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

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Articles

Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial P M Schofield, L D Sharples, N Caine, S Burns, S Tait, T Wistow, M Buxton, J Wallwork

Summary 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 medicalmanagement 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 medicalmanagement 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.

Lancet 1999; 353: 519–24 See Commentary page xxx

Introduction Most patients with angina due to coronary artery disease respond adequately to treatment with antianginal medication, coronary angioplasty with or without stenting, or coronary-artery bypass surgery. Some patients, however, present with angina that is refractory to such treatments, generally because the coronary disease is diffuse and in the distal part of their coronary circulation. Transmyocardial laser revascularisation (TMLR) is a new technique that uses laser ablation to create transmural channels in ischaemic myocardium. Animal studies have shown improvements in mortality, decreases in infarct size, and preservation of contractile function.1–3 Early results of TMLR in human beings, sometimes used in combination with coronary-artery bypass surgery, have been encouraging.4–6 The effectiveness of TMLR remains largely unproven, although a multicentre uncontrolled trial in the USA7 has suggested improvements in anginal symptoms and myocardial perfusion. A subsequent US randomised controlled trial is yet to publish its findings, but its results have led the Food and Drug Administration to approve the technology.8 We undertook a randomised controlled single-centre trial to assess the effectiveness and costs of TMLR in terms of exercise capacity, angina, myocardial perfusion, health-related quality of life, mortality, and resource use.

Patients and methods Patients All patients who were referred for recruitment were assessed at the trial centre. Refractory angina was generally due to diffuse and distal distribution of disease. Eligible patients were required to have reversible ischaemia seen on radionuclide myocardial perfusion scan. Patients were excluded if they were unable to do treadmill exercise testing, had a left-ventricular ejection fraction of less than 30%, were suitable for conventional revascularisation, were on intravenous therapy to control angina, or had a life expectancy of less than 12 months because of a non-cardiac disorder such as malignant disease. Between October, 1993, and September, 1997, 312 patients were assessed and 188 suitable patients recruited (figure 1).

Trial design Papworth Hospital NHS Trust, Papworth Everard, Cambridge, UK (P M Schofield FRCP, N Caine B A, S Burns MRCP, S Tait BSc, J Wallwork FRCS); MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge (L D Sharples PhD); Norfolk and Norwich Hospital, Norwich (T Wistow MRCP); and Health Economics Research Group, Brunel University, Uxbridge, Middlesex (M Buxton B A) Correspondence to: Mr John Wallwork, Papworth Hospital NHS Trust, Papworth Everard, Cambridge CB3 8RE, UK

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Suitable patients were randomly assigned treatment with TMLR plus normal antianginal therapy or medical management with antianginal therapy alone. A simple randomisation list was generated and held by the trial’s statistician. For practical reasons, randomisation was by consecutively numbered opaque sealed envelopes which were opened by a research fellow after the patient had given informed consent; this investigator was masked to the contents before opening. Allocation was returned to the trial coordinator and the number of patients assigned to each group was checked against the statisticians’ list.

