P.M. Schofield

Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

BACKGROUND Vitamin E (alpha-tocopherol) is thought to have a role in prevention of atherosclerosis, through inhibition of oxidation of low-density lipoprotein. Some epidemiological studies have shown an association between high dietary intake or high serum concentrations of alpha-tocopherol and lower rates of ischaemic heart disease. We tested the hypothesis that treatment with a high dose of alpha-tocopherol would reduce subsequent risk of myocardial infarction (MI) and cardiovascular death in patients with established ischaemic heart disease. METHODS In this double-blind, placebo-controlled study with stratified randomisation, 2002 patients with angiographically proven coronary atherosclerosis were enrolled and followed up for a median of 510 days (range 3-981). 1035 patients were assigned alpha-tocopherol (capsules containing 800 IU daily for first 546 patients; 400 IU daily for remainder); 967 received identical placebo capsules. The primary endpoints were a combination of cardiovascular death and non-fatal MI as well as non-fatal MI alone. FINDINGS Plasma alpha-tocopherol concentrations (measured in subsets of patients) rose in the actively treated group (from baseline mean 34.2 micromol/L to 51.1 micromol/L with 400 IU daily and 64.5 micromol/L with 800 IU daily) but did not change in the placebo group. Alpha-tocopherol treatment significantly reduced the risk of the primary trial endpoint of cardiovascular death and non-fatal MI (41 vs 64 events; relative risk 0.53 [95% Cl 0.34-0.83; p=0.005). The beneficial effects on this composite endpoint were due to a significant reduction in the risk of non-fatal MI (14 vs 41; 0.23 [0.11-0.47]; p=0.005); however, there was a non-significant excess of cardiovascular deaths in the alpha-tocopherol group (27 vs 23; 1.18 [0.62-2.27]; p=0.61). All-cause mortality was 36 of 1035 alpha-tocopherol-treated patients and 27 of 967 placebo recipients. INTERPRETATION We conclude that in patients with angiographically proven symptomatic coronary atherosclerosis, alpha-tocopherol treatment substantially reduces the rate of non-fatal MI, with beneficial effects apparent after 1 year of treatment. The effect of alpha-tocopherol treatment on cardiovascular deaths requires further study.

Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial

BACKGROUND Transmyocardial laser revascularisation (TMLR) is used to treat patients with refractory angina due to severe coronary artery disease, not suitable for conventional revascularisation. We aimed in a randomised controlled trial to assess the effectiveness of TMLR compared with medical management. METHODS 188 patients with refractory angina were randomly assigned TMLR plus normal medication or medical management alone. At 3 months, 6 months, and 12 months after surgery (TMLR) or initial assessment (medical management) we assessed exercise capacity with the treadmill test and the 12 min walk. FINDINGS Mean treadmill exercise time, adjusted for baseline values, was 40 s (95% CI -15 to 94) longer in the TMLR group than in the medical-management group at 12 months (p=0.152). Mean 12 min walk distance was 33 m (-7 to 74) further in TMLR patients than medical-management patients (p=0.108) at 12 months. The differences were not significant or clinically important. Perioperative mortality was 5%. Survival at 12 months was 89% (83-96) in the TMLR group and 96% (92-100) in the medical-management group (p=0.14). Canadian Cardiovascular Society score for angina had decreased by at least two classes in 25% of TMLR and 4% of medical-management patients at 12 months (p<0.001). INTERPRETATION Our findings show that the adoption of TMLR cannot be advocated. Further research may be appropriate to assess any potential benefit for sicker patients.

Early Complications After Dual Chamber Versus Single Chamber Pacemaker Implantation

This study was performed to compare the frequency of early complications after single chamber versus dual chamber permanent pacemaker implantation. Early complication was defined as one occurring in the 6‐week period following implantation. We prospectively analyzed consecutive pacemaker implantation from January 1987 to June 1993 at our regional center. All complications were also analyzed for the relationship to operator experience, the venous access route, and the presence of temporary pacing wire at the time of implantation of the permanent pacing system. A total of 2019 new pacemaker units were implanted during this period. 1733 patients (85.8%) received a VVI pacemaker and 286 (14.2%) a DDD unit. Wound infection occurredin 11 (0.6%) VVI patients and 6 (2.1%) DDD patients. Lead displacement occurred in 18(1 %) VVI patients and 15 (5.2%) DDD patients (11 [3.8%] atrial and 4 [1.4 %] ventricular). There were 10 (0.6%)pneumothoraces, 9 (0.5%) hematomas requiring drainage, 1 (0.06%) chylocele, and 2 (0.1%) deaths in the VVI group. There were 2 (0.7%) pneumothoraces, 2 (0.7%) hematomas, and no deaths in the DDD group. There was no significant increase in complications for experienced infrequent implanters (< 12 systems per year). In both groups the subclavian approach was associated with a risk of pneumothorax when compared to the cephalic approach. The rate of wound infection was higher in patients who had a temporary pacing wire in place. The use of prophylactic antibiotics does not appear to affect the incidence of wound infection. The early complications in the DDD group were higher than in the VVI group (8.7% vs 2.9%, P < 0.05), being mainly due to an increased incidence of wound infection and atrial lead displacement.

