Universidade Federal de Santa Catarina, Instituto de Cardiologia de Santa Catarina - Florianópolis, SC
Desde 1933, quando Wearn e cols.1 descreveram uma rede de sinusóides no coração humano, algumas formas de revascularização indireta do miocárdio foram propostas na tentativa de melhorar sintomas cardio-isquêmicos. Em 1935, Beck2 desenvolveu a cardio-omentopexia na qual o omento era suturado ao coração com o objetivo de aumentar sua perfusão. Em 1946, o cirurgião canadense Arthur Vineberg3 propôs o implante da artéria torácica interna diretamente sobre o miocárdio como forma de restabelecer o fluxo coronário em pacientes com angina. A ausência de resultados consistentes e o desenvolvimento das técnicas de revascularização coronária direta levaram ao progressivo abandono daquele procedimento. Em 1965, Sen e cols.4 propuseram a criação de canais transmurais na parede do ventrículo esquerdo para permitir a perfusão direta do miocárdio isquêmico com sangue oxigenado do VE. Este conceito se baseava no coração dos répteis, no qual o ventrículo esquerdo é diretamente perfundido por canais revestidos de endotélio que se irradiam da cavidade ventricular. Na década de 80, o conceito dos "sinusóides cardíacos" foi retomado e teve início a era da revascularização a laser5,6. Com o auxílio do
Atualmente há duas modalidades de revascularização a laser. A primeira é cirúrgica (TMLR-
Até o presente momento, foram publicados apenas 3 ensaios randomizados duplos-cego placebo-controlados com laser transmiocárdico, todos por via percutânea.
Stone e cols.9 avaliaram pacientes com angina refratária causada por uma ou mais oclusões totais de artérias coronárias nativas. Um total de 141 pacientes consecutivos com angina classes CCS (
Salem e cols.10 randomizaram 82 pacientes com angina graus CCS III e IV para PMLR ou procedimento placebo. Os dois grupos eram comparáveis quanto às suas características basais e foram excluídos casos de infarto agudo do miocárdio, insuficiência cardíaca, angina instável requerendo hospitalização nos 14 dias que precederam o procedimento, entre outros. O desfecho primário foi a melhora da classe de angina (CCS). Na avaliação de 6 e 12 meses após o procedimento, houve melhora significativa do grupo tratado com PMLR quando comparado ao grupo placebo
Leon e cols.11 realizaram ensaio randomizado duplo-cego e placebo-controlado com PMLR com 298 pacientes refratários à terapia usual com beta-bloqueador, antagonista do cálcio e nitrato. Eles foram randomizados para 3 grupos (laser placebo, dose baixa e dose alta de laser). O desfecho primário era a duração do teste ergométrico. Pacientes que receberam laser (dose baixa ou alta) tiveram mortalidade de 30 dias após o procedimento maior que o grupo placebo (p = 0,03). Aos seis meses, não houve diferença entre os 3 grupos na tolerância ao exercício. Da mesma forma, não houve melhora significativa de qualquer dos grupos quanto às classes CCS de angina. Também não houve mudanças na perfusão miocárdica medida pelo SPECT nuclear (repouso e
Existem 6 estudos randomizados controlados com terapia medicamentosa, sem grupos placebo e não-cegos publicados.
Frazier e cols.12 publicaram em 1999 os resultados de um estudo randomizado de 192 pacientes (91 tratados com TMLR e 101 com terapia medicamentosa), tendo como desfecho principal o grau de angina aferido pelo padrão CCS. Houve aferição aberta e cega que não mostraram diferenças entre si. Pacientes submetidos a TMLR tiveram escores de angina melhores quando comparados ao grupo de controle (67% vs 20%). Não houve diferença na mortalidade de 12 meses entre os grupos. Da mesma forma, os estudos de perfusão SPECT com
Allen e cols.14 (publicaram seus resultados simultaneamente ao estudo anterior. Foram randomizados 275 pacientes com angina refratária classe IV sem potencial para angioplastia ou cirurgia. Desses, 132 receberam TMLR e terapia medicamentosa, e 143 apenas terapia medicamentosa. Os parâmetros relacionados à classe da angina e tolerância ao exercício (esta, medida apenas em um terço dos indivíduos e não medida no início do estudo), assim como ao número de indivíduos considerados falhas terapêuticas foram melhores no grupo TMLR. A mortalidade não diferiu entre os grupos no seguimento de um ano. Entretanto, mais uma vez, os estudos de perfusão não mostraram diferença entre os grupos, colocando em cheque um dos mecanismos aventados para explicar os efeitos benéficos da terapia a laser. Também não se verificou melhora da função ventricular após o procedimento.