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312 patients considered

124 excluded

188 randomised

94 assigned and received medical management

11 did not reach primary endpoint

83 analysed for primary endpoint at 1 year

94 assigned and received TMLR

17 did not reach primary endpoint

77 analysed for primary endpoint at 1 year

Figure 1: Trial profile Outcome measures were recorded at initial assessment and at 3 months, 6 months, and 12 months after assessment or surgery. Follow-up was to at least 1 year for all patients, with no crossovers from the control to the treatment group. The primary outcome was duration of the treadmill exercise test at 12-month follow-up. We did treadmill exercise testing according to a modified Bruce protocol,9 in which exercise intensity is increased every 3 min. The treadmill test was symptom limited; in exceptional cases the test was stopped because of increased blood pressure or arrhythmia. Maximum exercise time was recorded, as well as reasons for stopping. Patients were given no medication during the treadmill test. The 12 min walk test measured the maximum distance covered within the time;10 patients were allowed to stop as often as they wished during assessment. We recorded use of nitrates and presence of angina during or after the 12 min walk. Survival was measured from the day of randomisation; date and cause of death were recorded. We noted admissions to hospital and verified them with patients during follow-up visits. We measured left-ventricular ejection fraction by radionuclide multigated acquisition scan at assessment and at 12 months. Chest pain perceived by patients was recorded on the 11-point box scale (0 no pain, 10 pain as bad as it could be).11 The Canadian Cardiovascular Society score for angina was not part of the original trial protocol but we took measurements at initial assessment and follow-up after October, 1994, to enable comparison with the US studies. Radionuclide scans were taken with use of technetium-99mlabelled sestamibi, according to the 2-day rest-stress protocol. 400 MBq sestamibi was administered at rest and imaging was done 60–90 min later. On a separate day, a further 400 MBq sestamibi was administered at peak stress and imaging done 60 min later. We classified the left ventricle in five segments: anterior, inferior, lateral, apex, and septum. Segments with decreased tracer uptake during stress compared with rest were scored as having a reversible perfusion defect (ie, ischaemia). Patients with abnormal perfusion at rest were scored as having a fixed perfusion defect (ie, scar). If abnormal perfusion during stress improved only partly with rest segments were scored as having a partially reversible perfusion defect (ie, mixed ischaemia). Information on health-related quality of life and detailed resource use was collected and will be reported elsewhere. TMLR was carried out through a small anterolateral thoracotomy to expose the areas of reversible ischaemia previously identified. The laser used (PLC Medical Systems, MA, USA) was a 1000 W carbon dioxide device that delivers 850 W of peak power to the tissue. Only one shot is necessary

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to make a clear channel. The maximum output is 80 J and the pulse width can be varied from 1 ms to 99 ms. The laser is triggered to fire on the R wave of the electrocardiogram, when the ventricle is distended to the maximum with blood and is electrically quiescent. Blood emerges at the epicardial surface if the channel traverses the myocardium. The channels were about 1 mm in diameter and were distributed at about one per cm2. Channels were confirmed by transoesophageal echocardiography or carotid doppler. The median number of channels created per patient was 30 (range six to 75) and the median pulse energy was 34 J (25–60). An independent data monitoring committee met twice, in August, 1996, and August, 1997, to review trial results and future conduct of the trial. They recommended that the trial should continue as planned until 190 patients were recruited, by which time the difference in exercise time would be measured to a precision of 30 s. The study was approved by the local research ethics committee and all patients gave written, informed consent.

Statistical analysis Analysis was by treatment received since all patients randomised received assigned treatment. Results are presented as mean (SD) or frequency (%) for descriptive purposes, and mean (95% CI) for inference. We gathered information on surviving patients at the latest follow-up visit or by telephone. We calculated Kaplan-Meier survival curves and 95% CI and compared them by means of the log-rank test. Improvement was defined, a priori, as a 50% improvement in maximum exercise time from 5·250 min to 7·875 min. To show this difference, recruitment of 95 patients per group was required12 (␣=5%, 1⫺␤=80%). Initially, exercise time was assumed to follow an exponential distribution, and sample size was calculated on this basis. Analyses prepared for confidential meetings of the data-monitoring committee showed that treadmill exercise times were normally distributed but that the trial size remained appropriate. At the design stage, loss to follow-up was expected to be less than 5%, which would result in negligible loss of power. Although loss to follow-up was 15%, normality of distributions and lower than expected SDs meant that we retained at least 80% power to detect predefined clinically significant improvements. Maximum exercise time on the treadmill and distance covered during the 12 min walk were modelled by multivariate ANOVA, with baseline assessment values as covariates and group as a factor. Left-ventricular ejection fraction and the 11point pain scale (since it was symetrically distributed) were modelled similarly by ANOVA. We tested significance of the effect of TMLR on Canadian Cardiovascular Society score for TMLR (n=94)

Medical management group (n=94)

11 (12%)/83 (88%) 60 (7·9)

8 (9%)/86 (91%) 61 (7·4)

Cardiac status CCS class III CCS class IV Stable angina Mean (SD) left-ventricular ejection fraction (%)