Effect of transcutaneous electrical nerve stimulation on coronary blood flow.

BackgroundAlthough neurostimulation has been shown to be of benefit in angina pectoris, the exact mechanism of its action is not clear. This study was performed to examine the effect of transcutaneous electrical nerve stimulation on coronary blood flow. Methods and ResultsThe effect of transcutaneous electrical nerve stimulation was studied in 34 syndrome X patients (group 1), 15 coronary artery disease patients (group 2), and 16 heart transplant patients (group 3). Coronary blood flow velocity (CBFV) in the left coronary system was measured at rest and after a 5-minute stimulation period with a Judkins Doppler. There was a significant increase in the resting CBFV in group 1 (from 6.8±4.1 to 10.5±5.7 cm/s, P < .001) and group 2 (from 6.8±4.1 to 10.5±5.7 cm/s, P < .001). However, there was no significant change in the resting CBFV in group 3. There were no significant changes in the coronary arterial diameters as a result of neurostimulation. There was a significant decrease in the epinephrine levels in group 1 (from 79.6±17.8 to 58.5±17.5 ng/L, P = .01) and group 2 (from 102.2±27.2 to 64.1 ± 19.1 ng/L, P = .01). ConclusionsTranscutaneous electrical nerve stimulation can increase resting coronary blood flow velocity. The findings suggest that the site of action is at the microcirculatory level and that the effects may be mediated by neural mechanisms.

Is coronary flow reserve in response to papaverine really normal in syndrome X

BACKGROUND An impaired coronary flow reserve in syndrome X has been demonstrated by many studies. Recently, however, a normal coronary flow reserve in response to papaverine was reported, but the number of patients in these studies was small. The aim of this study was to investigate whether coronary flow reserve in response to intracoronary papaverine is really impaired in syndrome X. METHODS AND RESULTS We investigated 53 syndrome X patients (typical angina, a positive exercise test, and completely normal coronary arteries on angiography) and 26 heart transplant patients with normal coronary arteries (control group). All antianginal medications were stopped 48 hours before the study. A 3.6F intracoronary Doppler catheter was positioned in the proximal left anterior descending coronary artery and was connected to a Millar velocimeter. The coronary blood flow velocity at rest and in response to a hyperemic dose of papaverine was measured. Coronary flow reserve was defined as the ratio of hyperemic coronary blood flow velocity in response to papaverine and resting coronary blood flow velocity. The coronary flow reserve (mean +/- SD) in the syndrome X group was 2.72 +/- 1.39. The coronary flow reserve in the control group was significantly higher at 5.22 +/- 1.26 (P < .01). In both groups there was no significant difference in the heart rate or the mean arterial pressure during the study. CONCLUSIONS Our study shows that coronary flow reserve in response to intracoronary papaverine is impaired in syndrome X patients.

Maze 3 for Atrial Fibrillation: Two Cuts Too Few?

The Maze procedure has been developed as a surgical approach to the management of patients with atrial fibrillation refractory to medical treatment. The recent modification of the technique (Maze 3) achieves good rate control with coordinated AV contractions. However, the procedure involves cuts that completely isolate a block of left atrial (LA) wall, including the four ostia of the pulmonary veins. The electrical and mechanical activity of this isolated LA block are dissociated from the rest of the atrium, and the area may, in fact, continue to fibrillate. This may provide a nidus for the development of mural thrombus. The weight and endocardial surface area of the LA block and of the entire LA were estimated in ten formalin fixed hearts from trauma victims with no evidence of cardiac disease. In these samples, the LA block represented 35% of the endocardial surface area of the entire LA and 29% of the weight. The LA block is of sufficient size to allow macroreentrant circuits to form and has the potential to fibrillate if isolated from the rest of the atrium. We modified the Maze 3 procedure to recruit the otherwise isolated LA block by using two additional cuts around each pair of pulmonary veins as they enter the LA. The first patient who underwent the modified procedure demonstrated sinus rhythm on Holter monitoring postoperatively and remained in sinus rhythm following burst atrial pacing at 300 and 420 beats/min each for 30 seconds. In addition, atrial contractions were found to contribute 19% of the cardiac output. The majority of the atrial wall and, in particular, the recruited area between the pulmonary veins contracted well, as demonstrated by transesophageal echocardiography. We suggest that this modification of Maze 3 has a potential advantage over the standard procedure by recruiting the entire LA without leaving any dyskinetic endocardial surface for thrombus formation. This should in turn reduce the risk of thromboembolic complications.