No editorial que acompanha os 2 estudos acima, Lange e Hills13 comentam que a TMLR não é isenta de riscos, e que nos estudos observacionais iniciais a mortalidade estava entre 10% e 20% e era maior nos indivíduos com fração de ejeção deprimida. Quando esses pacientes eram excluídos, a mortalidade reduzia-se a 5%. A morbidade perioperatória se encontra, nos diversos estudos, entre 32% e 68% (infarto não fatal, insuficiência cardíaca, arritmias, e infecções cirúrgicas e respiratórias). Os editorialistas também comentam que os custos do procedimento não são desprezíveis e finalizam em um tom de ceticismo quanto ao procedimento de revascularização com laser.
Schofield e cols.15 estudaram 188 indivíduos com angina refratária no Reino Unido. Estes foram avaliados aos 3, 6 e 12 meses na sua capacidade física com teste em esteira e com o teste de 12 minutos de caminhada. Não foi constatada diferença nesses parâmetros entre os grupos randomizados para TMLR e terapia medicamentosa. A mortalidade foi similar entre os grupos, mas os escores para angina foram melhores no grupo TMLR. Mais uma vez, os estudos de perfusão não mostraram diferença entre os grupos após 12 meses, o mesmo acontecendo com a fração de ejeção do VE. Os editorialistas que comentam a contradição destes resultados com os de outro estudo, dizem que no estudo de March 16 há inúmeros problemas na apresentação de dados importantes, que comprometem seriamente a interpretação dos achados. Finalizam dizendo que "relegar o laser apenas a um mero e caro procedimento analgésico arruína a maioria das expectativas daqueles que acreditavam em uma 'revascularização' pelo laser"17.
Burkhoff e cols18. foram os investigadores do estudo ATLANTIC (
O estudo PACIFIC (
Os estudos ATLANTIC e PACIFIC foram inteiramente financiados pela indústria que produz o equipamento laser utilizado. Os investigadores reconhecem que um dos problemas com ambos os estudos foi o não-cegamento dos investigadores e pacientes, o que introduz um importante viés de aferição, principalmente quando se lida com desfechos subjetivos. Além disso, comentam que o mecanismo da eventual melhora dos pacientes é ainda desconhecido e não negam que o efeito placebo possa explicar, em parte, os resultados.
Um estudo norueguês conduzido por Aaberge e cols.20 randomizou 100 pacientes para terapia médica ou TMLR usando como desfecho primário os sintomas, a capacidade física e o consumo máximo de oxigênio aferidos pelo teste ergométrico. Embora os escores para angina tenham sido melhores no grupo TMLR em relação ao grupo tratado clinicamente, os parâmetros objetivos de capacidade física, como tempo de esteira e consumo máximo de oxigênio, não diferiram entre os grupos. A morbidade e mortalidade após 12 meses foi semelhante nos 2 grupos. Não se observou modificação na fração de ejeção após um ano do procedimento. Os autores comentam que o "tratamento cardíaco a laser" (refutando o termo 'revascularização transmiocárdica') pode funcionar na redução dos sintomas mas "não há evidência convincente de que ele melhore a função cardíaca ou reduza o número de eventos isquêmicos". Reconhecem que, para que se avalie o papel do "efeito placebo" sobre os resultados do procedimento são fundamentais os estudos duplos-cegos, placebo-controlados com PMLR.
