Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective.

BACKGROUND: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study. AIMS: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral. METHODS: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1--6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil). RESULTS: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial. CONCLUSIONS: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.

Similar late revascularization rates 10 to 12 years after angioplasty or bypass surgery for multivessel coronary artery disease: a report from the Lady Davis Carmel Medical Center (LDCMC) Registry.

We compared completed long-term outcome and late repeat revascularization rates in 272 consecutive patients with multivessel coronary disease who underwent revascularization (95 angioplasty cohort, 177 surgical cohort) between 1984 and 1986. Long-term survival was similar at 12 years in the angioplasty (70%) and surgical (74%) cohorts (p = NS), and repeat revascularization, although more frequent in the angioplasty patients during the first 5 years of follow-up, was performed equally in the 2 patient cohorts after 10 to 12 years of follow-up.

Late-onset heart failure as a mechanism for adverse long-term outcome in diabetic patients undergoing revascularization (a 13-year report from the Lady Davis Carmel Medical Center registry).

The adverse long-term prognosis following myocardial revascularization in diabetic patients has been ascribed to accelerated coronary disease, a higher incidence of late coronary restenosis after revascularization, and myocardial dysfunction. To examine the development of heart failure and its prognostic implications in diabetic patients, we analyzed the long-term (13-year) follow-up data of 363 patients-193 percutaneous transluminal coronary angioplasties and 170 coronary artery bypass operations-revascularized in a single cardiovascular center from 1984 to 1986. Baseline characteristics (age, previous infarction, baseline ventricular function) were similar in the 80 diabetic and 283 nondiabetic patients; multivessel disease and hypertension were marginally more common in diabetics (p = NS). Cumulative incidence of hospitalization for heart failure was high in the diabetic cohort (25% vs 11%, p = 0.001), with a rapidly increasing incidence after 5 years. Survival after first hospitalization for heart failure was markedly reduced in diabetics (11 of 20 [55%] vs 25 of 31 [81%] at 3 years; p = 0.04), as was survival free of further hospitalization for heart failure (5 of 20 [25%] vs 20 of 30 [63%]; p <0.005). Long-term 13-year survival (43% vs 78%, p <0.0001) and survival free of heart failure (33% vs 71%, p <0.0001) were decreased in diabetics, especially those with reduced ventricular function at baseline (17% vs 42%, p = 0.07). Multivariate analysis showed diabetes to be the strongest independent predictor of decreased survival (odds ratio 3. 6, 95% confidence interval 2.0 to 6.2; p <0.0001) and survival free of heart failure (odds ratio 4.0, 95% confidence interval 2.2 to 7. 1; p <0.0001) in patients undergoing revascularization. In summary, late-onset heart failure was frequent in diabetic patients after percutaneous transluminal coronary angioplasty or coronary artery bypass grafting, and once present heralded an unrelenting progressive downhill clinical course.

Patient comprehension and reaction to participating in a double-blind randomized clinical trial (ISIS-4) in acute myocardial infarction.

BACKGROUND: Although randomized clinical trials are currently the standard for the evaluation of new therapeutic strategies, little attention has been paid to the viewpoint of the patients recruited to these trials. OBJECTIVES: To examine the perspective of the Israeli patient cohort who participated in the Fourth International Study of Infarct Survival, a randomized trial in acute myocardial infarction. METHODS: A patient questionnaire was mailed to 360 Israeli patients who participated in the Fourth International Study of Infarct Survival and was returned by 150 of them. Main outcome measures included patient perception of consent procedures, comprehension of the study, subjective reaction to participating in the trial, and interest in present and future trials. RESULTS: Forty (31%) of 129 patients perceived that they had full comprehension of the trial, while 64 (50%) claimed partial understanding and 25 (19%), no understanding at all. Comprehension was related to a recollected explanation of 5 minutes or more (P<.001) and to an opportunity for discussion at the time of consent (P<.001). Most patients recollected the oral explanation; fewer, the written material. Patient consent was given by 64 (43%) of 150 patients in the hope of better treatment. In 36 cases (25%), the patients felt they received better treatment because of participation in the trial. CONCLUSIONS: Despite proper attention to accepted ethical and legal standards, perceived patient comprehension in this trial in acute myocardial infarction was incomplete or lacking in a considerable number of subjects. Much progress must be made toward the goal of true informed consent in clinical trials.

