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Cardiovascular registries: a novel platform for randomised clinical trials
  1. Stefan James1,
  2. Ole Fröbert2,
  3. Bo Lagerqvist1
  1. 1Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  2. 2Örebro University Hospital, Örebro, Sweden
  1. Correspondence to Dr Stefan James, Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; stefan.james{at}akademiska.se

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Registries in cardiovascular medicine in general, and within interventional cardiology in particular, have gained more attention in medical journals over the past few years. By consecutive enrolment of complete patient populations, the methodology is a powerful tool for describing healthcare, including the complications and benefits of different therapies. However, it is very important to be cautious in the interpretation of the comparison of outcomes between different treatment alternatives in observational studies and always consider them non-definitive and hypothesis generating. In order to avoid selection bias, randomisation of patients may be included within a clinical registry, combining some of the most important features of a prospective randomised trial with the key strengths of a large scale clinical registry. Thereby prospective use of quality registries could potentially revolutionise clinical trials by the fast inclusion of large patient numbers, focus on hard endpoints and complete follow-up, and at a fraction of the costs of today's randomised controlled trials.

Good clinical practice should be based on sound evidence derived from well-conducted studies. The highest levels of scientific clinical evidence stem from prospective randomised clinical trials. The European Society of Cardiology and other guideline committees and authorities generally require more than one adequate prospective randomised study for giving the procedure the highest class of recommendation reflecting the need for independent confirmation of experimental results. A single clinical experimental finding of efficacy, unsupported by other independent evidence, is not considered adequate scientific support for a definitive conclusion of efficacy. In the medical field and particularly within cardiology, an increasing number of pharmaceutical agents, medical devices and clinical procedures are tested in appropriately designed prospective randomised trials. Despite this, only about half the recommendations given in international guidelines are class one recommendations based on prospective randomised trials,1 and a large proportion of recommendations are based on expert opinion only without support from any appropriate randomised clinical trials. Thus, there is a continuous need for prospective randomised studies based on patient-related outcomes that are important to medical care.

Despite the high scientific methodological standards of randomised trials, their clinical applicability is often limited by including selected populations through narrow inclusion criteria and multiple exclusion criteria. Furthermore, they are expensive and cumbersome to perform. Economic revenue is typically the primary incentive to inaugurate such trials on the part of commercial interests. It cannot be expected that this model of primarily industry-supported clinical trials can address many of the important clinical strategies or issues with the evaluation of medical devices, clinical strategies and pharmacological therapies. In times of economic restraints, individual physicians and consortia of academic representatives may experience difficulties in finding sufficient financial resources for conducting large investigator-initiated and investigator-driven prospective randomised trials. Furthermore, the requirements for documentation in randomised clinical trials developed to protect patient anonymity, ensure high data standard and reproducibility, and impede realisation of relevant trials because of the associated cost and complexity. A catch-22 situation may therefore develop. In order to protect scientific standards and eventually patient interests, several relevant clinical problems are not addressed and thus evidence is never established.

By contrast, observational registry studies are inexpensive and relatively simple to perform and more often reflect the true clinical situation. Therefore, results from surveys and registries provide valuable complementary data to prospective randomised trials and are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines. They are thus completing the loop between clinical research, writing of guidelines and implementing them in clinical practice.

Retrospective analyses of prospectively collected data are ideally used for descriptive studies, and for outcome analyses for a given therapy, but have limited value for comparisons between therapeutic options. A clinician always chooses a specific treatment alternative for a specific reason resulting in a high degree of selection. This selection bias makes direct comparisons of different therapeutic options challenging and often impossible. Despite appropriate statistical methodologies to adjust for differences in baseline characteristics there are always known and/or hidden confounders that cannot be completely compensated for. Therefore, it is important to be cautious in the interpretation of observational studies comparing outcomes between different treatment alternatives and to always consider the results as non-definitive and hypothesis-generating. However, for various reasons in many areas of medicine, randomised trials are highly unlikely to be performed. For these patient subsets and clinical scenarios, observational studies provide the second best and often the only available alternative to evaluate outcome.

However, by including a randomisation module in a clinical quality registry, it is possible to combine some of the finest attributes of a prospective randomised trial (box 1) with the best features of a large-scale clinical registry (box 2) including the key strength of unselected consecutive enrolment. Such a trial has been described as a prospective randomised clinical registry trial by way of analogy with a prospective randomised clinical trial (box 3). This concept is currently developed within the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) in which manual thrombus aspiration as adjunctive treatment for primary percutaneous coronary intervention (PCI) is being tested prospectively in a large number of patients adequately powered for the evaluation of mortality as the primary endpoint.2 The Danish stent trials (SORT OUT) have also successfully used national registries as the base for performing very important clinical trials. Also in the Cath/PCI Registry of the National Cardiovascular Data Registry (NCDR, http://www.ncdr.com) in the USA, this concept is under development for the evaluation of a radial versus femoral access for PCI in women.

