RAMIT: Making sense of its findings and flaws
West and colleagues' recently published randomised controlled trial (RCT) exemplifies successful failure. Because and not despite of its null findings and flaws, RAMIT provides lessons for the future of prevention. Skeptics and proponents of traditional hospital-based cardiac rehabilitation (CR) should not use the study's findings or flaws to defend their respective positions but harness its failure constructively for innovation in designing more accessible and effective services.
Regarding doubts raised by the findings over the benefits of CR in the modern age, commendably and post-hoc, the study was powered to detect differences in mortality at 7-9years and in all likelihood risk factors at one-year. Yet, its failure to find benefits in these outcomes potentially points to the need for CR interventions to evolve from time-limited, exercise-focused programmes into more accessible and individually tailored ones. Such programmes could equally address all modifiable risk factors, as necessary, and include long-term follow-up with ongoing support.
While the RAMIT design was originally a large-scale RCT it was ultimately flawed because it was stopped early for unclear reasons having enrolled around 22% (n=1813) of the targeted sample size in approximately 3years. Also, over 20% of the intervention group dropped out and did not complete the rehabilitation programme and any contamination among controls is unclear. Such barriers are common amongst CR trials and clinical programmes and suggest that flexible programmes that overcome indifference, transport and work-related issues are important to pursue and develop.
RAMIT's findings also highlight the need for better description of the intervention. As CR programmes are complex interventions, CONSORT recommends they be described comprehensively with "precise details" of content. This not only improves trial quality but also uptake of evidence by clinicians. In RAMIT, specific content of the intervention for each risk factor and corresponding behaviour change techniques used are poorly described.
Finally, the benefits of trials should not be reduced to headline effects. Findings, whether positive or negative, can yield useful insights to improve interventions and methodology. A focus on increasing participation in evidence-based risk factor management strategies that are individualised and multidimensional will help researchers keep pace with advances in medical management.
References 1. West RR, Jones DA, Henderson AH. Rehabilitation after myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myocardial infarction. Heart 2012 (Published on December 22, 2011 as 10.1136/heartjnl-2011-300302). 2. Wood DA, Kotseva K, Connolly S, et al, on behalf of EUROACTION Study Group. Nurse-coordinated multidisciplinary, family-based cardiovascular disease prevention programme (EUROACTION) for patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster randomised controlled trial. Lancet 2008;371:1999-2012. 3. Redfern J, Maiorana A, Neubeck L, Clark AM, Briffa T. Achieving coordinated Secondary Prevention of coronary heart disease for All in Need (SPAN). Int J Cardiol 2011;146(1):1-3. 4. Clark AM, Redfern J, Thompson D, Briffa T. More data, better data or improved evidence translation: what will improve cardiovascular outcomes? Int J Cardiol 2012;155:347-349.
Conflict of Interest:
Is RAMIT reflecting the real world?
RAMIT explored the effect of a phase II outpatient-based cardiac rehabilitation (CR) concept. The authors reported no effect on mortality, cardiac or psychological morbidity, risk factors, health-related quality of life or physical activity of a comprehensive CR programme after myocardial infarction. However, to our opinion these findings cannot be generalized and merit an in-depth critical analysis. In many European countries a residential CR programme starts within weeks after myocardial infarction. After 3-4 weeks of intense residential CR (physical training ~ 3-4 hrs/week) patients are offered to participate in an outpatient CR programme for additional 8-12 weeks. The intensity of the physical activity is essential for the success of a CR programme. In the RAMIT trial the minimum CR duration was 10 hours, which included exercise as well as education and counseling. In fact, the mean CR duration was 20 hours within 6-8 weeks. This comprised approximately 10 hours of exercise training per patient. According to current recommendations an appropriate combination of endurance and resistance training seems crucial for effective CR. Hence, most guidelines recommend a minimum of 30 minutes of moderate exercise training per day at least five days per week. 1, 2 The lack of detailed information on resistance/endurance units and the well known dose-response relation of physical activity on cardiovascular risk reduction, rises the question whether the negative results of RAMIT may merely reflect an insufficient amount of physical exercise. 3 4 The somehow unexpected lower physical activity in the CR patients compared to the control group questions the motivational effect of physical activity counseling during CR. The benefit of regular exercise was shown in several trials and a recent meta-analysis showed a significant reduction in all cause-mortality.4 Moreover, the all-cause mortality in the RAMIT trial was 6% in the CR and 5.2% in the control arm, which seems rather high for this population compared to other trials. Myers et al. and Hammil et al. reported an average annual mortality rate of 2.6% and 2.2% for a comparable CR population, again with a dose-dependent response/behavior.4,5 Nonparticipants, however, showed similar mortality rates compared to RAMIT patients. A potential explanation for the high mortality despite CR participation may reflect a suboptimal medical therapy with lower adherence to statins or ACE inhibitors as compared to the EUROASPIRE III registry.6 Finally, the author?s conclusion with such potential clinical implication should not be based on an underpowered, although well-designed study, as the initial sample size calculation was 8000 patients with final inclusion of only 1813 patients in the randomised arm.