Same-day combined coronary angioplasty and minimally invasive coronary surgery.

Integrated myocardial revascularization combines the advantages of angioplasty, stenting, and minimally invasive surgery to revascularize patients with multivessel coronary artery disease without cardiopulmonary bypass. This pilot study showed that a new same-day management strategy, consisting of percutaneous coronary intervention followed immediately by minimally invasive surgery, was feasible and provided complete all-arterial revascularization with minimal surgical trauma, short hospital stay, and excellent early therapeutic result in 14 patients with multivessel coronary disease.

Effects of exposure to low concentrations of carbon monoxide on exercise performance and myocardial perfusion in young healthy men.

OBJECTIVE: To assess the effects of exposure to low concentrations of carbon monoxide (CO), as commonly measured in atmospheric urban air pollution and certain occupational environments, on exercise performance and myocardial perfusion in young healthy men, and the possible need for tighter restrictions on ambient concentrations of CO. METHODS: 15 young, healthy non-smoking men, 18-35 years old, were exposed blindly and randomly to air or to a mixture of CO and air, followed by an exercise treadmill test with thallium heart scintigraphy. Blood was drawn for determination of carboxyhaemoglobin before and at the end of the exposure, and for lactic and pyruvic acid at the beginning and the end of the exercise test. The main outcome measures include the duration of the exercise test, the maximal effort expressed in metabolic equivalent units (METs), the mean plasma lactic to pyruvic acid ratio at the end of the ergometry, ECG changes in the exercise test, and perfusion deficits in thallium heart scintigraphy. RESULTS: At the end of exposure to CO, the mean (SD) blood carboxyhaemoglobin concentration rose from 0.59% (0.08%) to 5.12% (0.65%) (p < 0.0001). At the end of the exercise period, the mean (SD) plasma lactate/pyruvate ratio, which reflects the level of anaerobic metabolism (69.9 (5.9) after air and 75.9 (7.0) after CO), was not significantly different between the two experimental groups. Exercise induced electrocardiographic changes were noted in only one subject after exposure to CO. No arrhythmias were detected in any of the subjects. Significant differences were found in the mean duration of the exercise test (p = 0.0012) and the METs (p = 0.0001). The mean adjusted difference of exercise duration between exposure to air and CO was 1.52 minutes 95% confidence interval (95% CI) 0.73 to 2.32 minutes. The mean adjusted difference of METs between exposure to air and CO was 2.04 95% CI 1.33 to 2.76. The models for duration of exercise and METs showed no significant sequence and period effects. Thallium myocardial perfusion imaging disclosed normal perfusion in all regions of the heart, with no significant differences in perfusion between the two exercise tests (after air or CO). CONCLUSION: Acute exposure to a low concentration of CO which produces blood carboxyhaemoglobin concentrations of 4%-6% significantly decreases exercise performance in young healthy men. No ischaemic electrocardiographic changes or disturbances in myocardial perfusion were found by graded exercise with thallium scintigraphy. Our findings suggest that pollution of atmospheric air by CO at concentrations which are commonly found in urban and industrial environments may exert an adverse effect on skeletal muscles, manifesting as decreased exercise performance.

Long-term (10-year) outcome in patients with unstable angina pectoris treated by coronary balloon angioplasty.