Uma meta-análise de Liao e cols.21 incluiu 7 ensaios randomizados concluídos até 2003. Eram estudos randomizados abertos e sem controle com placebo. O grupo de controle era, usualmente, constituído por pacientes em uso da terapia convencional para angina. As conclusões da meta-análise são de que não há diferença na mortalidade entre os grupos com tratamento a laser e aqueles com tratamento-padrão. O grupo tratado com laser mostrou redução dos sintomas (
Estudos observacionais não são metodologicamente adequados para estudar a eficácia de intervenções na prática clínica. Em uma recente revisão sobre revascularização a laser no tratamento da coronariopatia refratária22, as várias séries de casos não controlados e não randomizados mostravam, de um modo geral, melhora sintomática e, em poucos estudos, melhora da capacidade física medida pelo tempo de exercício. Entretanto, não havia comprovação objetiva de melhora da perfusão miocárdica com os métodos de imagem utilizados. Como já é conhecido o fenômeno da maior presença de "estudos positivos" nos registros e séries de casos, essas conclusões não devem servir de norte para o uso de intervenções, mas apenas como geradoras de hipóteses a serem testadas em ensaios randomizados. Nesta revisão, os autores concluem que "os resultados dos recentes estudos duplos-cegos são conflitantes, sugerindo um efeito placebo significativo na resposta ao PMLR. Recomenda-se a realização de ensaios clínicos maiores para examinar o valor dessa técnica".
A diretriz brasileira de doença coronariana crônica23 recomenda a TMLR como classe IIb-B (
Toda pesquisa científica pode ser invalidada por erros sistemáticos chamados vieses. No caso do laser na angina refratária, as fontes de vieses começam pela avaliação da angina. Por se tratar de um sintoma, sua avaliação objetiva e precisa não é possível. Os 3 estudos randomizados9-11 e cegos publicados até o momento não evidenciaram diferenças no tempo de exercício e na perfusão após o procedimento a laser quando comparados aos resultados do grupo de controle. Apenas um desses estudos10, com uma amostra pequena, evidenciou melhora dos sintomas 6 meses após o procedimento. Essas discrepâncias têm sido explicadas por diferenças técnicas na aplicação do laser26,27. Entretanto, é possível que as diferenças observadas entre estudos não-cegos e sem controle com placebo e aqueles randomizados, cegos e com placebo se deva a diferenças na metodologia do estudo mais que às questões técnicas do procedimento.
Em estudos clínicos, médicos e pacientes sempre têm expectativas quanto aos resultados do procedimento a ser avaliado. Pacientes altamente motivados e desesperados por uma nova forma de tratamento que alivie seus sintomas, naturalmente esperam por benefício clínico. A palavra "laser" está associada, no imaginário dos pacientes, e também no dos médicos, a uma tecnologia de ponta e de alta eficácia usada como "último recurso"28 no tratamento da angina. Portanto, há uma grande chance de que os sintomas sejam avaliados de forma distorcida, já que "se espera" que o laser produza um efeito positivo. Sabe-se, também que há uma relação direta entre o grau de
O controle do viés de aferição é feito pelo duplo mascaramento (investigador e paciente) ou duplo-cego. O uso de placebo em estudos de intervenções novas é uma necessidade para definir sobre a sua utilidade ou futilidade. Até os mais recentes estudos com laser placebo, a terapia com laser na angina do peito era comparada com a terapia convencional medicamentosa. No caso da intervenção a laser transmiocárdica cirúrgica, o mascaramento era impraticável e os resultados eram, assim, enfraquecidos por vieses potenciais. No caso do laser percutâneo na angina, a comparação com placebo, embora metodologicamente mais complexa, é factível9-11. No mais recente estudo randomizado que se publicou, comparando laser em duas "doses" e placebo laser11, este grupo apresentou melhora de 30% nos sintomas e no tempo de exercício após o procedimento, resultado que não diferiu dos grupos que receberam o laser.
O efeito placebo nas doenças cardiovasculares já tem sido descrito em várias situações, incluindo na angina30. Estima-se que a melhora dos sintomas em pacientes com angina crônica de esforço estável pode ser atingida, com placebo, em 30% a 80% dos casos30. Procedimentos invasivos e cirúrgicos têm um grande potencial de efeito placebo31. O exemplo clássico de efeito placebo na cirurgia cardiovascular fica por conta da técnica de ligadura da artéria mamária interna no tratamento da angina. Esse procedimento foi proposto na década de 50 e usado rotineiramente até que um estudo randomizado32 usando um grupo de controle (fazia-se a incisão torácica sem ligar a artéria) mostrou que não havia diferença entre os grupos quanto à melhora dos sintomas. Ou seja, o mero ato de seccionar a pele do tórax foi capaz de mostrar benefícios subjetivos.