1. Smith SC, Jr., Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation 2011;124(22):2458- 73. 2. Piepoli MF, Corra U, Benzer W, Bjarnason-Wehrens B, Dendale P, Gaita D, et al. Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 2010;17(1):1-17. 3. Sattelmair J, Pertman J, Ding EL, Kohl HW, 3rd, Haskell W, Lee IM. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation 2011;124(7):789-95. 4. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. The New England journal of medicine 2002;346(11):793-801. 5. Hammill BG, Curtis LH, Schulman KA, Whellan DJ. Relationship between cardiac rehabilitation and long-term risks of death and myocardial infarction among elderly Medicare beneficiaries. Circulation 2010;121(1):63-70. 6. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009;373(9667):929-40.
Conflict of Interest:
The future of Cardiac Rehabilitation in the UK
The recent paper by West et al  was critiqued by the current cohort of students taking the MSc Preventive Cardiology at Imperial College London. The following opinions summarise the consensus reached in a group discussion.
Although all programmes included were reported to conform to contemporary 1995 BACR guidelines for phase three rehabilitation, these varied markedly, as highlighted by the variability in healthcare disciplines involved, and programme duration, described by the authors. Indeed, although the discipline of cardiac rehabilitation was founded in the late 1960's, the evolution of this model of care has varied widely, as demonstrated by the diversity of centres in this study. The heterogeneity of programme delivery in this trial therefore limits the conclusions that can be drawn about the value of cardiac rehabilitation compared to usual care. More recent guidelines from the BACR in 2007  define more stringent core competencies and a trial conducted today might provide a more valid assessment of comprehensive prevention and rehabilitation programmes.
The authors state that the required sample size was estimated at 8000 from power calculations for their primary endpoint of 2-year all-cause mortality. The final inclusion of 1817 participants means the trial was unable to answer this question. Centres that were unwilling to randomise patients were included as 'elective hospitals'. This sub-analysis of centres not participating in the trial is a non-randomised comparison, and therefore using these observational data in order to 'enlarge the sample size' is inappropriate. Given the small sample size it is not surprising that no significant reduction was demonstrated in the primary endpoint. Given the heterogeneity of these programmes, it is also unsurprising that no significant reductions were seen in one year outcomes for smoking, diet and medication adherence. However, a common theme to all programmes was the emphasis they placed on physical exercise. Therefore, it is surprising that despite exercise being the cornerstone of these programmes, physical activity levels were significantly lower in patients receiving cardiac rehabilitation.
Therefore the authors are right to question the value of cardiac rehabilitation, as delivered in this trial, compared to usual care. And the same question could be asked about cardiac rehabilitation programmes today and their ability to deliver all aspects of secondary prevention of cardiovascular disease.
1. West RR, Jones DA, Henderson AH. Rehabilitation after myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myocardial infarction. Heart. 2011 Dec 22. [Epub ahead of print]? 2. BACR. Standards and core components for cardiac rehabilitation 2007. Available at http://www.bcs.com/documents/affiliates/bacr/BACR%20Standards%202007.pdf
Rashid MA, Arefaine Abraha N, Bhatti N, Chinedu-Ezepue N, Dhomun G, Gill V, Nusrat M, Nwa-Amadi M, Paracha A, Pelina A, Sheikh M, Tornada A, Tueny M, Vedanthachari R, Lock C, Roszczynska A, Xuereb C.