OBJECTIVES: We sought to examine completed 10-year survival and event-free survival in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty. BACKGROUND: Patients with unstable angina are at increased risk for recurrent acute coronary events. METHODS: The study included 208 consecutive patients (133 with stable and 75 with unstable angina pectoris) undergoing angioplasty from 1984 to 1986. The balloon crossed the lesion in 185 patients (121 with stable and 64 with unstable angina pectoris). Angioplasty was performed in patients with unstable angina pectoris 12+/-15 days (median 8) after symptom onset. Patients with unstable angina pectoris were classified retrospectively into Braunwald class I (n=3), class II (n=20), class III (n=28), class B (n=52) and class C (n=12). Follow-up data were obtained from hospital charts, telephone interview and official death certificates where applicable. The study had >80% power to detect a clinically significant 20% difference in survival and a 20% difference in event-free survival between the stable and unstable patient groups. RESULTS: Despite similar baseline characteristics, early (40-day) mortality was slightly higher in patients with unstable angina (4.7% [3 of 64 patients] vs. 0.8% [1 of 121 patients], p=NS). Long-term outcome was not different, because survival curves were parallel thereafter (10-year survival was 83% for those with stable and 77% for those with unstable angina, p=NS). Survival free of myocardial infarction or coronary artery bypass graft surgery at 10 years was 53% in patients with stable and 47% in patients with unstable angina (p=NS), and survival free of infarction, bypass surgery or repeat angioplasty was 32% for both groups at 10 years. In patients with Braunwald class III unstable angina, 10-year survival was 80%, as compared with 85% in other patients with unstable angina, due to the early hazard (p=NS). Survival and event-free survival were similar in patients who had had a recent myocardial infarction (Braunwald class C) and in patients with acute electrocardiographic changes. Repeat hospital admissions were not more frequent in patients with unstable angina (3.1+/-3.5 vs. 3.0+/-2.6, p=NS). CONCLUSIONS: Ten-year survival and event-free survival were similar in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty, with no evidence of an increased rate of recurrent cardiovascular events in the unstable group.

Importance of diabetes mellitus and systemic hypertension rather than completeness of revascularization in determining long-term outcome after coronary balloon angioplasty (the LDCMC registry). Lady Davis Carmel Medical Center.

The study examined the 10-year outcome in a cohort of 227 unselected, consecutive patients (age 58+/-10 years) undergoing coronary balloon angioplasty between 1984 and 1986 and followed in a single cardiac center (Lady Davis Carmel Medical Center registry). In particular, we sought to identify the relative importance of the systemic risk factors diabetes and hypertension and the extent of coronary disease as opposed to procedure-related technical variables, the immediate success of the procedure, or completeness of revascularization. By life-table analysis (99% follow-up), 94% of the patients were alive at 5 years, and 77% at 10 years after angioplasty. Ten-year survival was reduced in patients with diabetes mellitus (59% vs 83%, p = 0.0008), in patients with previous myocardial infarction (68% vs 85%, p = 0.01), in patients with ejection fraction <50% (55% vs 82%, p = 0.005), and in patients with 3-vessel disease (58% vs 84% and 86% for 1- and 2-vessel disease, respectively, p = 0.04). Diabetes mellitus was the major independent predictor of poor survival (adjusted odds ratio 3.1, 95% confidence interval 1.55 to 6.19, p = 0.001). Survival at 10 years was identical in 199 patients in whom angioplasty was complete and in 25 in whom the balloon catheter did not cross the lesion, although bypass surgery was more frequent in the latter group (45% vs 21%, p = 0.001). Incomplete revascularization did not predict poor survival (72% vs 79% with complete angioplasty, p = NS). Event-free survival at 10 years for the whole group was 29%, and 49% of patients survived with no event other than a single repeat angioplasty procedure. Multivessel disease, hypertension, and diabetes mellitus were independent predictors of decreased event-free survival, but incomplete revascularization was not. Thus, long-term outcome after coronary balloon angioplasty was related to diabetes mellitus, systemic hypertension, and extent of coronary disease, but not to the immediate success of the procedure or completeness of revascularization.

Accuracy of exercise-induced left axis QRS deviation as a specific marker of left anterior descending coronary artery disease.

