Transcatheter versus optimal medical treatment and surgical aortic valve replacement for aortic valve stenosis

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the benefits and harms of TAVI versus optimal medical therapy or versus SAVR in patients with severe AV stenosis.


Description of the condition

Acquired aortic valve (AV) stenosis is the degenerative disease of the AV in adults. In Europe, 2% to 7% of the population older than 65 years suffers from severe disease, and it is the most frequent heart valve disease (Iung 2003; Nkomo 2006). Other more rare aetiologies are rheumatic and congenital AV stenosis.

The disease has a chronic course, usually over decades, with gradual lipid accumulation, inflammation, calcification and sclerosis of the valve, and obstruction of the left ventricular outflow (Freeman 2005; Carabello 2009). The cardiac intracavitary pressure overload leads to adaptive concentric left ventricular hypertrophy keeping the wall stress within normal ranges and preserving the chamber volume and ejection fraction (Spann 1980). The hypertrophic left ventricle will eventually become insufficient to overcome the high systolic pressure and/or be in a depressed contractile state and this leads to decreasing ejection fraction (Krayenbuehl 1988). Concomitant coronary artery disease (CAD) will exacerbate this myocardial dysfunction (Marcus 1982).

The natural history of the disease consists of a prolonged latent asymptomatic period which varies widely between individuals (Ross 1968; Otto 1997; Rosenhek 2000; Pellikka 2005). In adults over 65 years of age, about 26% have sclerosis and thickening of the AV without obstruction of the left ventricle (Stewart 1997; Otto 1999). Among those without CAD, 10% will have died from cardiovascular causes after five years compared to 6% of adults with a normal AV (adjusted relative risk 1.66 (95% confidence interval, 1.23 to 2.23)) (Stewart 1997; Otto 1999). About 2% to 7% of adults over 65 years of age have symptomatic and haemodynamic significant severe AV stenosis (Iung 2003; Nkomo 2006). Often symptoms of dyspnoea on exertion, angina and syncope will develop, and the prognosis changes dramatically with an average survival of two to three years with a risk of sudden death (Ross 1968; Turina 1987; Horstkotte 1988; Iivanainen 1997; Rosenhek 2010; Clark 2012).

Most asymptomatic patients are closely monitored for disease progression and development of symptoms and usually not considered for corrective surgery. In symptomatic patients with severe AV stenosis (defined echocardiographically as effective opening valve area less than 1 cm2 (indexed effective opening valve area less than 0.6 cm2/m2 body surface area), mean valve gradient greater than 40 mm Hg or jet velocity greater than 4.0 m/s) and no prohibitive co-morbidities, surgical aortic valve replacement (SAVR) is usually considered indicated. Concomitant coronary artery bypass grafting (CABG) is also indicated if concurrent significant CAD exist (Bonow 2008; Vahanien 2012).

AV stenosis is associated with some of the same genetic and clinical factors contributing to atherosclerosis in CAD such as increased age, male sex, smoking, hypertension, diabetes mellitus, and raised serum low-density lipoprotein (Stewart 1997; Thanassoulis 2013).

Description of the intervention

Since the AV stenosis disease process is similar to CAD (Carabello 2009), statins have been suggested but failed to slow the progression of the disease in randomised clinical trials (Rossebø 2008; Chan 2010). Patients with evidence of decompensated congestive heart failure can cautiously be treated with digitalis, diuretics and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, but the outcome will not improve compared to the natural history (Vahanien 2012). Associated hypertension and atrial fibrillation should be managed cautiously in the usual fashion, and cardiac risk factors should be modified. No other disease modifying agents have been identified (Bonow 2008; Vahanien 2012).

In retrospective observational studies, SAVR has been shown to improve symptoms, quality of life, and left ventricular ejection fraction compared to the preoperative status (Murphy 1981; Lund 1990; Khan 1998; Vahanien 2012). In a small observational study comparing patients receiving SAVR to patients not receiving SAVR, both the one year survival (90% compared to 65%) and the three-year survival (87% compared to 21%) were significantly higher in the SAVR group (Schwarz 1982). After SAVR, mid-term and long-term survival may be close to the age-matched general population in older low-risk patients, e.g., 80 years and older, with survival rates of 84% to 93%, 56% to 77% and 38% to 56% at one, five and ten years, respectively (Leontyev 2009; ElBardissi 2011; Mølstad 2012). However, in younger patients and in moderate-risk and high-risk older patients lower survival rates compared to age-matched controls may be expected (Leontyev 2009; Vahanien 2012).