Conflict of Interest:
West et al. Rehabilitation after myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myocardial infarction. Heart.2011 Dec 22. [Epub ahead of print]
Dear Professor Timmis,
We, members of the council of the British Association for Cardiovascular Prevention and Rehabilitation (BACPR), representing over 800 health professionals, strive to ensure that our guidance for cardiac rehabilitation (CR) programmes is based on best evidence. Whilst, the topic of the RAMIT study1 is a welcome one, we have significant concerns about this study and feel the authors have made judgements that we do not believe can be supported. Our concerns are outlined within this letter.
Firstly, in the opinion of West et al. the evidence for the effect of CR on mortality is out of date. However, the authors did not include the systematic review published last year by the Cochrane Heart Group2. The Cochrane review2, which included 47 studies with over 10,000 patients, clearly continues to demonstrate that CR reduces death from any cause by 13% and cardiac deaths by 26%. (The West et al. study does not report effect on cardiac deaths).
Secondly, there are substantial omissions from the paper in terms of the study population.The paper purports to follow CONSORT guidelines3 but it does not. We do not know how many programmes were approached to participate, thus we have no idea how representative the study sample was of CR programmes at that time. Additionally, there are no details about the numbers of participants who were approached and the numbers who refused (rather than did not meet the inclusion criteria). The numbers of people recruited per programme were small; 1813 people from 14 centres approximates to 130 people per hospital, over 32 months, so very small numbers per year, only half of which would receive CR. Therefore, we have no real idea of uptake of CR within the hospitals in the study, nor of numbers of people who refused to participate. If large numbers (of programmes and patients) refused to participate then this would mean that the study may not reflect the people who usually attended CR. We also have no idea of how many people in the study completed their full CR programme. Despite numerous requests to the primary author listed for access to the final full report we are yet to receive further details.
Thirdly, it should be noted that the study was carried out over 10 years ago and presents a very traditional viewpoint of CR, during an era associated with gross under-funding of CR in the UK4 and one which preceded the publication of the first BACR Minimum Standards and Core Components (2007)5. These extended the remit of CR programme beyond 'exercise, education and relaxation' and included smoking cessation, diet and weight management, medical risk factor management, cardioprotective therapies and much more. This publication does not adequately describe these programmes in any detail so we have no real idea of either their standard or their homogeneity (the programmes are reported to include exercise, education and relaxation but there are insufficient details of the format, frequency or intensity of the exercise, and most did not include stress management). Lastly, there are significant discrepancies in the study results when compared to the findings of the National Audit for Cardiac Rehabilitation (NACR). In the West et al. study, the people who attended CR were exercising less at 12 months than they had been at the start of the programme, but year on year the NACR consistently reports that patients are doing significantly more exercise 12 months after being referred to CR.6
In the conclusion to the abstract, West et al. state ""The value of cardiac rehabilitation as practised in the UK is open to question." It is of course entirely possible that this statement is true but only in reference to practice of CR at that time in those particular centres. Of course all evidence is open to question but these (very dated) study results about which we have considerable reservations should not be used as a basis for decision making regarding the contemporaneous worth of cardiac rehabilitation in the UK.
Jenni Jones (BACPR President, Physiotherapist) Professor Gill Furze (BACPR Scientific Chair, Nurse) Dr John Buckley (Immediate Past-President, Exercise Physiologist) Dr Linda Speck (Elected Council Member, Consultant Clinical Health Psychologist) Kathryn Carver (Elected Council Member, Nurse) Dr Susan Connolly (Elected Council Member, Consultant Cardiologist) Dr Iain Todd (Elected Council Member, Consultant in Cardiovascular Rehabilitation) Charlotte-Anne Wells (Elected Council Member, Occupational Therapist) Dr Joe Mills (Elected Council Member, Consultant Cardiologist) Jemima Traill (Elected Council Member, Nurse) Lucy Aphramor (Elected Council Member, Dietitian) Brian Begg (Elected Council Member, Exercise Specialist) Professor Patrick Doherty (Co-opted Council Member, Past-President BACR) Annie MacCallum (Co-opted Council Member, British Society for Heart Failure)
1. West RR, Jones DA, Henderson AH. Rehabilitation after myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myocardial infarction. Heart.2011 Dec 22. [Epub ahead of print]
2. Heran BS, Chen JM, Ebrahim S, Moxham T, Oldridge N, Rees K, Thompson DR, Taylor RS. Exercise-based cardiac rehabilitation for coronary heart disease.Cochrane Database Syst Rev. 2011 Jul 6;(7):CD001800.