In this prospective study, we examined the diagnostic accuracy of exercise-induced left QRS axis deviation as a marker of LAD coronary artery stenosis. The mean frontal QRS axis of 66 consecutive patients with chest pain and exercise-induced ST segment depression referred for diagnostic coronary angiography was analyzed and related to the angiographic findings. An exercise-induced leftward QRS axis deviation was found in 9/40 patients with and 0/26 patients without obstructive (> or = 70%) LAD disease (sensitivity 23%, specificity 100%, p = 0.025). In 7 of the 9 patients with left axis deviation, the lesion was proximal to and in 2 in the region of the first septal perforator. Inclusion of patients with 0 degrees exercise-induced QRS axis deviation provided a more sensitive but less specific marker of LAD disease [sensitivity 53% (21/40), specificity 81% (21/26), p = 0.015]. The findings were similar in patients with single and with multivessel coronary artery disease. Grouping all patients in the present prospective and two previous retrospective studies (n = 165), the sensitivity was 29% and specificity 100% (p < 0.0001). Exercise-induced left QRS axis deviation was a highly specific marker of LAD coronary artery stenosis.

Exercise testing in patients with chest pain and normal coronary arteries: improving test specificity by use of a simple logistic model.

Despite an exercise electrocardiogram (ECG) positive for ischemia by established criteria, many patients referred for coronary angiography to evaluate chest pain are found to have angiographically normal coronary arteries (NCA). Exercise ECG were analyzed from 27 patients with chest pain and angiographically NCA and 28 patients with chest pain and coronary artery disease (CAD) using univariate and multivariate logistic regression analysis. We derived the following logistic model for the logit probability of CAD: 3 + SEX x 4 - METs x 0.7 + STDV5 x 0.8, where SEX = 0 for female and SEX = 1 for male, METs = maximal estimated work load (metabolic equivalents) and STDV5 = horizontal or downsloping ST depression (mm) in V5. A logit probability > or = 0 identified CAD with a sensitivity of 79% and a specificity of 89%. The model correctly identified 28/36 (78%) patients with CAD, and 7/10 (70%) patients with NCA (correct diagnosis 76%; p < 0.02) in a separate random group of 46 unselected patients with positive exercise tests undergoing diagnostic coronary angiography.

Determinants of improvement in exercise capacity in patients undergoing cardiac rehabilitation.

In order to identify patients who benefit most from a cardiac rehabilitation program, we studied retrospectively all patients who completed a 3-month comprehensive cardiac rehabilitation program during a 2-year period. Questionnaires regarding physical exercise habits were sent to 122 patients and returned by 117 (96%) of them (53 post-acute myocardial infarction, 50 post-coronary artery bypass surgery, 14 post-infarction and surgery, 2 post-angioplasty). Exercise capacity (subset of 66 patients) improved by 19% after rehabilitation (7.8 +/- 3.1 to 9.3 +/- 2.7 METs, p < 0.0001). Univariate and multivariate analysis identified initial exercise capacity as the only independent variable predicting improvement in exercise performance (inverse relationship) (r2 = 0.24, p < 0.0001). The improvement was not related to age, sex, left ventricular function or time from cardiac event to rehabilitation. Patients recovering from both infarction and coronary artery bypass surgery showed a greater improvement (delta exercise capacity 2.8 +/- 1.4 METs) than patients after myocardial infarction alone (delta exercise capacity 0.8 +/- 2 METs, p < 0.02). Improvement was sustained for up to 2 years after completion of the program.

Importance of immediate and very early postprocedural angiographic and thallium-201 single photon emission computed tomographic perfusion measurements in predicting late results after coronary intervention.