Nesta revisão procuramos sintetizar a experiência clínico-científica do uso da terapia a laser no tratamento da angina do peito refratária. Estudos observacionais e randomizados preliminares mostravam resultados positivos desta terapia. Entretanto, estudos randomizados e placebo-controlados e, portanto, metodologicamente mais robustos, apontam fortemente para a possibilidade da existência de efeito placebo da terapia a laser na angina refratária.
1. Wearn JT, Mettier SR, Klumpp TG, Zschiesche LJ. The nature of vascular communications between the coronary arteries and the chambers of the heart. Am Heart J. 1933; 9: 143-64.
2. Beck C. The development of a new blood supply to the heart by operation. Ann Surg. 1935; 102: 801-13.
3. Vineberg A. Development of anastomosis between coronary vessels and transplanted internal mammary artery. Can Med Assoc J. 1946; 55: 17-9.
4. Sen PK, Udwadia TE, Kinare SG, Parulkar GB. Transmyocardial acunpuncture: a new approach to myocardial revascularization. J Thorac Cardiovasc Surg. 1965; 50:181-9.
5. Mirhoseini M, Cayton MM. Revascularization of the heart by laser. J Microsurg. 1981; 2: 253-60.
6. Mirhoseini M, Muckerheide M, Cayton MM. Transventricular revascularization by laser. Lasers Surg Med. 1982; 2: 187-98.
7. Kim MC, Kini A, Sharma SK. Refractory angina pectoris: mechanism and therapeutic options. J Am Coll Cardiol. 2002; 39: 923-34.
8. Peterson ED, Kaul P, Kaczmarek RG, Hammill BG, Armstrong PW, Bridges CR, et al. From controlled trials to clinical practice: monitoring transmyocardial revascularization use and outcomes. J Am Coll Cardiol. 2003; 42: 1611-6.
9. Stone GW, Teirstein PS, Rubenstein R, Schmidt D, Whitlow PL, Kosinski EJ, et al. A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiol. 2002; 39: 1581-7.
10. Salem M, Rotevatn S, Stavnes S, Brekke M, Vollset SE, Nordrehaug JE. Usefulness and safety of percutaneous myocardial laser revascularization for refractory angina pectoris. Am J Cardiol. 2004; 93: 1086-91.
11. Leon MB, Kornowski R, Downey WE, Weisz G, Baim DS, Bonow RO, et al. A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol. 2005; 46: 1812-9.
12. Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med. 1999; 341: 1021-8.
13. Lange RA, Hillis LD. Transmyocardial laser revascularization. N Engl J Med. 1999; 341: 1075-6.
14. Allen KB, Dowling RD, Fudge TL, Schoettle GP, Selinger SL, Gangahar DM, et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med. 1999; 341: 1029-36.
15. Schofield PM, Sharples LD, Caine N, Burns S, Tait S, Wistow T, et al. Transmyocardial laser revascularization in patients with refractory angina: a randomised controlled trial. Lancet. 1999; 353: 519-24.
16. March RJ. Transmyocardial laser revascularization with the CO2 laser: one year results of a randomized, controlled trial. Semin Thorac Cardiovasc Surg. 1999; 11: 12-8.
17. Pretre R, Turina MI. Laser to the heart: magic but costly, or only costly? Lancet. 1999; 353: 512-3.
18. Burkhoff D, Schmidt S, Schulman SP, Myers J, Resar J, Becker LC, et al. Transmyocardial laser revascularization compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. ATLANTIC Investigators. Angina Treatments-Lasers and Normal Therapies in Comparison. Lancet. 1999; 354: 885-90.
19. Oesterle SN, Sanborn TA, Ali N, Resar J, Ramee SR, Heuser R, et al. Percutaneous transmyocardial laser revascularization for severe angina: the PACIFIC randomised trial. Potential Class Improvement From Intramyocardial Channels. Lancet. 2000; 356: 1705-10.