69 (73%) 25 (27%) 94 (100%) 48 (9·4)

69 (73%) 25 (27%) 94 (100%) 49 (10·6)

Medical history Previous myocardial infarction Congestive cardiac failure Coronary-artery bypass grafting Percutaneous transluminal coronary angioplasty

69 (73%) 8 (9%) 89 (95%) 27 (29%)

71 (75%) 6 (6%) 85 (90%) 24 (26%)

18 (19%) 3 (3%)

15 (16%) 4 (4%)

Demography Female/male Mean (SD) age (years)

Risk factors Insulin-dependent diabetes melitus Current smoker

CCS=Canadian Cardiovascular Society score for angina.

Table 1: Population characteristics at initial assessment

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class. We later used these data to assess the robustness of the results. In two sensitivity analyses, we took all deaths to have zero exercise tolerance and maximum angina score, and missing observations and refusals were replaced by: 1) zero exercise/maximum pain; 2) the average of values recorded after surgery for each individual.

Cumulative probability of survival (%)

100 90 80 70 60

Results

50

188 (60·3%) of 312 patients were enrolled (figure 1). 124 patients were excluded: 57 had no evidence of reversible ischaemia; 29 underwent conventional revascularisation procedures; nine had a left-ventricular ejection fraction of less than 30%; two were unable to participate in treadmill testing; 17 refused to participate; six patients had other contraindications; one died before making a decision; and three did not complete their assessment. At initial assessment, the medical-management and TMLR groups were similar (table 1). Of the 182, 179, and 173 survivors at 3 months, 6 months, and 12 months, 97%, 97%, and 90% of TMLR patients attended for follow-up and 94%, 92%, and 92% of medical-management patients attended. At each followup, three (two TMLR, one medical-management) patients who did not attend completed their healthrelated quality of life questionnaires by post. One TMLR patient, with a history of alcohol abuse, was lost to follow-up. Five medical-management patients withdrew soon after recruitment because they were unhappy about their treatment allocation. The remaining four non-attenders (three TMLR, one medical management) were unwell or had personal problems or commitments. The mean hospital stay for the TMLR procedure was 10·5 days (SD 5·2), of which 1·5 days (0·6) were before surgery and 1·5 days (0·6) were spent in intensive care after surgery. Morbidity associated with TMLR included wound or respiratory infections in 31 (33%) patients, three of whom had pneumonia; arrhythmias (generally transient atrial fibrillation) in 14 (15%); and left-venticular failure, which responded to increased diuretics, in 11 (12%) patients. 64 (68%) of 94 patients experienced at least one complication but most of these were minor and not unexpected in patients such as these. 12-month survival was 89% (95% CI 83–96) for the TMLR group and 96% (92–100) for the medicalmanagement group (p=0·14, figure 2). Five (5%) deaths occurred perioperatively—three acute myocardial infarctions, one pulmonary embolism, and one pulmonary oedema. A further six TMLR and four

40 30 TMLR

20

Medical management

10 0 0

TMLR 94 Medical 94 management

365

730

1095

82 87

48 49

23 19

Time from randomisation (days) Figure 2: Kaplan-Meier survival curves from randomisation to last contact Vertical lines are 95% CI. Not all survivors returned for follow-up at 12 months.

angina, readmissions, and antianginal drug use by Poisson regression.13 To account for any extra uncertainty arising from two sources of variation, between patient and within patient but between follow-up visits, we used Breslow’s random effects method.14 Trend tests were used to take into account the ordered nature of the Canadian Cardiology Society score for angina. Areas of reversible and irreversible ischaemia are expressed as the number and proportion of graded sites, and were modelled with logistic regression, adjusted for visit, site, and ischaemia status before surgery, and for random effects. We took p<0·05 to be significant. Initially, patients who died or refused follow-up were excluded from the analysis of exercise tolerance and angina 10

Exercise times p=0·079

Time (min)

9

p=0·134

p=0·152

p=0·536

8 7 6

Distance in 12 min 700

p=0·005

p=0·005

p=0·108

Distance (m)