A UK trial-based cost–utility analysis of transmyocardial laser revascularization compared to continued medical therapy for treatment of refractory angina pectoris

OBJECTIVE Transmyocardial laser revascularization (TMLR) is used to treat patients with refractory angina considered unsuitable for conventional forms of revascularization. Using patient specific data from a single centre UK randomised-controlled trial, we aimed to determine whether, from a UK National Health Service (NHS) perspective, TMLR plus standard medical management is cost-effective when compared with standard medical management alone. METHODS One hundred and eighty-eight patients assessed as having refractory angina, and not suitable for conventional forms of revascularization were randomized to receive TMLR and medical management (94) or medical management alone (94). Costs to the UK NHS of TMLR (where appropriate), and all secondary sector health care contacts and cardiac-related medication in the 12 months following randomization, were collected. Patient utility as measured using the EuroQol EQ-5D questionnaire was combined with 12-month survival data to generate quality adjusted life years (QALYs). RESULTS The mean cost per patient over the year from hospitalization for TMLR was 11,470 pounds sterling and for medical management alone was 2586 pounds sterling, giving a cost difference of 8901 pounds sterling (95% confidence interval (CI) 7502 pounds sterling--10,008 pounds sterling: P < 0.0001). The mean QALY difference, in favour of TMLR was 0.039 (95% CI -0.033 to 0.113: P = 0.268). This gives an incremental cost per QALY of over 228,000 pounds sterling. Analysis of stochastic uncertainty and of sensitivity to gross changes in key parameters consistently produces very high costs per QALY. CONCLUSIONS The policy implications are clear: for such patients TMLR is an inefficient use of UK health service resources. This conclusion would not be changed by considerable improvements in effectiveness or reductions in cost.

Excellent outcome of cardiac transplantation using domino donor hearts

OBJECTIVE Domino cardiac transplantation affords flexible and optimal organ utilization, provides hearts unaffected by brain death, allows prospective tissue matching, and subsequent transplantation with short allograft ischemic times. A retrospective review of our experience with domino cardiac transplantation has been made. METHODS Seventy-two of 119 patients who underwent heart-lung transplantation from 1988 on served as domino cardiac donors (40 males, 32 females; mean age of 32 years; mean weight of 51 kg). The domino donor diagnoses were cystic fibrosis (n = 47), bronchiectasis (n = 9), primary pulmonary hypertension (n = 6), emphysema (n = 7), pulmonary fibrosis (n = 2) and Eisenmengers syndrome (n = 1). Forty-seven domino hearts were transplanted at our institution and 25 were exported to other centres in the United Kingdom. The 72 domino cardiac recipients were 62 males and 10 females, mean age of 47 years, mean weight of 60 kg, with ischemic heart disease (n = 32), cardiomyopathy (n = 36) and other conditions (n = 4). RESULTS There were four deaths (5.6%) at less than 30 days (2 from multiple organ failure, 1 from primary allograft failure and 1 from acute rejection). Actuarial survival estimates and 1 and 5 years were 77 +/- 5.2% nd 69 +/- 6.3%, respectively. This compared favourably with survival data obtained in 234 non-domino cardiac recipients. In the patients transplanted at Papworth, there was no difference in the incidence of rejection (0.6 +/- 0.05 versus 0.7 +/- 0.03 events per 100 patient days for the first 12 months) or in the freedom from graft atherosclerosis (74 +/- 3% versus 70 +/- 3% at 5 years) between the domino and non-domino groups. CONCLUSIONS The use of domino hearts donated by recipients of heart-lung transplants is beneficial and is associated with an excellent early and longer-term outcome.

The Utility of Pacemaker Evoked T Wave Amplitude for the Noninvasive Diagnosis of Cardiac Allograft Rejection

Previous work suggested that pacemaker evoked T wave amplitude (ETWA) may be a sensitive noninvasive marker of cardiac allograft rejection. A Topaz QT sensing rate responsive pacemaker (Vitatron Medical) was implanted at transplantation using epicardial ventricular leads in 45 recipients (35 males; median age 51 years, range 20‐63). The median duration of followup was 129 days (range 4‐327). The ETWA at a paced rate of 100 beats/min was measured daily during hospitalization and at each outpatient attendance (900 readings). Endomyocardial biopsies were at routine intervals or when otherwise clinically indicated (257 biopsies with concurrent ETWA data). There were 58 episodes of rejection ≥ grade 3a in 28 patients. The biopsies were classed as either no rejection (grade < 3a) or rejection requiring treatment (grade ≥ 3a). The median normalized ETWA was 100.8% (range 24.6‐239.7) without rejection and 89.9% (17.0 ‐189.7) with rejection (Mann‐Whitney U Test: P = 0.028). The performance of ETWA monitoring as a diagnostic test for the individual recipient was evaluated with exponentially weighted moving average quality control charts. For the diagnosis of all rejection episodes, ETWA monitoring had a sensitivity of 55%, a specificity of 62%, a positive predictive value of 30%, and negative predictive value of 83%, It is concluded that although analysis of pooled data showed a significant reduction in normalized ETWA with biopsy proven rejection, ETWA monitoring requires further refinement to improve sensitivity before it can be considered a clinically useful technique for the noninvasive diagnosis of cardiac allograft rejection in individual recipients.

The Ethics of Assessment for Transplantation

Over and above the clinical criteria influencing acceptance for transplantation how do we choose recipients? I would like to present the method by which we choose and the process involved.