20. Aaberge L, Nordstrand K, Dragsund M, Saatvedt K, Endresen K, Golf S, et al. Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris. Clinical results from the Norwegian randomized trial. J Am Coll Cardiol. 2000; 35: 1170-7.
21. Liao L, Sarria-Santamera A, Matchar DB, Huntington A, Lin S, Whellan DJ, et al. Meta-analysis of survival and relief of angina pectoris after transmyocardial revascularization. Am J Cardiol. 2005; 95: 1243-5.
22. Saririan M, Eisenberg MJ. Myocardial laser revascularization for the treatment of end-stage coronary artery disease. J Am Coll Cardiol. 2003; 41: 173-83.
23. Diretrizes de doença coronariana crônica: angina estável. Arq Bras Cardiol. 2004; 83 (Supl 2): 37-8.
24. Oliveira SA, Dallan LA, Lisboa LA, Chavantes MC, César LA, Pardi MJ, et al. Revascularização transmiocárdica com laser de CO2: experiência clínica inicial. Arq Bras Cardiol. 1999; 72: 441- 50.
25. Modest GA. Guidelines for the management of patients with chronic stable angina. Ann Intern Med. 2002; 137: 548-9; author reply 548-9.
26. Mouli SK, Fronza J, Greene R, Robert ES, Horvath KA. What is the optimal channel density for transmyocardial laser revascularization? Ann Thorac Surg. 2004; 78:1326-31; discussion 1326-31.
27. Hamawy AH, Lee LY, Samy SA, Polce DR, Szulc M, Vazquez M, et al. Transmyocardial laser revascularization dose response: enhanced perfusion in a porcine ischemia model as a function of channel density. Ann Thorac Surg. 2001; 72: 817-22.
28. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol. 2000; 53: 786-92.
29. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001; 344: 1594-602.
30. Bienenfeld L, Frishman W, Glasser SP. The placebo effect in cardiovascular disease. Am Heart J. 1996; 132: 1207-21.
31. Johnson AG. Surgery as a placebo. Lancet 1994; 344: 1140-2.
32. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol. 1960; 5: 483-6.
Mário Sérgio Soares de Azeredo Coutinho R. Dr. Percy João de Borba, 129 88036-200 – Florianópolis, SC E-mail:
Artigo recebido em 28/03/06; revisado recebido em 01/05/06; aceito em 18/05/06.
Universidade Federal de Santa Catarina, Instituto de Cardiologia de Santa Catarina - Florianópolis, SC, Brazil
Since 1933, when Wearn et al1 described a sinusoidal network in the human heart, some forms of indirect myocardial revascularization have been proposed in an attempt to improve cardioischemic symptoms. In 1935, Beck2 developed the cardio-omentopexy, in which the omentum was sutured to the heart with the objective of increasing its perfusion. In 1946, Arthur Vineber3, a Canadian surgeon, proposed the direct implantation of the internal thoracic artery on the myocardium as a form of reestablishing the coronary flow in patients with angina. Due to inconsistent results and the development of direct coronary artery revascularization techniques this procedure was gradually abandoned. In 1965, Sen et al4 proposed the creation of transmural channels in the left ventricular wall to enable the direct perfusion of the ischemic myocardium with oxygenated blood from the LV. This concept was based on reptilian hearts, in which the left ventricle is directly perfused by endothelium-lined channels radiating from the ventricular cavity. In the 1980's, the "cardiac sinusoids" concept was resumed and the laser revascularization era began5,6. Using carbon dioxide or Holmium
Currently, two modalities of laser revascularization are available. The first is surgical (TMLR – transmyocardial laser revascularization), via a small lateral thoracotomy through which laser perforations are performed; the second is performed percutaneously (PMLR – percutaneous myocardial laser revascularization). The laser catheter is advanced up to the left ventricle and the perforations are performed from the endocardium toward the epicardium. The first method was approved by the FDA in 1998, and the second is still considered experimental. The FDA did not approve the concomitant use of laser with revascularization, although in a recent record 67% of the procedures were associated with myocardial revascularization surgery8.
To date, only three randomized double-blind placebo-controlled trials with transmyocardial laser, all percutaneous, have been published.