SAVR involves sternotomy, cardio-pulmonary bypass, aortic cross-clamping, and cardioplegic arrest before the diseased valve can be excised and a valve prosthesis can be sutured in place. The procedure carries a low operative risk in younger patients without any significant co-morbidities (30-day mortality 1% to 4% in patients younger than 70 years) (Brown 2009). The risk increases substantially with increasing age, reduced left ventricular function, concomitant CAD, frailty and other co-morbidities (30-day mortality 4% to 8% in selected older patients) (Pereira 2002; Florath 2003; Florath 2010; Thourani 2011; Vahanien 2012).

Different operative risk calculators in cardiac surgery including the Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) score and the European System for Cardiac Operative Risk Evaluation (EuroSCORE I and II) have been developed to identify the high-risk surgical patient (Nashef 1999; O'Brien 2009; Nashef 2012), but these are inadequate and generally overestimate the operative mortality in SAVR (Wendt 2009). Almost one-third of patients referred for valve intervention will not receive valve replacement because of presumable prohibitive high surgical risk, and a less invasive treatment option would be attractive (Iung 2005; Bach 2009).

At the end of the 1980s, AV balloon valvuloplasty was developed for inoperable patients. The treatment resulted in mid-term improvements in quality in life, but the recurrence of stenosis in most patients after 6-12 months and the lack of survival benefit rapidly terminated its use (Tissot 2011). In 1989, the first animal experiments with a biological, balloon-expandable valve prosthesis mounted in a catheter were carried out in pigs, and in 2000 the first stented valve prosthesis was implanted in a human with a diseased pulmonary valve (Cribier 2012).

Transcatheter aortic valve implantation (TAVI) was originally developed in 1992 in a porcine model (Andersen 1992), and clinically introduced in 2002 as a minimally-invasive treatment for patients who are considered ineligible for valve surgery (Cribier 2002). The term TAVI comprises different valve prosthesis types, deployment systems, and approaches to the stenosed valve. Originally developed as a transvenous transseptal technique, the procedure is currently performed on the beating heart either antegrade transapically through a small left anterior thoracotomy or retrograde through the arterial system using either the femoral, subclavian, or carotid artery, or with the direct transaortic approach. The artery can be surgically exposed or punctured. Before prosthesis deployment a standard AV balloon valvuloplasty is typically performed (Walther 2011; Webb 2011).

Currently, there are a number of European Conformity marked TAVI prostheses and deployment systems available for commercial use in Europe, and more are being developed. The two most widely-used systems are the Edwards SAPIEN system with a balloon-expandable bioprosthesis (Edwards Lifescience Inc., Irvine, CA, USA), which has also been FDA approved for inoperable patients in the United States, and the CoreValve System with a self-expandable bioprosthesis (Medtronic Inc., Minneapolis, MN, USA) (Cribier 2012).

Postoperative complications related to SAVR stem from the surgical trauma with sternotomy, cardio-pulmonary bypass, aortic cross clamping, and cardioplegic cardiac arrest. In TAVI many of the SAVR complications are potentially avoided but others are potentially exacerbated such as neurological and vascular lesions (Kahlert 2010; Rodés-Cabau 2011; Stortecky 2012). Retrograde catheter passage in the aortic arch and ascending aorta can generate atherosclerotic emboli. At the same time, TAVI specific complications have been encountered including conduction abnormalities (typically atrio-ventricular and bundle branch block), prosthesis misplacement, incomplete frame expansion leading to valvular and paravalvular leakage, prosthesis embolisation, aortic and ventricular perforations, and arterial access lesions (Nuis 2011a).

Since operator experience has grown, pre-procedure measurements of the aortic root and native valve size have become more precise, imaging techniques and implantation systems have improved and decreased in size, many of the above complications have become more rare (Nuis 2011b).

National and international registries have documented good short and mid-term safety results after TAVI in patients considered at prohibitive high risk for surgery with a 95% to 100% procedure success rate, and a 30-day mortality, stroke and myocardial infarction rate at 5% to 12%, 2% to 10%, and 1% to 4%, respectively. These figures are combined with sustained prosthesis function, clinical and quality of life improvements, and survival rates of 76% to 79% after one year and 71% to 74% after two years (Piazza 2008; Moat 2011; Zahn 2011; Gilard 2012; Jilaihawi 2012; Krane 2012). However, about 25% of patients treated with the CoreValve System and 10% of patients treated with the Edwards Sapien system will require a permanent pacemaker (Khawaja 2011; Gilard 2012). Long-term durability results beyond five years are lacking, and it is unclear how the prevalent paravalvular leakage will affect symptoms, cardiac structure and function (Ye 2010; Buellesfeld 2011; Moat 2011; Litzler 2012; Rodés-Cabau 2012; Toggweiler 2012; Ussia 2012).