We examined prospectively the hypothesis that the adequacy of initial dilatation may be a major determinant of the late result of coronary angioplasty and that a better assessment of initial dilatation can be made from a combined angiographic and perfusion study than from angiography alone. Angiographic and perfusion (thallium-201 single-photon-emission computed tomography) measurements were made very early (18 to 24 hours) after coronary angioplasty in 59 patients (67 lesions) and also immediately (37 +/- 16 minutes) after the procedures in 19 of them (23 lesions). The early measurements, singly, in combination, and as a restenosis index (restenosis index = thallium-201 ischemic score (units) - minimal luminal area (squared millimeters) were examined as predictors of the late angiographic result. At late angiography (5.5 +/- 2.2 months after angioplasty), residual stenosis was related to the immediate and very early postangioplasty minimal luminal dimension, thallium-201 ischemic score, and restenosis index, and also to day-1 loss and lesion length. The combination of a normal result in the immediate or early thallium-201 perfusion study with a large ( > or = 2 mm) angiographic luminal dimension stratified a group of patients with better long-term results after angioplasty and a lower incidence of late restenosis (p = 0.03). The findings emphasize the importance of the initial procedure as a determinant of the late result of angioplasty.

Use and limitations of Holter electrocardiography in assessing drug therapy of myocardial ischemia during the peri-PTCA period.

Incidence and pattern of myocardial ischemia during the peri-PTCA (percutaneous transluminal coronary angioplasty) period and the possible role of continuous intravenous isosorbide dinitrate in its prevention were examined prospectively in 30 patients. Holter electrocardiographic monitoring was performed for 21 +/- 3 h before PTCA and continued during and for 41 +/- 8 h after the procedure. Before PTCA, 19 ischemic episodes were present in 10 (33%) of 30 patients. PTCA produced an abrupt decrease in number (p = 0.015) and duration (p = 0.03) of spontaneous ischemic episodes. The rarity of recurrent myocardial ischemic events by Holter monitoring after PTCA negated any attempt at assessing the efficacy of intravenous isosorbide dinitrate in their prevention. Holter monitoring could not be used as an early predictor of late coronary restenosis.

Haemodynamic and neurohumoral effects of flosequinan in severe heart failure: similarities and differences compared with intravenous nitroglycerin therapy.

The acute haemodynamic and neurohumoral effects of flosequinan, a new direct-acting vasodilator, were studied in 12 patients with severe (eight in New York Heart Association grade 3, four in grade 4) cardiac failure. Flosequinan was administered in a single oral dose of 100 mg, with haemodynamic monitoring over a 22 h period. The effects were compared with those observed during high dose intravenous nitroglycerin therapy (276 +/- 100 micrograms.min-1), given to the same patients for an identical period on the previous day. Both flosequinan and nitroglycerin produced significant haemodynamic improvement during the 22 h monitoring period. Cardiac and stroke indices increased with both drugs. However, while systemic and pulmonary vascular resistance were reduced similarly by both drugs, the decrease in right atrial and pulmonary capillary wedge pressures was greater with nitroglycerin and less with flosequinan, indicating a greater venodilator effect for nitroglycerin and a more balanced arterial and venodilator effect for flosequinan. Systemic arterial pressure and heart rate tended to increase with flosequinan and to decrease with nitroglycerin. In contrast to nitroglycerin, flosequinan did not increase plasma renin activity and serum aldosterone levels. Atrial natriuretic peptide decreased appropriately after both drugs, in keeping with the decreases in left and right heart filling pressures. The favourable haemodynamic and neurohumoral profiles of flosequinan suggest that it may be a useful vasodilating drug in the management of patients with severe heart failure.

Usefulness of intracoronary isosorbide dinitrate in alleviating myocardial ischaemia during coronary balloon angioplasty.

