***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: CONTEXT Many patients with chronic angina experience anginal episodes despite revascularization and antianginal medications . In a previous trial , antianginal monotherapy with ranolazine , a drug believed to partially inhibit fatty acid oxidation , increased treadmill exercise performance ; however , its long-term efficacy and safety have not been studied in combination with beta-blockers or calcium antagonists in a large patient population with severe chronic angina . OBJECTIVES To determine whether , at trough levels , ranolazine improves the total exercise time of patients who have symptoms of chronic angina and who experience angina and ischemia at low workloads despite taking st and ard doses of atenolol , amlodipine , or diltiazem  and to determine times to angina onset and to electrocardiographic evidence of myocardial ischemia , effect on angina attacks and nitroglycerin use , and effect on long-term survival in an open-label observational study extension . DESIGN , SETTING , AND PATIENTS A r and omized , 3-group parallel , double-blind , placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were r and omly assigned to receive placebo or 1 of 2 doses of ranolazine . Patients treated at the 118 participating ambulatory outpatient setting s in several countries were enrolled in the Combination Assessment of Ranolazine In Stable Angina ( CARISA ) trial from July 1999 to August 2001 and followed up through October 31 , 2002 . INTERVENTION Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine . Treadmill exercise 12 hours ( trough ) and 4 hours ( peak ) after dosing was assessed after 2 , 6 ( trough only ) , and 12 weeks of treatment . MAIN OUTCOME MEASURES Change in exercise duration , time to onset of angina , time to onset of ischemia , nitroglycerin use , and number of angina attacks . RESULTS Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups ( pooled ) vs 91.7 seconds in the placebo group ( P = .01 ) . The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups , at peak more than at trough . The increases did not depend on changes in blood pressure , heart rate , or background antianginal therapy and persisted throughout 12 weeks . Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo ( P<.02 ) . Survival of 750 patients taking ranolazine  during the CARISA trial or its associated long-term open-label study was 98.4 % in the first year and 95.9 % in the second year . CONCLUSION Twice-daily doses of ranolazine increased exercise capacity and provided additional antianginal relief to symptomatic patients with severe chronic angina taking st and ard doses of atenolol , amlodipine , or diltiazem , without evident adverse , long-term survival consequences over 1 to 2 years of therapy Twenty-four patients with stable angina were evaluated in a 14 week crossover trial . A single-blind placebo period ( baseline 1 ) was followed by two double-blind periods evaluating maximum tolerated doses of diltiazem ( up to 360 mg daily ) vs placebo . Over the next 1 to 4 weeks , propranolol was started and increased until clinical ly documented beta-blockade was achieved ( baseline 2 ) . The final phase consisted of a pair of evaluation periods comparing propranolol plus the maximum tolerated dose of diltiazem to propranolol and placebo . The daily rate of angina attack was 1.6 during baseline , was unchanged during placebo therapy , but fell during treatment with diltiazem to 0.6 ( p less than .005 ) . With the addition of diltiazem to propranolol , the angina rate was improved ( 0.3 ) compared with that with either propranolol alone ( 0.6 ) or propranolol and placebo ( 0.5 ) ( p less than .01 ) . Total exercise duration during baseline 1 was 360 sec and increased to 497 sec with diltiazem , 481 sec with propranolol , and 527 sec with the combination of diltiazem and propranolol . Two patients with reduced ejection fractions developed congestive heart failure with propranolol . The combination of diltiazem and propranolol similarly result ed in congestive heart failure in one patient who had tolerated both drugs alone Summary The effect of isosorbide-dinitrate ( ISDN ) 20 mg 4 times daily against placebo has been tested in 12 patients with stable effortinduced angina pectoris receiving prophylactic treatment with metoprolol . ISDN did not decrease the attack rate or nitroglycerine consumption , nor was exercise tolerance increased after it . Left ventricular function , assessed by radionucleide ventriculography , increased in 6 out of 8 patients ( p<0.1 ) . It is concluded that ISDN has no place in the treatment of haemodynamically intact patients with severe angina pectoris in spite of beta-blocking treatment , but that it may be of value in the treatment of patients with left ventricular failure , including those whose left ventricular failure has been brought about by beta-blocking treatment necessitated by angina pectoris One hundred and fourteen patients ( 94 male ) with chronic stable angina who had a positive exercise test after 4 weeks on atenolol alone were r and omized to receive either atenolol alone or the fixed combination of atenolol and nifedipine slow release formulation for 4 weeks in a double-blind cross-over manner . Exercise stress testing ( Bruce protocol ) at the end of each treatment period demonstrated that the time to the onset of pain and occurrence of 1 mm ST segment depression improved significantly ( P < 0.05 and P < 0.001 respectively ) whilst on the fixed combination compared to atenolol alone . In order to achieve sufficient sensitivity in the analysis of the exercise times , novel statistical methods based on survival analysis were used . Maximum ST segment depression was 0.13 mm less ( P < 0.04 ) while on the fixed combination . The incidence of withdrawals and adverse effects was similar on both treatments The antianginal and anti-ischemic efficacy of isosorbide dinitrate ( ISDN ) retard 120 , verapamil 120 sustained-release ( s.r . ) and their combination was evaluated in 30 patients with chronic angina pectoris . The study was a r and omized , double-blind crossover comparison . The evaluation was determined by exercise testing and 24-hour electrocardiographic ambulatory monitoring . The sum of ST-segment depression at comparable exercise levels was reduced by 37 % ( p less than 0.001 ) after verapamil 120 s.r . and by 45 % ( p less than 0.001 ) after combination therapy . After ISDN retard 120 the sum of ST-segment depression was also slightly reduced by 18 % without attaining statistical significance . Total walking time and time to angina pectoris during treadmill exercise were significantly prolonged after all treatments . The sum of ST-segment depression in the 24-hour Holter ECG was reduced by 46 % ( p less than 0.001 ) after verapamil and by 39 % ( p less than 0.01 ) after combined therapy . After ISDN retard 120 the mean reduction was 34 % ( p less than 0.01 ) . In conclusion , the result of the study indicated that ISDN retard 120 , verapamil 120 s.r . and a combination of both drugs are effective in reducing the frequency and duration of ischemic episodes in patients with ischemic heart disease Nine patients with severe coronary artery disease and disabling angina receiving either regular metoprolol or oxprenolol , together with glyceryl trinitrate tablets as required for chest pain , were studied . Nifedipine 10 mg three times per day was compared to placebo in a double blind r and omized control trial , using patient diary cards and exercise tests . The number of recorded episodes of angina during the placebo period of 15.0 + /- 2.1 ( mean + /- s.e.m . ) per patient per week was significantly reduced to 11.2 + /- 2.5 during the nifedipine period ( P less than 0.05 ) . Similarly , the recorded number of glyceryl trinitrate tablets consumed during the placebo period of 12.6 + /- 2.1 was significantly reduced to 9.1 + /- 2.0 tablets per patient per week during the nifedipine period ( P less than 0.05 ) . There was a statistically significant increase in both the duration of exercise to onset of chest pain ( from 241 + /- 16.3 seconds on placebo to 306 + /- 38.4 seconds on nifedipine ( P less than 0.05 ) ) and the total work performed to the onset of chest pain during the nifedipine period compared to the control and placebo periods ( P less than 0.05 ) . There was a significant increase ( P less than 0.05 ) in exercise time before the onset of appreciable ST depression ( greater than 1 mm ) on exercise testing during the nifedipine period ( 66.2 + /- 4.2 sec ) compared to the control period ( 51.2 + /- 3.0 sec ) and placebo periods ( 58.7 + /- 3.5 sec ) . Although nifedipine was generally well tolerated , one patient experienced a severe episode of angina whilst taking the drug , which