antihypertensive therapy .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Therapeutic strategies in resistant hypertension include adding another drug or changing drugs in search for a better synergic combination . Most patients , however , receive all of their drugs in a single morning dose . We have evaluated the impact on the circadian pattern of blood pressure on modifying the time of treatment without increasing the number of prescribed drugs . We studied 250 hypertensive patients who were receiving 3 antihypertensive drugs in a single morning dose .  Patients were r and omly assigned to 1 of 2 groups according to the modification in their treatment strategy : changing 1 of the drugs but keeping all 3 in the morning or the same approach but administering the new drug at bedtime .  Blood pressure was measured for 48 hours before and after 12 weeks of treatment . There was no effect on ambulatory blood pressure when all of the drugs were taken on awakening . The baseline prevalence of nondipping ( 79 % ) was slightly increased after treatment ( 86 % ; P=0.131 ) . The ambulatory blood pressure reduction was statistically significant ( 9.4/6.0 mm Hg for systolic/diastolic blood pressure ; P<0.001 ) with 1 drug at bedtime . This reduction was larger in the nocturnal than in the diurnal mean of blood pressure . Thus , whereas only 16 % of the patients in this group were dippers at baseline , 57 % were dippers after therapy ( P<0.001 ) . Results indicate that , in resistant hypertension , time of treatment may be more important for blood pressure control and for the proper modeling of the circadian blood pressure pattern than just changing the drug combination Several previous studies found that too great a reduction of clinic blood pressure ( BP ) by treatment increased cardiovascular disease ( CVD ) risk , whereas moderate reduction decreased it . Thus , it has been suggested that the relationship between BP and CVD events is J-shaped , with CVD risk decreasing as BP is lowered , and then rising as BP is further decreased . Correlation between BP level and CVD risk , however , is stronger for ambulatory BP monitoring ( ABPM ) than clinical BP measurements . We previously established that the hypertension treatment-time regimen , upon awakening versus at bedtime , exerts differential effect on BP control during the day and nighttime , which translates into a differential degree of CVD risk prevention . We , therefore , investigated the role of hypertension treatment-time scheme on the nature of the relationship between achieved clinic and ambulatory BP and CVD risk in the MAPEC ( Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares , i.e. , Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events ) study , a prospect i ve , open-label , blinded-endpoint trial on 2156 hypertensive patients ( 1044 men/1112 women ) , 55.6 ± 13.6 ( mean ± SD ) yrs of age , r and omized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime  . Ambulatory BP was measured for 48-h at baseline and annually thereafter , and more frequently ( quarterly ) when adjustment of treatment was necessary . After a median follow-up of 5.6 yrs , a J-shaped relationship was detected between total CVD events and clinic as well as awake BP mean , but only for the group of patients ingesting all medications upon awakening . The relationship was different in the group of patients who ingested ≥1 medications at bedtime ; the risk of CVD events progressively diminished in a linear , rather than J-shaped , manner with treatment-induced decrease in awake BP mean . The adjusted hazard ratio of CVD events was significantly lower with the progressive reduction in the asleep BP mean , independent of the hypertension treatment-time regimen . There was no single major event , i.e. , CVD death , myocardial infa rct ion , or stroke , in patients who achieved an asleep systolic BP mean < 103 mm Hg . Our findings indicate that bedtime hypertension treatment is not associated with a J-shaped relationship between achieved BP and CVD risk . The decreased CVD risk associated with the progressive reduction in asleep BP , more feasible by bedtime than morning hypertension treatment , has clinical implication s , in particular , the need to consider the proper timing of hypertension medications , in conjunction with ABPM for proper assessment of BP control , as an improved and potentially safer means of reducing CVD risk of hypertensive patients . ( Author correspondence : rhermida@uvigo.es CONTEXT Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk , but the benefit compared with other drug classes is controversial . OBJECTIVE To determine whether initial therapy with controlled-onset extended-release ( COER ) verapamil is equivalent to a physician 's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized clinical trial conducted at 661 centers in 15 countries . A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31 , 2000 . After a mean of 3 years of follow-up , the sponsor closed the study before unblinding the results . INTERVENTION Initially , 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide . Other drugs ( eg , diuretic , beta-blocker , or an angiotensin-converting enzyme inhibitor ) could be added in specified sequence if needed . MAIN OUTCOME MEASURES First occurrence of stroke , myocardial infa rct ion , or cardiovascular disease-related death . RESULTS Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group . There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group ( hazard ratio [ HR ] , 1.02 ; 95 % confidence interval [ CI ] , 0.88 - 1.18 ; P = .77 ) . For fatal or nonfatal stroke , the HR was 1.15 ( 95 % CI , 0.90 - 1.48 ) ; for fatal or nonfatal myocardial infa rct ion , 0.82 ( 95 % CI , 0.65 - 1.03 ) ; and for cardiovascular disease-related death , 1.09 ( 95 % CI , 0.87 - 1.37 ) . The HR was 1.05 ( 95 % CI , 0.95 - 1.16 ) for any prespecified cardiovascular disease-related event and 1.08 ( 95 % CI , 0.93 - 1.26 ) for all-cause mortality . Nonstroke hemorrhage was more common with participants in the COER-verapamil group ( n = 118 ) compared with the atenolol or hydrochlorothiazide group ( n = 79 ) ( HR , 1.54 [ 95 % CI , 1.16 - 2.04 ] ; P = .003 ) . More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil ( 99/277 ) and atenolol or hydrochlorothiazide ( 88/274 ) groups ; HR , 1.15 ( 95 % CI , 0.86 - 1.53 ) . CONCLUSIONS The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker . When considered in the context of other trials of calcium antagonists , these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment OBJECTIVE ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism . The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events R and omized Trial ( FACET ) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension . Prospect ively defined cardiovascular events were assessed as secondary outcomes . RESEARCH DESIGN AND METHODS Inclusion criteria included a diagnosis of NIDDM and hypertension ( systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg ) . Exclusion criteria included a history of coronary heart disease or stroke , serum creatinine > 1.5 mg/dl , albuminuria > 40 μg/min , and use of lipid-lowering drugs , aspirin , or antihypertensive agents other than beta-blockers or diuretics . A total of 380 hypertensive diabetics were r and omly assigned to open-label fosinopril ( 20 mg/day ) or amlodipine ( 10 mg/day ) and followed for up to 3.5 years . If blood pressure was not controlled , the other study drug was added . RESULTS Both treatments were effective in lowering blood pressure . At the end of followup , between the two groups there was no significant difference in total serum cholesterol , HDL cholesterol , HbA1c , fasting serum glucose , or plasma insulin . The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infa rct ion , stroke , or hospitalized angina than those receiving amlodipine ( 14/189 vs. 27/191 ; hazards ratio = 0.49 , 95 % CI = 0.26–0.95 ) . CONCLUSIONS Fosinopril and amlodipine had similar effects on biochemical measures , but the patients r and omized to fosinopril had a significantly lower risk of major vascular events , compared with the patients r and omized to amlodipine In the HOPE-trial , the ACE inhibitor ramipril significantly reduced cardiovascular morbidity and mortality in patients at high risk for cardiovascular events . The benefit could only partly be attributed to the modest mean reduction of office blood pressure ( OBP ) during the study period ( 3/2 mm Hg ) . However , because according to the HOPE protocol ramipril was given once daily at bedtime and blood pressure was measured during the day , the 24-hour reduction of blood pressure may be underestimated based on OBP . Thirty-eight patients with peripheral arterial disease enrolled in the HOPE study underwent  24-hour ambulatory blood pressure ( ABP ) measurement  before r and omization and after 1 year . OBP was measured in the sitting position immediately before fitting the ABP measuring equipment to the patients . Ramipril did not significantly reduce OBP ( 8/2 mm Hg , P = NS ) or day ABP ( 6/2 mm Hg , P = NS ) after 1 year . Twenty-four – hour ABP was significantly reduced ( 10/4 mm Hg , P = 0.03 ) , mainly because of a more pronounced blood pressure lowering effect during nighttime ( 17/8 mm Hg , P < 0.001 ) . The night/day ratio was also significantly lowered in the ramipril  group . ABP shows greater falls , especially at night , than OBP during treatment with ramipril given once daily at bedtime . Although , OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies , the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may , to a larger extent than previously ascribed , relate to effects on blood pressure patterns over the 24-hour period 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 
    Output:
    