Stone et al9 evaluated patients with refractory angina caused by one or more total occlusions of native coronary arteries. A total of 141 consecutive patients with CCS (Canadian Cardiovascular Society) class III-IV angina and complete coronary artery obstructions – in which percutaneous balloon intervention failed – were randomized at 17 medical centers to PMLR plus maximum medical therapy (MMT) or MMT only. Patient blinding was achieved through sedation and dark goggles. Assessment of endpoints in the follow-up period was made without awareness of the treatment used. Patients with LVEF<30%, MI in the past three months, inability to perform an exercise test, among other criteria, were excluded. The primary endpoint was improvement in the exercise test duration. PMLR was performed using Holmium laser with fluoroscopic guidance. The exercise test duration was assessed in only half of the patients six months after the procedure and did not show any difference between the groups. Anginal symptoms after six months were also similar between the groups. No differences were observed as regards clinical events, including mortality and MI, although a higher tendency of events in the laser group was observed (cardiac tamponade, pericardial effusion, ventricular tachycardia / fibrillation, cardiac marker elevation).
Salem et al10 randomized 82 patients with CCS III and IV angina to PMLR or placebo procedure. The two groups were comparable as regards their baseline characteristics, and patients with myocardial infarction, heart failure, unstable angina requiring hospitalization within 14 days prior to the procedure, and others, were excluded. The primary endpoint was improvement of angina class (CCS). In the six and 12-month post-procedure assessment, a significant improvement of the group treated with PMLR in comparison with the placebo group was observed. However, in the objective measurements of exercise tolerance (treadmill time, respiratory exchange rate, and oxygen consumption), the two groups showed similar results. No changes in ejection fraction were observed after 12 months of follow-up, and the event-free survival showed to be similar in the two groups by the end of one year.
Leon et al11 conducted a randomized double-blind placebo-controlled trial with PMLR in 298 patients refractory to the usual therapy with beta-blocker, calcium antagonist and nitrate. They were randomly assigned to three groups (laser-placebo, low-dose, and high- dose laser). The primary endpoint was exercise test duration. Patients who received laser (low or high dose) had a 30-day mortality higher than the placebo group (p=0.03). At six months, no difference was observed between the three groups as regards exercise tolerance. Likewise, no significant improvement was observed in any of the groups as regards CCS angina class. No changes in myocardial perfusion as measured by nuclear SPECT (rest and stress) performed 6 months after the procedure were observed either. The authors conclude that "all other randomized studies on this subject should be analyzed with caution and skepticism, unless appropriate attention is given to the placebo-effect of experimental laser therapies".
Six other randomized open-label medical-treatment controlled trials without placebo control were published.
In 1999, Frazier et al12 published the results of a randomized study of 192 patients (91 treated with TMLR and 101 with medical therapy), where the primary endpoint was severity of angina according to the CCS classification. Open and blind assessments were performed and no difference was observed between them. Patients undergoing TMLR had better angina scores when compared with the control group (67% vs. 20%). No difference was observed in the 12-month mortality between the groups. Likewise, no difference was observed between the groups of pharmacologic-stress perfusion SPECT studies at any moment of the follow-up, that is, no objective evidence of perfusion improvement was demonstrated with the procedure. Of the 101 patients randomized for medical therapy, 60 (59%) eventually underwent TMLR, which, to a certain extent, distorted the results, since randomization was disregarded. The investigators acknowledge this study limitation and argue that the patients were offered the cross-over to TMLR as an encouragement to remain in the study. This shows that there was a bias on the part of the investigators who took a pro-TMLR attitude. In the face of these flaws, this study was heavily criticized in its respective editorial13.
Allen et al14 published their results concomitantly with Frazier's study. A total of 275 patients with class IV refractory angina with no potential for angioplasty or surgery were randomized. One hundred and thirty two received TMLR plus medical therapy and 143 received only medical therapy. Parameters related to angina class and tolerance to exercise (the latter measured only in one third of the individuals and not measured in the study baseline), as well as the number of individuals considered as therapeutic failures were better in the TMLR group. No difference in mortality was observed between the groups in the 1-year follow-up. However, once again, perfusion studies did not show any differences between the groups, raising doubts about one of the mechanisms proposed to explain the beneficial effects of laser therapy. Also, no improvement in ventricular function after the procedure was verified .