The effect of intracoronary isosorbide dinitrate on provoked myocardial ischaemia during percutaneous transluminal coronary angioplasty (PTCA) was studied in 60 patients who had at least 1 mm electrocardiographic (ECG) ST segment deviation during a 70 s control balloon inflation period. Isosorbide dinitrate (dose 1 mg, 2 mg or 3 mg) or placebo (saline) was administered by slow intracoronary injection, and the ST segment changes recorded again during an identical dilatation period 2-4 min later. Following injection of isosorbide dinitrate, the severity of ST segment deviation decreased (1 mg -31 +/- 30%, P = 0.03; 2 mg -51 +/- 35%, P = 0.0001; 3 mg -36 +/- 32%, P = 0.002) during coronary balloon inflation, and the time until onset of 1 mm ST deviation was prolonged (1 mg +79 +/- 137%, P = 0.06; 2 mg +85 +/- 87%, P = 0.02; 3 mg +78 +/- 109%, P = 0.02). With the 3 mg dose, the time to maximum ECG change increased (+37 +/- 87%, P = 0.02). In the placebo group, there was a small decrease in the severity of ST segment deviation in patients receiving placebo (-23 +/- 32%, P = 0.03), but no change in the time to its onset or in the time to maximum ST deviation. Isosorbide dinitrate did not alter heart rate, systolic arterial pressure or the rate-pressure product at maximum ST segment change, implying that when isosorbide was administered by direct intracoronary injection, a direct cardiac effect was responsible for the major anti-ischaemic effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of nisoldipine on exercise performance in heart failure following myocardial infarction.

The effects of the second generation calcium channel blocking drug nisoldipine on subjective and objective measurements of exercise performance were studied in 19 patients with moderate to severe heart failure (9 New York Heart Association functional class 2, 9 class 3 and 1 class 4) due to fixed ventricular dysfunction following myocardial infarction. Nisoldipine (10 mg 3 times daily) or placebo were administered for 8 weeks in a double-blind parallel study, assessing exercise performance by symptom-limited treadmill exercise testing using a modified Naughton protocol. Nisoldipine was well-tolerated and produced a small increase in peak estimated workload performed (6.2 +/- 2.9 to 8.2 +/- 3.0 METs, p = 0.06). The rate of perceived exertion (Borg scale) increased from 17.5 +/- 2.2 to 18.8 +/- 1.2 (p less than 0.02). The higher workload was performed at a lower peak systolic blood pressure (p = 0.03), higher peak heart rate (p = 0.06) and identical double product (NS). There was no change in resting and peak heart rate and blood pressure or in exercise performance in patients receiving placebo. Resting left ventricular ejection fraction, measured by radionuclide ventriculography, was unchanged after 8 weeks both in the placebo (21 +/- 9 to 20 +/- 9%) and nisoldipine (34 +/- 17 to 36 +/- 19%) groups.

Failure of captopril to prevent nitrate tolerance in congestive heart failure secondary to coronary artery disease.

The possible role of angiotensin-converting enzyme inhibition in preventing or minimizing tolerance to intravenous nitroglycerin in severe congestive heart failure (CHF) was studied by quantitating the degree of tolerance in 12 patients receiving nitroglycerin (group 1) and in 9 patients (group 2) receiving nitroglycerin and concurrent treatment with captopril (60 +/- 29 mg/day). At peak effect, nitroglycerin produced almost identical hemodynamic changes in both groups, with significant decreases in right atrial and pulmonary arterial wedge pressure, systolic blood pressure and systemic and pulmonary vascular resistances. Cardiac index increased. The extent of nitrate tolerance was calculated for each hemodynamic parameter as the percentage loss of the peak effect achieved by the drug. At 24 hours, 98 +/- 80% of the benefit achieved with respect to right atrial pressure was lost in group 1 and 61 +/- 74% in group 2 (group 1 vs 2, difference not significant). For pulmonary arterial wedge pressure, 51 +/- 31% (group 1) and 85 +/- 53% (group 2) (difference not significant) of the effect was lost, and for cardiac index, 53 +/- 58% (group 1) and 54 +/- 44% (group 2) (difference not significant). Tolerance was also almost identical regarding systolic blood pressure and systemic and pulmonary vascular resistance. Thus, the extent of tolerance to high-dose intravenous nitroglycerin in CHF was unaltered by administration of captopril, indicating that in clinical dosage, counter-regulatory neurohumoral mechanisms involving the renin-angiotensin system appear to be unimportant in its development.