Factors influencing efficacy of nitrate therapy for stable angina pectoris: a multiple linear regression analysis

In an open-label self-controlled study of 1,350 patients with stable angina pectoris (SAP), we previously demonstrated that 50 mg of isosorbide mononitrate (ISMN) slow release formulation once daily not only provided a better antianginal effect but also a better quality of life (QOL) than did the daily administration of multiple small doses of the compound. It is unknown whether certain patient characteristics contribute to this benefit. The objective of this article was to determine what independent factors contribute to this benefit. Multiple linear regression analysis was performed on the data from these 1,350 patients. Quality of life was assessed by the Marquis QOL-questionnaire for patients with angina and included the domains of immobility, pain, and psychological distress. For the purpose of this study, overall QOL was calculated as the pooled sums of the domain scores and expressed as mean scores on an ordinal scale of 10. Age did not influence the beneficial effect of nitrate therapy on QOL. Neither did gender, rhythmic disturbances, peripheral artery disease, or the concomitant use of calcium channel blockers or beta blockers. New York Heart Association (NYHA) angina classification was an independent variable: patients with a NYHA class I or II benefited less than did patients with NYHA III or IV (p = 0.02). Obese patients as well as hypertensive patients benefited less (p = 0.04 and 0.02), and smokers tended to benefit less also (p = 0.08). In contrast, hypercholesterolemia and diabetes mellitus improved the beneficial effect of nitrates on QOL (p = 0.03 and 0.05). The authors conclude that patients with coronary artery disease (CAD) and concomitant diabetes mellitus or hypercholesterolemia, a category particularly prone to early endothelial dysfunction and thus dysfunctional endogenous nitric oxide (NO) production, may benefit more from NO-donor therapy than patients without such concomitant conditions.     

Absence of rebound from diltiazem therapy in Prinzmetal's variant angina

To determine the frequency of rebound anginal symptoms on abrupt withdrawal of calcium channel blocking agents, anginal symptoms were retrospectively examined in patients with Prinzmetal's variant angina abruptly withdrawn from diltiazem therapy as part of the design of a placebo-controlled multiple crossover trial. Rebound was defined as a return of anginal symptoms to levels exceeding those of the pretreatment baseline state. Values for daily frequency of angina were compared (after subtracting corresponding baseline values) between placebo periods following diltiazem periods and placebo periods following placebo periods. No intergroup differences existed between mean changes in daily frequency of angina from baseline value (-0.61 for placebo following diltiazem versus -1.10 for placebo following placebo) (p greater than 0.4). Furthermore, in 13 (28%) of 46 occurrences when placebo followed placebo, daily frequency of angina exceeded baseline value in the immediate 3 day period following placebo compared with 17 (21%) of 80 occurrences when placebo followed diltiazem. There was no increased rebound occurrence comparing high dose (240 mg/day) with low dose (120 mg/day) diltiazem therapy. No significant symptoms such as myocardial infarction or unstable angina occurred after withdrawal of diltiazem or placebo. The lack of difference in rebound after diltiazem or placebo withdrawal was consistent using paired and unpaired analyses. In conclusion, there appears to be no evidence that abrupt withdrawal of therapy with diltiazem results in rebound anginal symptoms.     

Isosorbide mononitrate 30% immediate-release 70% sustained-release formulation: a review. DUMQOL (DUtch Mononitrate Quality of Life) Study Group