Box 1

Pros and cons of randomised clinical trials

Randomised clinical trials

Strengths
  • Gold standard for comparative clinical trials.

  • Extinguishes baseline differences between the groups.

  • High data quality with appropriate monitoring.

  • Adjudication of events.

Weaknesses
  • Expensive.

  • Long time to plan and complete.

  • Highly selected populations.

  • Often selected study centres.

  • Often surrogate endpoints (late lumen loss, target lesion revascularisation versus angina, myocardial infarction).

  • Often sponsored by industry–only studies with economic interest will be performed.

Box 2

Pros and cons of observational studies from registries

Observational registry studies

Strengths
  • Clinically important hard and endpoints possible.

  • Large cohorts allow collection of infrequent events.

  • Unselected populations of consecutive patients—generalisable to all patients.

  • Quick enrolment.

  • Inexpensive.

Weaknesses
  • Confounding factors impossible to adjust for despite complex statistical models.

  • Data quality not as good.

  • Missing variables—not desirable selection.

  • Limited monitoring.

  • Advanced statistics with multivariable analyses–difficult to understand.

Box 3

Pros and cons of randomised clinical registry trials

Randomised clinical registry studies

Strengths
  • Extinguishes baseline differences between the groups.

  • Clinically important endpoints—hard endpoints possible.

  • Large cohorts of consecutive patients allow collection of infrequent events.

  • Unselected populations—generalisable to all patients.

  • Quick enrolment.

  • Inexpensive.

  • Large cohorts of consecutive patients allow collection of infrequent events.

Weaknesses
  • Data quality not as good.

  • Missing variables—not desirable selection.

  • Less complete monitoring.

  • Less opportunity for mechanistic substudies and follow-up on softer endpoints.

The Swedish SCAAR registry is nationwide and 100% complete in terms of patient enrolment. Every patient undergoing coronary angiography or angioplasty in Sweden can be found in the database. In 2010, SCAAR was merged with the Swedish coronary care unit registry (RIKS-HIA), the thoracic surgery registry, the Transcatheter AorticValve Implantation registry and the secondary prevention registry into a nationwide registry called the SWEDEHEART.3 ,4 All data in SWEDEHEART are collected in a common web-based entry page, and follow-up is automatically merged with other national databases. Data in SCAAR are entered by the interventional cardiologist to the web page directly in the cath lab forming a cath report that is part of the clinical files. In the TASTE trial, the extra work associated with inclusion of each patient is minimal and restricted to activating a minute randomisation module within the database. Clinical endpoint parameters are obtained from continuous national health registries. No study-specific clinical follow-up is therefore needed. Mandatory variables and automated data checks for inconsistencies will limit missing values and incorrect reporting.

Collection of long-term outcome is, of course, of great importance and in order to make the collection automated it is crucial to have an automated linkage to national mortality and diagnosis registries or claims databases. Variables of importance in the field of interventional cardiology are repeat revascularisation procedures, recurrent myocardial infarction, restenosis, stent thrombosis and bleeding complications. In a modern world with patients moving between different healthcare providers and regions or countries this may become especially challenging. In order to collect complete information, the quality registry needs to cover large geographical areas, preferably national or international.

The concept of a trial design using a national registry as the basis for continuous enrolment and randomisation of all-comers is potentially limited by the lack of formal central adjudication of clinical events. Therefore, a hard reliable endpoint, such as all-cause mortality derived from the national complete mortality registry, is preferred as the primary endpoint. Secondary endpoints such as bleeding events, complications and re-hospitalisation for ischemia or heart failure (need to be investigator reported and collected from the registry) are useful but may be subject to bias. These events may also suffer from a lower overall quality. Other softer non-adjudicated endpoints may be of limited value. Missing values of important data and outcome variables should be reduced to minimal. The proposed trial design is not ideal for mechanistic studies, and may be insufficient for approval of new devices and pharmacological therapies. However, the trial design is ideal for confirmatory studies, post-approval phase 4 trials in larger more generalisable populations and for post-marketing surveillance studies.

The future of evidence-based medicine belongs to large healthcare quality registries. The impact of registries on treatment and excellence of care will depend on data quality, completeness and coverage, and the possibility of collecting long-term outcome data. Prospective use of quality registries with randomised built-in trials could potentially revolutionise clinical trials by the fast inclusion of large patient numbers, focus on hard endpoints and complete follow-up and at a fraction of the costs of today's randomised clinical trials as an important complement to observational studies and well-performed, high-quality, prospective randomised trials. With the organisation of large quality registries in European countries with reliable outcome data, the crisis of clinical science may turn into success. Despite harder economic times and shrinking incentives for large pharmaceutical industries to support clinical science, examples from Scandinavia have shown that the bright future is here.

References

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Footnotes

  • Competing interests SJ has received institutional research grants and honoraria from Terumo Inc., Medtronic Inc., Boston Scientific, Vascular Solutions, Abbot Vascular, Eli Lilly, Astra Zeneca, BMS and Merck.

  • Provenance and peer review Commissioned; internally peer reviewed.

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