The effect of the specific valve bioprosthesis and deployment system used, mode of implantation (transarterial versus transapical), and concomitant CAD are not known in detail (Dewey 2010; Moat 2011).

How the intervention might work

The TAVI intervention is designed to treat degenerative AV stenosis. The diseased stenosed valve is first dilated by a balloon-valvuloplasty and, to avoid re-stenosis and valve insufficiency, a valve prosthesis is implanted. The intervention is minimally invasive since it can be done on the beating heart using a catheter either through a small thoracotomy or through an arterial puncture. By avoiding sternotomy, cardio-pulmonary bypass, and aortic cross-clamping the intervention might lower complication and morbidity rates, without compromising the favourable functional and prognostic results as seen in the current standard treatment (SAVR) (Vahanian 2008).

Why it is important to do this review

Degenerative AV stenosis is the most prevalent heart valve disease. TAVI is a new attractive treatment modality with an extremely rapid dissemination in clinical use. Originally developed for inoperable patients, the technique is now used in patients with lower operative risk profiles based primarily on data from national and international registries (Vahanian 2008; Leon 2011; Kappetein 2013). The severity of AV stenosis per se for which intervention is considered has apparently not changed yet (Vahanien 2012). Clear evidence from randomised data and not observational studies is essential to guide patients and clinicians in finding the most effective and safe intervention for different subsets of patients with severe AV stenosis (Vahanian 2008; Higgins 2011; Leon 2011; Kappetein 2013).


To assess the benefits and harms of TAVI versus optimal medical therapy or versus SAVR in patients with severe AV stenosis.


Criteria for considering studies for this review

Types of studies

We will consider all randomised clinical trials irrespective of language, publication status, or blinding for benefits and harms. Cohort studies, quasi-randomised studies and cohort studies will be excluded for benefits, but not for harms. We will not conduct extensive searches for such studies, but include what is captured during our searches for randomised clinical trials.

Types of participants

We will include patients with first-time severe degenerative sclerotic AV stenosis with and without concomitant CAD eligible for intervention. There will be no age restriction.

Severe AV stenosis will be defined by the following echocardiographic criteria according to current guidelines (Vahanien 2012):

  • effective opening valve area < 1 cm2;

  • indexed effective opening valve area < 0.6 cm2 per metres2 body surface area;

  • mean valve gradient > 40 mm Hg;

  • maximum jet velocity > 4.0 metres per second;

  • velocity ratio < 0.25.

Patients with other significant heart valve disease or previous heart valve replacement will be excluded, whereas patients with previous percutaneous coronary intervention (PCI) or CABG will be included.

Types of interventions

We will include trials comparing TAVI versus optimal medical therapy (including standard best-evidence therapy for congestive heart disease with or without AV balloon valvuloplasty). We will also include trials comparing TAVI versus SAVR.

All types of TAVI in both local and general anaesthesia with percutaneous puncture or surgical cutdown using the transapical, transseptal, or transarterial (from the femoral, subclavian, carotid artery, or aorta) access route will be accepted. No specific type of bioprosthesis, deployment or access closure system is required.

For SAVR all types of the procedure and bioprosthesis used are accepted irrespective of access to the thorax (full or partial sternotomy). Co-intervention for CAD before or during TAVI, with PCI or CABG, and co-intervention for atrial fibrillation, with cryo or radiofrequency ablation, is accepted. Hybrid procedures will be included.

Types of outcome measures

Primary outcomes
  • All-cause mortality

  • Quality of life

  • Serious adverse events. Serious adverse events will be defined as any untoward medical occurrence that resulted in death, was life threatening, or caused persistent or significant disability, or any medical event, which might have jeopardised the patient, or required intervention to prevent it (ICH 1996)

Secondary outcomes
  • Cardiac mortality

  • New York Heart Association (NYHA) functional classification

  • Left ventricular ejection fraction

  • All other adverse events that are non-serious (see above), i.e., any medical occurrence not necessarily having a causal relationship with the treatment and were not serious will be considered as non-serious (ICH 1996)

  • Valve prosthesis regurgitation (valvular leakage and paravalvular leakage)

  • Valve prosthesis effective opening area, mean gradient and jet velocity

We will define our post-TAVI outcomes as those suggested by the Valve Academic Research Consortium (Leon 2011; Kappetein 2013).