Since the first publication of isosorbide mononitrate 30% immediate-release 70% sustained-release (IR-SR) formulation in 1985, a considerable body of literature concerning its clinical efficacy and safety has become available. Theoretically, the formulation has the advantage over conventional isosorbide mononitrate or dinitrate (ISMN/ISDN) that it has a simpler and more predictable pharmacokinetic profile. The objectives of this paper are to review published data so far and to see whether the theoretical advantages translate into better clinical effectiveness. 1. After oral administration, isosorbide mononitrate IR-SR has a rapid onset of action (30 minutes), and effects are evident for up to 17 hours. 2. The antianginal effects of once-daily isosorbide mononitrate IR-SR increased with increasing dosages, were generally larger than those of either placebo or equipotent doses of conventional ISMN/ISDN, and were somewhat larger than those of the beta blocker bupranolol. The effects were generally similar to those of sustained release nifedipine. 3. Patients showed significantly greater improvement in some quality-of-life indices with once-daily isosorbide mononitrate IR-SR than with twice or three times daily regimens of conventional ISMN/ISDN. This was particularly so with mobility, psychological distress, and life satisfaction indices. 4. Tolerance did not develop after 13 months of once daily isosorbide dinitrate IR-SR. No rebound increase in incidence of ischemic episodes was observed after discontinuation of treatment. 5. Long-term efficacy data both of isosorbide mononitrate IR-SR and of conventional ISMN/ISDN are limited so far. Large studies in patients with angina pectoris and patients with heart failure addressing long-term effects are ongoing, and some of the data will be completed within the next months. Isosorbide mononitrate IR-SR has a rapid onset of action and has been shown to be clinically efficient and, in addition, to be more so than conventional ISMN / ISDN. Nitrate tolerance with continued use of the formulation has not yet been reported. Long-term effects on morbidity and mortality are currently being assessed.     

Double-blind, multicenter, active-controlled, randomized clinical trial to assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in China.

BACKGROUND: The efficacy and safety of nicorandil were evaluated in Chinese patients with stable angina pectoris (AP) in a double-blind, multicenter, active-controlled, randomized clinical trial. METHODS AND RESULTS: After a 2-week washout period, 232 patients with stable AP were randomized to receive either nicorandil (5 mg tid; 115 patients) or isosorbide mononitrate (ISMN: 20 mg bid; 117 patients) for 2 weeks. Exercise capacity, number of weekly anginal attacks, nitroglycerin (NTG) consumption, and safety were evaluated. Nicorandil and ISMN significantly prolonged the time to 1 mm ST-segment depression in an exercise tolerance test. Both drugs improved the total exercise time and the time to onset of chest pain. There was no significant difference between the 2 groups. Nicorandil significantly decreased the number of anginal attacks and NTG consumption. ISMN decreased the number of anginal attacks significantly; however, there was no significance in NTG consumption, and the ratio of anginal attack reduction was at least 50% was significantly higher with nicorandil. Nicorandil was well tolerated and there was no safety profile difference compared with ISMN. Thus, nicorandil may have equivalent or better antianginal effect than ISMN. CONCLUSIONS: Nicorandil is beneficial as treatment for AP.     

硝苯地平控释片与5-单硝异山梨醇酯对稳定性心绞痛疗效的比较

目的　比较硝苯地平控释片与 5 单硝异山梨醇酯对稳定性心绞痛的疗效。方法　 5 3例稳定性心绞痛患者停用抗心绞痛药物 1周 ,然后经 2～ 3周的单盲安慰剂治疗后 ,进入为期 6周的单盲随机对照试验 ,以平板运动负荷心电图为考察指标。结果　经过 6周的治疗后 ,硝苯地平控释片( 3 0mg ,每日 1次 )与 5 单硝异山梨醇酯 ( 2 0mg ,每日 2次 )均能显著减少心绞痛发作次数 (分别下降87%和 5 1% ,P <0 0 5 )及硝酸甘油消耗量 (分别下降 91%和 5 4 % ,P <0 0 5 ) ;提高运动能力 ,延长运动时间 (分别延长 114秒和 2 5秒 ,P <0 0 1) ,且对运动能力的改善作用分别在末次服药 (疗程结束 )后 2 4小时和 12小时仍然存在。结论　硝苯地平控释片和 5 单硝异山梨醇酯均能有效改善稳定性心绞痛患者的临床症状 ,心电图及运动能力 ,其有效作用分别持续 2 4和 12小时。     

Anti-ischemic effects of slow-release formulations of nifedipine, isosorbide-5-mononitrate and their combination in patients with coronary heart disease