Limiting factor p=0·681

600

Angina on treadmill TMLR Medical management p*

500

Initial assessment

3 months

6 months

12 months

61/87 (70%) 38/83 (46%) 39/82 (48%) 32/74 (43%) 67/93 (72%) 55/86 (64%) 52/81 (64%) 56/80 (70%) 0·904 0·017 0·032 <0·001

Nitrates used during 12 min walk TMLR 32/94 (34%) 13/86 (15%) 18/83 (22%) 16/78 (21%) Medical management 37/94 (39%) 30/86 (35%) 38/83 (46%) 32/82 (39%) p* 0·449 0·002 <0·001 0·01

400 TMLR MM Initial assessment

TMLR MM 3 months

TMLR MM 6 months

TMLR MM 12 months

Follow-up time Figure 3: Mean (95% CI) exercise times and distance during 12 min at initial assessment and months 3, 6, and 12 MM=medical management. TMLR n=77, medial management n=83.

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Angina during 12 min walk TMLR 66/94 (70%) 38/86 (44%) 40/84 (48%) 43/78 (55%) Medical management 76/94 (81%) 53/86 (62%) 65/83 (78%) 58/82 (71%) p* 0·089 0·022 <0·001 0·04 *Likelihood ratio test.

Table 2: Limiting factors in exercise testing

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100

Proportion patients (%)

80

assessment

Reversible

3 months

TMLR Medical management

Medical management

TMLR

Medical management

144/460 (31%) 79/404 (20%) 87/400 (22%) 78/370 (21%)

160/469 (34%) 104/430 (24%) 94/405 (23%) 86/399 (22%)

65/460 (14%) 81/404 (20%) 90/400 (22%) 69/370 (19%)

38/469 (8%) 51/430 (12%) 68/405 (17%) 68/399 (17%)

60

Assessment 3 months 6 months 12 months

40

Table 3: Number of myocardial sites with reversible or irreversible ischaemia

20 0

100 6 months

12 months

80 60 40 20 0

II III IV 0 I II III IV Candadian cardiovascular score Figure 4: Canadian Cardiovascular Society score for angina at initial assessment and follow-up visits

0

I

Initial assessment, n=94 in each group; 3 months TMLR n=79, medical management n=70; 6 months TMLR n=70, medical managment n=67; 12 months TMLR n=74, medical management n=78.

medical-management patients died within 12 months of surgery or recruitment, from cardiac-related events, and six TMLR and six medical-management patients died after 1 year. Necropsy reports were available for three of the 12 who died after discharge, two at 1 year and one at 3·5 years, and showed dense fibrous scarring with no evidence of open channels. 8 p=0·858

p=0·002

7 Score on 11-point scale

Irreversible

TMLR

p=0·046

p=0·053

TMLR MM 6 months

TMLR MM 12 months

6

5

4

3 TMLR MM Initial assessment

TMLR MM 3 months

Follow-up time Figure 5: Angina scores reported by patients at initial assessment and follow-up MM=medical management. TMLR n=77, medical management n=83.