3. Schulz, K. F., D. G. Altman, et al. "CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials." BMJ.2010;340: c332.
4. Brodie D, Bethell H, Breen S. Cardiac rehabilitation in England: a detailed national survey. Eur J Cardiovasc Pre v& Rehabil 2006;13:122- 8.
5. British Association for Cardiac Rehabilitation. Minimum standards and core components for cardiac rehabilitation. London, BACR 2007.
6. Lewin RJP, Petre C, Dale V, Onion N, Mortzou G. The National Audit of Cardiac Rehabilitation: Annual Statistical Report 2011. London, British Heart Foundation 2011. http://www.cardiacrehabilitation.org.uk/nacr
Conflict of Interest:
Exercise training as an essential component of cardiac rehabilitation.
We read with interest, but also great concern, the paper by West, et al.1 on their multi-centre randomized cardiac rehabilitation study, suggesting negligible results. This study was covered in the Belgian press and already led to questions about further reimbursement of such multi- disciplinary programs. We agree that re-evaluation of cardiac rehabilitation in the era of early revascularisation and thoroughly changed secondary prevention, is timely. However, this study does not involve a standard exercise training component. Patients only trained once a week or biweekly; this is nowhere near the general recommendations for physical activity in primary or secondary prevention. Intensity, modality and duration of training sessions are not described, and exercise testing pre and post rehabilitation to assess treatment effect is lacking. Also, significantly fewer patients were exercising after 1 year, suggesting exercise underdosage. We disagree with their presumption that improved secondary prevention precludes multi-disciplinary rehabilitation programs. The recently published EUROASPIRE III showed that cardiovascular prevention is still poorly implemented in daily practice. West et al. themselves reported a suboptimal preventive approach; only 54-62% of patients were taking a statin or beta-blocker at follow-up. The authors also failed to mention two recent studies demonstrating that cardiac rehabilitation led to a 45% reduction in long-term mortality in a registry of 2395 post-PCI patients.2 In a registry of 18809 patients with acute coronary syndrome, failure to comply with lifestyle and exercise recommendations was associated with an early almost 4-fold increased risk of adverse cardiovascular events.3 These patients were extremely well treated in terms of pharmacological prevention. The authors also concluded that cardiac rehabilitation had no effect on psychological morbidity or quality of life, but generic measures, such as the SF36, may have lacked sensitivity to detect actual changes in patient-reported outcomes. Previous work has shown that cardiac rehabilitation has a significant beneficial effect on psychological morbidity.4 To our opinion, the most important conclusion from this study is incorporated in the last line of the abstract; maybe it is time to re- think cardiac rehabilitation in the UK.
1. West RR, Jones DA, Henderson AH. Rehabilitation after myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myocardial infarction. Heart 2011; doi:10.1136/heartjnl-2011-300302 2. Goel K, Lennon RJ, Tilbury RT et al. Impact of cardiac rehabilitation on mortality and cardiovascular events after percutaneous coronary intervention in the community. Circulation 2011;123:2344-2352. 3. Chow CK, Jolly S, Rao-Melacini P et al. Association of diet, exercise, and smoking modification with risk of early cardiovascular events after acute coronary syndromes. Circulation 2010;121:750-758. 4. Denollet J, Brutsaert DL. Reducing emotional distress improves prognosis in coronary heart disease: 9-year mortality in a clinical trial of rehabilitation. Circulation 2001;104:2018-2023.
Conflict of Interest:
Register for free content
This recent issue is free to all users to allow everyone the opportunity to see the full scope and typical content of Heart.
View free sample issue >>
The full back archive is now available for Heart. Institutional subscribers may access the entire archive as part of their subscription. Personal subscribers will also have access to all content when logged in. Non-subscribers who register have free access to all articles published before 2006, back to volume 1 issue 1.
Register to access the free archive >>
Don't forget to sign up for content alerts so you keep up to date with all the articles as they are published.