In the editorial that accompanies the two studies described above, Lange and Hills13 mention that TMLR is not risk-free and that in early observational studies mortality was between 10% and 20% and was higher among individuals with depressed ejection fraction. When these patients were excluded, mortality dropped to 5%. Perioperative morbidity is between 32% and 68% in different studies (non-fatal infarction, heart failure, arrhythmias, and surgical and respiratory infections). The editorialists also mention that procedural costs are not negligible and conclude their comments in a skeptical tone as regards the laser revascularization procedure.
Schofield et al15 studied 188 individuals with refractory angina in the United Kingdom. They were assessed at 3, 6 and 12 months as to their physical ability in the treadmill test and 12-minute walking test. No difference in these parameters was demonstrated between the groups randomly assigned to TMLR and medical therapy. Mortality was similar between the groups, but angina scores were better in the TMLR group. Once again, perfusion studies did not show any difference between the groups after 12 months, and the same occurred with the LV ejection fraction. The editorialists mention the inconsistency between these results and those of another study, saying that in March et al's study16 countless problems occur regarding the presentation of key data, which seriously affects the interpretation of the findings. They conclude saying that "relegating laser to a mere and costly analgesic procedure ruins most of the expectations of those who believed in a laser 'revascularization'"17.
Burkhoff et al were the investigators in the ATLANTIC study (Angina Treatments-Lasers and Normal Therapies in Comparison)18. They recruited 182 patients from 16 centers in the USA with CCS III-IV angina, reversible ischemia, and incomplete response to other therapies. The patients were randomly assigned to TMLR (n=92) or medications (n=90). After 12 months a significant increase in exercise tolerance, as well as in angina scores, was observed in the TMLR group. Perfusion studies and LV ejection fraction did not show significant modifications at 3, 6, and 12 months post-procedure in both groups.
The PACIFIC study (Potential Angina Class Improvement From Transmyocardial Channels)19 randomly assigned 221 class III-IV patients with poor response to medication to Holmium laser TMLR plus medication or medication only. The primary endpoint was exercise tolerance at 12 months. The results showed an 89-second increase in exercise tolerance when compared with the 12.5-second increase in the TMLR and medication groups (p=0,008), respectively.
The PACIFIC and ATLANTIC studies were fully sponsored by the manufacturer of the laser equipment used. The investigators acknowledge that one of the problems with both studies was the non-blinding of the investigators and patients, which introduces an important assessment bias, mainly when dealing with subjective endpoints. Additionally, they mention that the mechanism of the occasional improvement of patients remains unknown, and they do not deny that the placebo effect may explain the results to a certain extent.
A Norwegian study conducted by Aaberge et al20 randomly assigned 100 patients to medical therapy or TMLR using symptoms, physical ability and maximum oxygen consumption as measured by the exercise test as the primary endpoint. Although angina scores were better in the TMLR group in relation to the group medically treated, the objective parameters of physical ability such as treadmill time and maximum oxygen consumption were not different between the groups. Morbidity and mortality after one year was similar between the two groups. No change in the ejection fraction was observed one year after the procedure. The authors mention that "cardiac laser treatment" (rejecting the term 'transmyocardial revascularization') may work in the reduction of symptoms but "there is no convincing evidence that it improves cardiac function or reduces the number of ischemic events". They acknowledge that double-blind, placebo-controlled studies with PMLR are essential to assess the role of the "placebo effect" in the results of the procedure.
A meta-analysis by Liao et al21 included seven randomized trials completed up to 2003. They were all randomized open-label non-placebo-controlled studies. Control groups were usually comprised of patients using conventional therapy for angina. The meta-analysis concludes that there are no differences in mortality between the groups with laser treatment and those with standard treatment. The group treated with laser showed a reduction of symptoms (
Observational studies are not methodologically adequate to study the efficacy of interventions in the clinical practice. In a recent review on laser revascularization in the treatment of refractory coronary artery disease22, the several non-randomized non-controlled case series showed an overall improvement of symptoms and, in a few studies, showed an improvement of the physical ability as measured by exercise time. However, there was no objective confirmation of improvement of myocardial perfusion with the imaging methods used. Since the phenomenon of a greater number of "positive studies" in the records and case series is already known, these conclusions should not be used as guidelines for the adoption of interventions, but only as generators of hypotheses to be tested in randomized trials. In this review, the authors conclude that "the results of recent double-blind studies are conflicting, suggesting a significant placebo effect in response to PMLR. Further larger clinical trials are recommended to elucidate the value of this technique".