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The difference in exercise times between the two groups was 43 s (⫺5 to 91) at 3 months, 36 s (⫺7 to 83) at 6 months, and 40 s (⫺15 to 94) at 12 months (figure 3), but no difference was significant (3 months p=0·377). Sensitivity analysis that made various assumptions about the outcome for patients who died or withdrew did not change these findings substantially. However, the test was stopped more frequently for angina among medicalmanagement patients than among TMLR patients at all follow-up times (table 2). TMLR patients were more likely to report dyspnoea or fatigue as the reason for stopping; the frequency of tests stopped by the cardiac technician did not differ significantly (data available from authors). TMLR patients walked a significantly greater distance than medical-management patients at 3 months and 6 months, but not at 12 months (figure 3). The overall difference was significant (p=0·022). There was a 6% difference between the groups in the mean distance walked, in favour of the TMLR group at 12 months (33 m [⫺7 to 74]). Nitrate use and frequency of angina during or after the 12 min walk were significantly lower in the TMLR group than in the medical-management group at 3 months, 6 months, and 12 months (table 2). After adjustment for repeated follow-up visits, TMLR had a significant effect on Canadian Cardiovascular Society score for angina (figure 4) at each visit (p<0·001 for each). A reduction of two Canadian Cardiovascular Society score classes was achieved in 23 (34%), 15 (22%), and 18 (25%) TMLR patients at 3 months, 6 months, and 12 months, respectively, and in two (3%), three (4%), and three (4%) medical-management patients. For angina scores recorded by patients on the 11-point scales, the difference was less striking than that recorded by physicians at 3 months (difference ⫺1·4 [⫺2·2 to ⫺0·6]), 6 months (⫺0·8 [⫺1·7 to 0·01]), and 12 months (⫺0·9 [⫺1·9 to 0·01], figure 5). There were fewer hospital admissions due to unstable angina in the first 12 months in the TMLR group (0·5 per patient-year [0·3–0·6]) than in the medicalmanagement group (0·8 [0·6–0·9], p=0·015), but there was no difference in the overall rate of hospital admissions (1·3 [1·1–1·5] vs 1·1 [0·9–1·3] per patientyear, p=0·110). Of the antianginal therapies recorded, use of two was lower with TMLR. Calcium antagonists were prescribed for 87 (93%) TMLR patients and 88 (94%) medical-management patients at initial assessment, whereas at 12 months, 66 (85%) of 78 TMLR patients and 83 (100%) medical-management patients required calcium antagonists (p<0·001). Use of nitrates in any form was also decreased by 12 months in TMLR patients (from 81 [86%] to 54 [69%]) compared with medical-management patients (from 74 [79%] to 67 [82%], p=0·025). In both groups, the number of sites with reversible ischaemia decreased and the number with irreversible

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ischaemia increased (table 3). The overall number of sites with reversible ischaemia did not differ significantly between groups (odds ratio 0·99 [0·82–1·20], p=0·975), but there was a small excess of sites with irreversible ischaemia among TMLR patients (1·27 [1·00–1·61], p=0·046). Mean resting left-ventricular ejection fraction at baseline was 49% (SD 10·6) for medical-management patients and 48% (9·4) for TMLR patients (table 1) and decreased to 48% (11·7) and 46% (12·3) at 12 months (p=0·22).

Discussion Our trial showed no clinically important difference between groups in treadmill exercise time or 12 min walking distance. Angina symptoms did, however, improve significantly, albeit less than in previous studies: 34% of TMLR patients improved by two Canadian Cardiovascular Society score for angina classes at 3 months, compared with 75% in a US report7 and 47% in the international registry.15 Scoring of physician-rated angina is variable between centres. Patients’ reports of perceived angina showed less improvement. In a surgical trial, in which masking is almost always impossible, results should be unequivocal to be convincing. Mirhoseini and colleagues4–6 published the first use of a high-energy carbon dioxide laser in human beings. Frazier and colleagues16 showed in 21 patients undergoing TMLR as sole therapy, an improvement in mean resting wall-motion score index and mean leftventricular ejection fraction at peak stress. A multicentre uncontrolled trial of TMLR based on 200 patients in eight hospitals in the USA7 involved similar patients to our trial. They reported 9% perioperative mortality and a further 9% mortality after a mean of 10 months’ follow-up. The number of perfusion defects decreased significantly in the treated left-ventricular wall. In uncontrolled European and Asian registry data from 967 patients with intractable angina not amenable to conventional revascularisation, mortality was 9·7% perioperatively, and morbidity included infection, transient arrhythmia, and left-ventricular dysfunction.15 The exact mechanism of action of TMLR remains uncertain. Various possibilities have been proposed, including placebo effect, direct perfusion, denervation, and angiogenesis.3–7,17–19 The concept of TMLR was based on knowledge of myocardial sinusoids and the thebesian system,20 which were thought to allow direct perfusion of the myocardium by ventricular blood. Myocardial neovascularisation has been achieved in the past by internal thoracic-artery implantation, with moderate clinical improvement.21 TMLR, theoretically, incorporates the possible combination of direct perfusion and new vessel formation, since the laser channels could provide blood directly to the myocardium and stimulate angiogenesis. Currently, angiogenesis seems to be the most likely mechanism.22 Clearly, this process takes time and may explain why in some patients’ improvement in angina and myocardial perfusion continues for up to 6 months after surgery.22 Our results did not, however, support this theory. In our trial, the number of left-ventricular segments with reversible myocardial ischaemia fell in both treatment groups, with no significant differences. The improvement in the control group could be related to