Eighteen patients (2 females, 16 males) with coronary artery disease and a positive bicycle exercise test were treated with 50 mg slow-release isosorbide-5-mononitrate (ISMN SR) once daily, 20 mg nifedipine SR twice daily and a combination of both drugs during 2 weeks in a randomized double-blind sequence. Fifteen patients completed the study. The efficacy of each therapy was assessed by ECG stress testing after each treatment period. Both substances were equally effective in the reduction of ischemic ST depression: 0.40 +/- 0.22 mV with placebo, 0.31 +/- 0.16 mV during nifedipine SR and 0.31 +/- 0.29 mV during ISMN SR, 0.28 +/- 0.21 mV during the combination. However, during monotherapy with either nifedipine SR or ISMN SR 6 patients did not improve. The alternative monotherapy was effective in 3 out of 6 patients. Combination treatment gave further advantage only to one third of the patients. We conclude that both nifedipine and ISMN in slow-release formulations are equally effective in the treatment of myocardial ischemia. In the individual patient, however, therapy failure may occur. These patients should be switched to another monotherapy. If both monotherapies are ineffective, combination treatment should be considered.     

Single-dose effects of isosorbide mononitrate alone or in combination with losartan on central blood pressure

Antihypertensive drugs can have different effects on central and brachial blood pressures, which may affect outcomes. Nitric oxide donors have acute effects on central blood pressure but have not been assessed with renin-angiotensin system blockade. Thirteen patients with prehypertensive/Stage 1 hypertension were randomized to five single-dose treatments separated by ≤4 days using a double-blind, crossover study design: angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours. Mean placebo-subtracted decrease from baseline in augmentation index (AIx) approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Administered with losartan 100 mg or alone, ISMN lowered AIx, demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. AIx is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.     

Transient myocardial ischemia during daily life in rest and exertional angina pectoris and comparison of effectiveness of metoprolol versus nifedipine

The clinical characteristics of 65 patients with mixed angina were classified by means of (1) a questionnaire investigating the proportion of symptoms occurring at rest and on effort, (2) an exercise stress test, (3) 24-hour ambulatory Holter monitoring, and (4) coronary arteriography. According to the questionnaire, the proportion of effort-induced anginal episodes ranged from 1 to 99%. The ischemic threshold during exercise testing ranged from 110 x 10(2) to 350 x 10(2) mm Hg x beats/min. At least 1 episode of ST-segment depression was observed in 29 of the 65 patients during Holter monitoring. Ischemic episodes during Holter monitoring were more frequent (p less than 0.05) in patients reporting greater than or equal to 50% of anginal attacks on effort, with moderate to severe limitation of exercise capacity and with multivessel coronary artery disease. The effect on ambulatory ischemia of a 6-week treatment with a beta blocker (metoprolol CR, 200 mg once daily) or a dihydropyridine calcium antagonist (nifedipine retard 20 mg twice daily) were then compared according to a double-blind, parallel group design. Metoprolol significantly reduced the number and duration of the ischemic episodes during daily life (p less than 0.05) irrespective of the patients' clinical characteristics. Nifedipine was ineffective, particularly in patients with angina predominantly on effort and with a moderate to severe reduction in exercise tolerance. It is concluded that in patients with mixed angina, ischemic episodes during daily life are more likely to occur in patients with a clinical presentation suggesting poor coronary reserve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of atenolol with propranolol in the treatment of angina pectoris with special reference to once daily administration of atenolol.

Fourteen patients with angina pectoris completed a double blind trial of atenolol 25 mg, 50 mg, and 100 mg twice daily and propranolol 80 mg thrice daily. In comparison with placebo, all active treatments significantly reduced anginal attacks, consumption of glyceryl trinitrate, resting and exercise heart rate, resting and exercise systolic blood pressure, and significantly prolonged exercise time. There was no significant difference between the effects of propranolol and atenolol. Nine patients completed a further trial comparing atenolol given once or twice daily. Both regimens were effective and there was no significant difference between the reductions in anginal attacks, glyceryl trinitrate consumption, systolic blood pressure, or heart rate. Twenty-four-hour ambulatory electrocardiograms showed that atenolol consistently reduced heart rate throughout the 24-hour period whether given once or twice daily. Atenolol is a potent antianginal agent which, in most patients, is likely to be effective once daily.     