required admission to hospital The purpose of this trial was to study the additional anti-ischaemic effects of amlodipine in coronary patients with ambulant ischaemia despite beta-blocker therapy . Beta-blockers are the most effective drug therapy for reducing the frequency and duration of ambulatory ischaemic episodes . However , the therapeutic advantage of combined calcium antagonist-beta-blocker treatment remains question able . Three hundred and thirteen patients with documented coronary artery disease , a positive exercise test within 6 months before entry and background beta-blocker therapy , were screened . Inclusion criteria ( > or = 4 episodes of transient ST segment depression of > or = 1.0 mm and /or > or = 20 min of ischaemia ) were demonstrated in a 48 h ECG during the placebo run-in period in 84 ( 25 % ) of the patients . Eighty-nine percent of the ischaemic episodes were silent . The eligible patients were then r and omized in a 2-week , double-blind , parallel group study comparing placebo to amlodipine 10 mg daily added to the beta-blocker . The anti-ischaemic efficacy of the combination therapy was assessed by 48 h ECG monitoring and exercise tests . Compared to placebo , amlodipine did not significantly reduce either the frequency ( 3.7 + /- 4.3 vs 4 + /- 4.8 episodes in the amlodipine group ) or the duration of ambulatory ischaemia ( mean duration : 43.9 + /- 57.1 vs 39.6 + /- 65.7 min , total duration 3.1 + /- 6.7 vs 2.8 + /- 6.1 h ) . Exercise-induced ST segment depression tended to decrease with amlodipine ( 58 % vs 73 % in the placebo group ) and the ischaemia-free workload capacity was increased ( + 1.7 stage vs 0.7 stage in the placebo group , P = 0.08 ) . These results suggest that 2 weeks treatment with amlodipine may not provide any additional anti-ischaemic benefit in patients with ambulant ischaemia resistant to a beta-blocker therapy The effects of the addition of slow-release nifedipine 20 mg twice daily and nisoldipine 10 mg twice daily to atenolol monotherapy were compared in a double-blind placebo-controlled study of 24 patients with chronic stable angina pectoris . Neither nisoldipine nor nifedipine was associated with significant subjective benefit at these doses . Two hours post-dosing , exercise capacity improved after both nisoldipine ( duration + 37 s , P < 0.01 ; time to angina + 67 s , P < 0.01 ; time to significant ST depression + 60 s , P < 0.01 ) and nifedipine ( duration + 21 s , ns ; time to angina + 56 s , P < 0.05 ; time to significant ST depression + 49 s P < 0.05 ) . However , this improvement was not maintained 12 h post-dosing . Ambulatory monitoring did not demonstrate a significant reduction in the amount of silent or total ischaemia following the addition of either nifedipine or nisoldipine to atenolol monotherapy . There was no significant difference between nifedipine and nisoldipine in any parameter tested . In conclusion , like slow-release nifedipine 20 mg , the effective duration of anti-ischaemic action of nisoldipine 10 mg is less than 12 h. Since several patients experienced vasodilatory unwanted effects , more frequent administration rather than larger individual doses may be desirable to achieve a clinical response Since not all patients tolerate beta-blockers , the efficacy of nifedipine and isosorbide dinitrate was evaluated alone and in combination in patients with stable angina pectoris . The study was a r and omized double-blind crossover design with patients titrated to maximally tolerated doses of both drugs . Phases included isosorbide dinitrate alone , nifedipine alone , and isosorbide dinitrate plus nif 
    Output:
    
The combination of ranolazine added to CCB or BB showed positive outcomes across all outcomes assessed .
Other combinations of BB , CCB , LAN and trimetazidine showed significant benefits for most but not all outcomes .
Ivabradine demonstrated benefits for ETT assessment s but these were not matched in clinical domains .
Conclusion Across a range of commonly assessed exercise and clinical outcomes , the effectiveness of BB+CCB used in combination is broadly confirmed .
Ranolazine used with BB or CCB showed benefits across all outcomes assessed , while LAN and trimetazidine used with BB or CCB have shown benefits across some outcomes .
Ivabradine added to BB shows inconsistent effects from a single study , whilst there is no relevant evidence for nicor and il