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the further development of collateral circulations in patients with advanced coronary artery disease. This finding emphasises the danger of reliance on the results of uncontrolled studies, many of which have suggested improved myocardial perfusion after TMLR on radionuclide scans7 and positron emission tomography (PET) scans.23 One centre has shown an increase in the subendocardial perfusion of the myocardium on PET scans, which was not detected by standard global measurements.16,23 The radionuclide techniques that we used may not have been sensitive enough to show a difference between the two groups. In a subgroup of our TMLR patients, however, PET scanning showed no improvement in myocardial perfusion.24 TMLR clearly carries a significant risk of morbidity and mortality. In our study, the perioperative mortality of 5% compared favourably with the 9–10% reported in previous series.7,15 Our lower rate may be due partly to exclusion of patients with resting left-ventricular ejection fractions of less than 30% and those on intravenous therapy to control angina. The excess of deaths in the TMLR group arose almost entirely in the early postoperative period. It has been suggested that patients who survive TMLR have improved survival,7 but we found no evidence of this effect. For each individual, therefore, the operative risks should be balanced against the potential benefits of moderate improvement in angina and minimal improvement in exercise capacity. In particular, extrapolation to sicker patients may give more scope for improvement in clinical outcomes but will be accompanied by increased surgical risk. For the health-care system, the costs of TMLR should also be considered. There are features of this trial that have implications for health-technology assessment in the UK. Ideally, all new technologies should undergo rigorous assessment before diffusion through the health service. Currently, however, companies producing new devices are not required to provide evidence of therapeutic efficacy before widespread marketing. This situation has two important effects. First, the obtaining of finance for a trial can be difficult since no provision for the funding of the technology exists; unlike the pharmaceutical industry, companies do not typically provide the technology free of cost during a trial. Second, other centres acquire the technology and perform the procedure while a trial is continuing, despite government advice to the contrary in their guidance to purchasing authorities.25 Such action may slow recruitment and add cost to the trial. Government commitment to change the regulations governing the introduction of technology to the National Health Service via the National Institute of Clinical Excellence may improve this situation.26 A policy for provision of funding of technology during trials, or regulation of marketing until evidence is available, is overdue. Our findings show that the adoption of the TMLR procedure cannot be advocated. Further research will help to find out whether any subgroup of patients will benefit. Contributors J Wallwork, P M Schofield, L D Sharples, N Caine, and M Buxton developed the trial design and planned and managed the study. S Tait, S Burns, and T Wistow did the research. L D Sharples, S Tait, and S Burns did the analyses. All the investigators were involved in the preparation of the paper.

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Acknowledgments We thank the participants, the physicians, and the cardiologists who referred their patients to the trial; the cardiothoracic surgeons and anaesthetists involved in TMLR; D L Stone and R Coulden for their help with the radionuclide scans; and the research assistants, Elizabeth Kelly and Divna Trkulja-Batas, who collected the data and interviewed the patients. The Medical Research Council Data Monitoring Committee members, Richard Himsworth and David Spiegelhalter, advised on the conduct of the trial. Research funding was provided by the Medical Research Council, service support for the research by the National Health Service Executive Research and Development Programme, treatment costs by NHS health authorities, and a grant to obtain the laser equipment by BUPA Healthcare.