Efficacy and optimal dose of sildenafil in primary pulmonary hypertension

PURPOSE: We aimed to assess the effects of sildenafil and evaluate optimal dosing in primary pulmonary hypertension (PPH). Sildenafil selectively inhibits phosphodiesterase 5 (PDE5), which is abundant in pulmonary and penile tissue. This results in increasing nitric oxide (NO) at tissue level leading to pulmonary vasodilatation. SUBJECTS AND METHODS: Our study was a prospective study of sildenafil in 15 consecutive patients with severe symptomatic PPH of NYHA class III-IV. All patients were stabilized for a minimum period of 5 days with antifailure medications. Sildenafil was started at 50 mg twice daily for 4 weeks and increased to 100 mg bid for 4 more weeks in a step-up protocol. Primary end-points were change in Borg dyspnea index, NYHA class and 6-min walk distance, estimated at baseline 1, 2, 4 and 8 weeks. RESULTS: NYHA class (baseline 3.8 +/- 0.4 vs. 4 weeks 2.4 +/- 0.5, p = 0.002), Borg dyspnea index (8.1 +/- 1.7 vs. 4.4 +/- 1.9, p = 0.0007), 6-min walk distance (234 +/- 44 vs. 377 +/- 128 m, p = 0.001) and Pulmonary artery pressure (125 +/- 15 vs. 113 +/- 18 mm Hg p = 0.05) are significantly improved with sildenafil 50 mg bid at 4 weeks. Increasing the dose to 100 mg bid did not produce further benefit. Echocardiography parameters of right heart dimensions and functions did not change markedly in the study period. CONCLUSION: Sildenafil is well tolerated with no adverse effects in severe pulmonary hypertension. It reduces symptoms, improves effort tolerance and controls refractory heart failure significantly by 2 weeks in 70% of patients at 50 mg twice daily. Three patients (20%) failed to respond with sildenafil.     

Effects of isosorbide-5-mononitrate on exercise-induced hemodynamic changes in angina pectoris

Hemodynamic effects of isosorbide-5-mononitrate (ISMN) were studied in 14 patients with effort angina pectoris. Hemodynamic and echocardiographic data were obtained by angina-limited supine multistage bicycle ergometer exercise testing before and 120 minutes after single oral administration of 20 mg of ISMN. Compared with control exercise testing, the ST segment at peak exercise showed less depression after administration of ISMN (p less than 0.001). At rest, systolic and diastolic blood pressure decreased significantly after administration of ISMN (p less than 0.001 and p less than 0.01, respectively). At rest and at peak exercise, pulmonary artery wedge pressure (both p less than 0.001), left atrial volume (both p less than 0.001) and left ventricular end-diastolic volume (both p less than 0.05) decreased, whereas cardiac index, pressure-rate product and systemic vascular resistance did not change significantly after administration of ISMN. Average time to peak plasma ISMN concentration was 90 minutes and average peak plasma concentration was 460 ng/ml with an elimination half-life of 7 hours. These data suggest that the main mechanism of the antianginal action of ISMN is a reduction in left ventricular preload followed by diminution of myocardial oxygen requirements.     

The anti-ischemic effect of gallopamil-retard in comparison with nifedipine-retard in stable angina pectoris]

To assess the antiischemic efficacy of slow-release (SR) gallopamil, 100 mg b.i.d., versus slow-release (SR) nifedipine, 20 mg b.i.d., 24 patients with chronic stable angina underwent symptom-limited bicycle ergometer exercise stress tests in a randomized, placebo-controlled, double-blind, cross-over protocol. Both medications caused a significant reduction in anginal attack frequency and nitroglycerin consumption as compared to placebo; similarly, exercise tolerance was augmented in association with a considerable reduction in ischemia-induced ST-segment depression. The antiischemic effect of gallopamil (SR) was marginally superior to that of nifedipine (SR). Since the incidence of adverse effects was also less with gallopamil (SR) this drug exhibited a more favorable risk-benefit ratio relative to nifedipine (SR).     

Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina

OBJECTIVE: We sought to study the effects of a single oral dose of sildenafil citrate (50 mg) on blood pressure (BP) in men taking the nitric oxide (NO) donor drugs isosorbide mononitrate (ISMN) or glyceryl trinitrate (GTN) for stable angina. BACKGROUND: Sildenafil, a selective phosphodiesterase type 5 inhibitor, is an orally effective treatment for erectile dysfunction. The presence of phosphodiesterases in the vasculature suggests the possibility of an interaction between sildenafil and NO donor drugs. METHODS: Two double-blind, placebo-controlled, randomized, two-way crossover trials were undertaken. Sixteen male patients received oral ISMN (20 mg twice a day) for five to seven days before their dose of sildenafil or placebo and continued receiving ISMN daily until administration of the alternate drug seven days later. For the second study, 15 male patients received sublingual GTN (500 microg) 1 h after sildenafil or placebo on each of two study days, which were seven days apart. Sitting or standing BP was measured before and for 6 h after the administration of the study drug. RESULTS: The effects of sildenafil plus ISMN on BP (standing mean maximum reductions from baseline in systolic/diastolic BP, -52/-29 mm Hg) were greater than the effects of placebo plus ISMN on BP (-25/-15 mm Hg; p < 0.001). Sildenafil plus GTN also resulted in greater sitting mean maximum reductions from baseline in systolic/diastolic BP (-36/-21 mm Hg) compared with placebo plus GTN (-26/-12 mm Hg; p < 0.01). CONCLUSIONS: Coadministration of sildenafil with ISMN or GTN produced significantly greater reductions in BP than ISMN or GTN alone. Based on these data, sildenafil should not be administered to patients taking nitrates.     

Successful treatment of refractory angina pectoris due to multivessel coronary spasm with valsartan

This case report describes a 78-year-old man with recurrent angina attacks due to coronary spasm. He was treated with maximum daily doses of antianginal and antioxidative medications, including isosorbide mononitrate (40 mg), diltiazem (200 mg), and tocopherol nicotinate (300 mg). Despite the use of these medications, rest angina occurred 2 or 3 times during sleep. Although his symptoms disappeared promptly with the use of sublingual glycerine trinitrate (GTN), an angiotensin II receptor blocker, valsartan (80 mg), was added on a daily basis with the intent of improving endothelial function and controlling his angina. After beginning 80 mg/day of valsartan, the number of the anginal attacks decreased by about 66%. The anginal attacks totally disappeared after the dose of valsartan was increased to 160 mg/day. To confirm the effect of valsartan on his angina, valsartan was stopped temporarily with his consent. His anginal attacks increased to the same frequency that was observed before valsartan; therefore, valsartan therapy was resumed. The data indicate that the addition of valsartan to maximum antianginal medications may be effective in helping to control angina attacks at rest due to coronary spasm.     

Selection of medical treatment in stable angina pectoris: Results of the International Multicenter Angina Exercise (IMAGE) study

Objectives. The present study was designed to investigate which characteristics of anginal symptoms or exercise test results could predict the favorable anti-ischemic effect of the beta-adrenergic blocking agent metoprolol and the calcium antagonist nifedipine in patients with stable angina pectoris.

Background. The characteristics of anginal symptoms and the results of exercise testing are considered of great importance for selecting medical treatment in patients with chronic stable angina pectoris. However, little information is available on how this first evaluation may be used to select the best pharmacologic approach in individual patients.

Methods. In this prospective multicenter study, 280 patients with stable angina pectoris were enrolled in 25 European centers. After baseline evaluation, consisting of an exercise test and a questionnaire investigating patients' anginal symptoms, the patients were randomly allocated to double-blind treatment for 6 weeks with either metoprolol (Controlled Release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) according to a parallel group design. At the end of this period, exercise tests were repeated 1 to 4 after drug intake.

Results. Both metoprolol and nifedipine prolonged exercise tolerance over baseline levels; the improvement was greater in the patients receiving metoprolol (p < 0.05). Multivariate analysis revealed that low exercise tolerance was the only variable associated with a more favorable effect within each treatment group. Metoprolol was more effective than nifedipine in patients with a lower exercise tolerance or with a higher rate-pressure product at rest and at ischemic threshold. None of the characteristics of anginal symptoms or exercise test results predicted a greater efficacy of nifedipine over metoprolol.