The Brazilian Guideline of Chronic Coronary Artery Disease23 recommends TMLR as class IIb-B (acceptable reasonable evidence, considered alternative treatment, based on small randomized studies, and non-randomized and observational studies), acknowledging the lack of consensus regarding its indications and its real efficacy. The study with 40 patients of the
Any scientific research may be invalidated by systematic errors called biases. In the case of laser in refractory angina, the sources of biases start with the assessment of angina. Since angina is a symptom, it is impossible to assess it objectively and precisely. The three randomized blind studies9-11 published to date did not show any differences in exercise time and in perfusion after laser procedure when compared with controls. Only one of these studies10 with a small sample showed improvement of symptoms six months after the procedure. These discrepancies have been explained by technical differences in laser application26,27. However, differences observed between non-blind non-placebo-controlled studies and randomized blind placebo-controlled studies may be possibly attributed to differences in the study methodology more than to technical issues related to the procedure.
In clinical studies, physicians and patients always have expectations regarding the results of the procedure being evaluated. Highly motivated patients eager for a new treatment modality able to relieve their symptoms naturally expect a clinical benefit. The word "laser" is associated with – in the patients imagination, as well as in the physicians' - a highly efficient state-of-the-art technology as a "last resource"28 in the treatment of angina. Therefore, symptoms will very likely be evaluated in a distorted manner, since laser is "expected" to produce a positive effect. A direct relation between the degree of stress and the placebo effect is also known to occur, especially if the endpoint assessed is pain29.
The control of assessment bias is achieved using double masking (investigator and patient) or double blinding. The use of placebo in studies on new interventions is a must to define usefulness or futility. Until the most recent studies with placebo-laser, laser therapy in angina pectoris was compared with the standard medical therapy. In the case of surgical transmyocardial laser intervention, blinding was unfeasible, thus results were weakened by potential biases. In the case of percutaneous laser in angina, the comparison with placebo is feasible, although methodologically more complex9-11. In the most recent randomized study published comparing laser at two "doses" and placebo-laser11, the latter group showed a 30% improvement in the symptoms and in exercise time after the procedure, a result that was not different from that of the groups that received laser.
The placebo effect in cardiovascular diseases has already been described in several situations, including angina30. Improvement of symptoms in patients with stable chronic effort angina is estimated to be possibly achieved with placebo in 30%-80% of the cases30. Invasive and surgical procedures have great potential for a placebo effect31. The classical example of placebo effect in cardiovascular surgery is credited to the internal mammary artery ligation procedure in the treatment of angina. This procedure was proposed in the 1950's and was routinely used until a randomized study32 with a control group (thoracic incision was performed without artery ligation) showed that there was no difference between the groups regarding the improvement of symptoms. That is, the simple act of sectioning the skin on the chest was able to provide subjective benefits.
In this review, we sought to synthesize the clinical and scientific experience on the use of laser therapy in the treatment of refractory angina pectoris. Preliminary randomized observational studies showed positive results with this therapy. However, randomized placebo-controlled, which are, therefore, methodologically stronger studies, highly suggest the possibility of occurrence of a placebo effect of laser therapy in refractory angina.
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Mário Sérgio Soares de Azeredo Coutinho R. Dr. Percy João de Borba, 129 88036-200 – Florianópolis, SC, Brazil E-mail:
Manuscript received March 28, 2006; revised Manuscript received May 1, 2006; accepted May 18, 2006.
20. Aaberge L, Nordstrand K, Dragsund M, Saatvedt K, Endresen K, Golf S, et al. Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris. Clinical results from the Norwegian randomized trial. J Am Coll Cardiol. 2000; 35: 1170-7.