References 1

Mirhoseini M, Cayton MM. Revascularisation of the heart by laser. J Microsurg 1981; 2: 253–60. 2 Mirhoseini M, Muckerheide M, Cayton MM. Transventricular revascularisation by laser. Lasers Surg Med 1982; 2: 187–98. 3 Horvath KA, Smith WJ, Laurence RG, Schoen FJ, Appleyard RF, Cohn LH. Recovery and viability of an acute myocardial infarction after transmyocardial laser revascularisation. J Am Coll Cardiol 1995; 25: 258–63. 4 Mirhoseini M, Fisher JC, Cayton MM. Myocardial revascularisation by laser: a clinical report. Lasers Surg Med 1983; 3: 241–245. 5 Mirhoseini M, Shelgikar S, Cayton MM. New concepts in revascularisation of the myocardium. Ann Thorac Surg 1988; 45: 415–20. 6 Mirhoseini M, Shelgikar S, Cayton MM. Transmyocardial laser revascularisation: a review. J Clin Laser Med Surg 1993; 11: 15–19. 7 Horvath K, Cohn LH, Cooley DA, et al. Transmyocardial laser revascularisation: results of a multicentre trial with transmyocardial laser revascularisation used as sole therapy for end-stage coronary artery disease. J Thorac Cardiovasc Surg 1997; 113: 645–54. 8 Josefson D. FDA approves heart laser treatment. BMJ 1998; 316: 1409. 9 Bruce RA, McDonough JR. Stress testing in screening for cardiovascular disease. Bull N Y Acad Med 1969; 45: 1288. 10 Cooper K. Correlation between field and treadmill testing as a means for assessing maximal oxygen intake. J Am Heart Assoc 1968; 203: 201. 11 Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with pain rating scale. Ann Rheum Dis 1978; 37: 378–81.

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12 Machin D, Campbell MJ. Statistical tables for the design of clinical trials. Oxford: Blackwell Scientific Publications, 1987: 136–37. 13 Breslow NE, Day NE. Statistical methods in cancer research, vol 2: the design and analysis of cohort studies. Lyon: IARC, 1987. 14 Breslow NE. Extra-poisson variation in log-linear models. Appl Stat 1984; 33: 38–44. 15 Burns SM, Sharples LD, Tait S, Caine N, Wallwork J, Schofield PM. The transmyocardial laser revascularisation international registry report. Eur Heart J 1999; 20: 31–37. 16 Frazier OH, Cooley DA, Kadiasaoglu KA, et al. Myocardial revascularisation with laser: preliminary findings. Circulation 1995; 92 (suppl II): 58–65. 17 Hardy RI, Bove KW, James FW, et al. A histologic study of laser induced transmyocardial channels. Lasers Surg Med 1987; 6: 563–73. 18 Hardy RI, James FW, Millard RW, et al. Regional myocardial blood flow and cardiac mechanisms in dog hearts with CO2 laser-induced intramyocardial revascularisation. Basic Res Cardiol 1990; 85: 179–97. 19 Mirhoseini M, Shelgikar S, Cayton MM. Clinical and histological evaluation of laser myocardial revascularisation. J Clin Med Surg 1990; 6: 73–78. 20 Mirhoseini M, Cayton MM, Shelgikar S, et al. Clinical report: laser myocardial revascularisation. Lasers Surg Med 1986; 6: 459–61. 21 Vineberg A. Clinical and experimental studies in the treatment of coronary artery insuffiency by internal mammary artery implant. J Int Coll Surg 1954; 22: 503–18. 22 Yamamoto N, Kohmoto T, Gu A, DeRosa C, Smith CR, Burkhoff D. Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularisation. J Am Coll Cardiol 1998; 31: 1426–33. 23 Cooley DA, Frazier OH, Kadipasaoglu KA, et al. Transmyocardial revascularisation: clinical experience with twelve-month follow-up. J Thorac Cardiovasc Surg 1996; 111: 791–97. 24 Burns SM, Schofield PMS, Rosen SD, Rimaldi O, Wistow TE, Camici PG. Measurement of myocardial blood flow using positron emission tomography before and after transmyocardial revascularisation. J Am Coll Cardiol 1998; 31 (2 suppl A): 226A (abstr). 25 Clinical effectiveness: executive letter 105. London: Department of Health, 1995. 26 A first class service: quality in the new NHS. London: Department of Health, 1998.

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