Conclusions. The results of a baseline exercise test, but not the characteristics of anginal symptoms, may offer useful information for selecting medical treatment in stable angina pectoris.     

Efficacy of nisoldipine combined with beta-adrenergic-blocking drugs in the treatment of chronic stable angina

A double-blind, placebo-controlled study was performed to assess whether a new calcium antagonist, nisoldipine, in doses of either 5 mg or 10 mg daily, in combination with beta-adrenergic-blocking drugs (combination therapy) was more effective than beta-adrenergic-blocking drugs alone (single therapy) in the treatment of chronic stable angina. Treatments were assessed at two-week intervals, using exercise electrocardiography and patients' anginal diaries. A significant improvement in exercise capacity and reduction in anginal attacks occurred only during nisoldipine (10 mg daily) combination therapy compared with single therapy. Mean exercise time increased from 419 +/- 146 s (single) to 454 +/- 158 s (p less than 0.02) after combination therapy. Exercise time to onset of 1 mm ST-segment depression improved from 326 +/- 145 s (single) to 331 +/- 139 s after combination therapy, although the change was not significant. Mean number of anginal attacks decreased from 21 +/- 22 (single to 15 +/- 19 (p less than 0.01) during combination treatment, with an associated significant reduction in glyceryl trinitrate consumption. Adverse effects during combined therapy were minor and tolerable. Thus patients limited by exertional angina despite beta-adrenergic-blocking drugs may obtain supplemental relief of angina and myocardial ischemia with the addition of nisoldipine in a dose of 10 mg daily.     

Abrupt withdrawal of isosorbide-5-mononitrate in Durules(R) (Imdur(R)) after long term treatment in patients with stable angina pectoris

In a single-blind study of 6 weeks' duration, 32 patients withstable angina pectoris, who hadbeen receiving controlled-release,Durules®, isosorbide-5-monoitrate (Imdur®) 60 to 180mg daily for at least 1 year, were assessed after abrupt withdrawalof the nitrate. After 2 weeks of placebo treatment nitrate therapywas re-instituted, and the patients followed for antoher 2 weeks.The possibility of developemnt of tolerance and rebound phenomenawas also investigated. Three patietns experienced severe anginal symptoms necessitatinghospitalization when controlled-release isosorbide-5-monoitratewas withdrawn abruptly. Patients complained of more severe anginalsymptoms during the placebo period, experienced more frequentanginal attacks and used more glyceryl trinitrate tablets thanduring active treatment. ST segment changes during exercisewere more pronounced with placebo. After controlled-releaseisosorbide-5-mononitrate was re-introduced, these variablesindicated significant improvement. On the other hand, no deteriorationoccurred in exercise performance during the placebo phase. Responsivenessto glyceryl trinitrate was maintained, as shown by comoparisonsof exercise tests performed after the long term treatment andduring the placebo phase. Controlled-release isosorbide-5-mononitrate retains a beneficialeffect in patients with angina pectoris during prolonged use,although some attenuation of the effect is seen. Abrupt withdrawarlof the drug is not recommended because of the possibility ofsevere exacerbation of anginal symptoms, although no clearcutrebound phenomena were seen.     

Effect of isosorbide-5-mononitrate on exercise performance and clinical status in patients with congestive heart failure. Results of the Nitrates in Congestive Heart Failure (NICE) Study.

BACKGROUND AND AIMS: Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied. METHODS: Oral isosorbide-5-mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients (NYHA Class 2-3) treated for heart failure, all receiving captopril and most also furosemide. Endpoints were treadmill exercise time at 12 weeks by modified Naughton protocol (primary), with an additional 12-week follow-up period. Secondary endpoints included left ventricular dimensions, ejection fraction, cardiothoracic ratio, functional class, quality of life, hospitalizations and plasma norepinephrine and atrial natriuretic peptide in a four-center substudy. RESULTS: Intention-to-treat analysis showed that mean change in treadmill exercise duration tended to be greater in patients receiving ISMN than placebo (treatment difference +42 s, 95% CI -5, +90 s at 12 weeks and +21 s, 95% CI -25, +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified subgroup with ejection fraction 31-40% (+55 s, 95% CI -11, +136 s at 12 weeks and +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e. hypotension) were observed with ISMN, although headache was reported in 19% of the active treatment group (p = 0.0001). CONCLUSIONS: ISMN added to captopril increased treadmill exercise time in patients with heart failure and a lesser reduction in baseline ejection fraction, although for the group as a whole, the increase in treadmill time was not significant.     

Quality of life in chronic heart failure: cilazapril and captopril versus placebo. Cilazapril-Captopril Multicentre Group

OBJECTIVE: To measure quality of life (QOL) in patients with mild to moderate heart failure treated with angiotensin converting enzyme (ACE) inhibitors cilazapril or captopril. DESIGN: Randomised, double blind, placebo controlled, parallel groups trial. SUBJECTS: 367 patients with New York Heart Association (NYHA) heart failure class II (62%), III (36%) or IV (1%). METHODS: Patients were randomised to receive cilazapril 1 mg daily (n = 191) or captopril 25 mg three times daily (n = 90) for 24 weeks, or placebo for 12 weeks followed by cilazapril 1 mg daily for a further 12 weeks (n = 86). If patients had not responded after four weeks cilazapril was increased to 2.5 mg daily and captopril to 50 mg three times daily. QOL was assessed at baseline, 12, and 24 weeks using the sickness impact profile (SIP), the profile of mood states (POMS), the Mahler index of dyspnoea-fatigue, and a health status index (HSI). RESULTS: The physical dimension of the SIP averaged 7 units at baseline and improved after 12 weeks by 2.24 units in the cilazapril group, 2.38 units in the captopril group, and 1.51 units in the placebo group. The difference between drug and placebo was therefore 0.73 units (95% CI -0.86 to 2.32) for cilazapril, and 0.87 units (95% CI -0.96 to 2.70) for captopril, with small non-significant effect sizes (a statistical method for estimating the importance of a treatment related change) of 0.12 and 0.14. Similar results were observed for the total POMS and HSI scores. Although QOL improved more on the ACE inhibitors than on placebo, the effect sizes were not significant (< or = 0.26). CONCLUSIONS: Improvements in QOL in mild to moderate heart failure were small when treated with cilazapril or captopril compared with placebo.     

Effect of dipyridamole therapy on myocardial ischemia in patients with stable angina pectoris receiving concurrent anti-ischemic therapy.

The effects of oral dipyridamole on exercise performance and anginal symptoms were evaluated in 15 men with stable angina pectoris. In a double-blind, randomized, crossover design, patients received 75 mg of dipyridamole or placebo every 8 hours for 2 weeks in addition to their previously prescribed cardiac medications. Graded exercise tolerance testing was performed twice before randomization, at the end of each treatment period, and after single-blind placebo washout. When compared with baseline tests, the time to onset of 0.1 mV ST-segment depression was similar between dipyridamole and placebo treatments (316 +/- 89 vs 345 +/- 102 seconds, respectively, p = not significant). No significant differences existed between treatments in the peak systolic blood pressure-heart rate product or in the duration of exercise. Angina pectoris occurred during all 3 baseline exercise tests in 7 of the 15 subjects; the time to onset of angina was unchanged by either treatment. Analysis of symptom diaries conducted in 13 patients revealed no significant alteration in reported anginal symptoms during dipyridamole treatment compared with placebo treatment (0.6 +/- 0.9 vs 0.3 +/- 0.4 episodes per week). Ambulatory electrocardiographic monitoring in 12 patients revealed few episodes of ischemia during daily activities with no alteration in frequency of episodes during treatment periods. Plasma concentrations of dipyridamole did not correspond with the outcomes of exercise testing. It is concluded that chronic oral dipyridamole therapy given in its usual clinical dose does not adversely affect exercise performance, daily anginal episodes or ambulatory ischemia in patients receiving concurrent anti-ischemic medication.