Search methods for identification of studies

Electronic searches

We will search the following databases:

  • the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library);

  • MEDLINE using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Higgins 2011);

  • EMBASE using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of RCTs (Higgins 2011);

  • Science Citation Index Expanded (Royle 2003).

Please see Appendix 1 for the search strategy, that we will be using to search MEDLINE. It will be adapted where necessary to search the other databases listed.

We will apply no language or date restrictions to the searches. We will include a PRISMA diagram to show the results of the searches.

Searching other resources

  1. Reference lists of cardiology and cardiac surgery textbooks, review articles and relevant studies

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies

  3. Bibliographies of relevant articles

  4. World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (

  5. metaRegister of controlled trials (mRCT) (

  6. (

  7. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) device approval reviews

Data collection and analysis

Selection of studies

We will use the search strategy described to obtain titles and abstracts of trials that may be relevant to the review. Two authors (HGHT, CHM) will independently assess trial eligibility. Excluded trials will be listed with the reason for exclusion. We will resolve any disagreements by discussion or by consultation with a third author (CG). We will contact trial authors if information about methodology or data is unclear or missing.

Data extraction and management

Two authors (HGHT, CHM) will independently select potential relevant trials based on the title and abstract. The same two authors will independently review the full text of potentially relevant trials using standard data extraction forms to assess trial eligibility (Moher 2009; Higgins 2011). Trials reported in non-English language journals will be translated before assessment. Where more than one publication of one trial exists, reports will be grouped together and we will include only the most complete data. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved by consultation with all authors.

From each trial we will extract the following information: first author, country of origin, study design, inclusion and exclusion criteria, number of participants, patients characteristics, prosthesis, access route, post-procedure antithrombotics, other medical treatment, follow-up period, primary and secondary outcomes, adverse events, patients lost to follow-up, and financial support of the trial.

Assessment of risk of bias in included studies

The following items will be assessed using the risk of bias assessment tool (Higgins 2011) (Appendix 2):

  • was there adequate sequence generation?

  • was allocation adequately concealed?

  • was knowledge of the allocated interventions adequately prevented during the trial?

  • were incomplete outcome data adequately addressed?

  • are reports of the trial free of suggestion of selective outcome reporting?

  • was there any risk of vested interest bias?

Trials with adequate generation of the allocation sequence, allocation concealment, blinding, outcome data reporting, selective outcome reporting, and without vested interests will be considered as trials with low risk of bias (high methodological quality) (Schulz 1995; Moher 1998; Kjaergard 2001; Gluud 2006; Wood 2008; Lundh 2012; Savović 2012). Trials with one or more unclear or inadequate quality component will be considered as trials with high risk of bias (low methodological quality) (Schulz 1995; Moher 1998; Kjaergard 2001; Gluud 2006; Wood 2008; Lundh 2012; Savović 2012). High inter-rater agreement between blinded and unblinded assessments as well as between two independent assessors has been found previously (Kjaergard 2001; Gluud 2006).

Measures of treatment effect

For dichotomous outcomes results will be expressed as risk ratio (RRs) with 95% confidence intervals (CIs). Where continuous scales of measurement are used to assess the effects of treatment, the mean difference (MD) will be used; the standardised mean difference (SMD) will be used if different scales have been used (Thompson 2002; Higgins 2003).

Unit of analysis issues

We will primarily include trials with a parallel group design. Should cluster-randomised trials be identified, they will also be included. Whenever outcomes are measured repeatedly, we will usually include data from the longest follow up.

Dealing with missing data

We will do the following to deal with missing data:

  • contact the original investigators to request missing data;

  • perform an intention-to-treat analysis;

  • perform sensitivity analyses to assess how sensitive results are to 'worst-worst' case scenario analyses, 'best-best' case scenario analyses, 'worst-best' case scenario analyses and 'best-worst' case scenario analyses;

  • address the potential impact of missing data on the findings of the review in the discussion section.

Assessment of heterogeneity

We will assess heterogeneity using a Chi2 test with N-1 degrees of freedom, with an alpha of 0.10 used for statistical significance and with the I2 test (Higgins 2002). I2 values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity, respectively (Higgins 2003).

Evidence of heterogeneity will also be sought by assessing the PICO (participants, intervention, comparison group, and outcomes) and by visually assessing the forest plots (Higgins 2011).

Assessment of reporting biases

We will use a funnel plot to explore bias (Egger 1997; Macaskill 2001). Funnel plot asymmetry of trial size will be used to assess this bias. We will use the linear regression approach to determine the funnel plot asymmetry (Egger 1997).

Data synthesis

We will use the Cochrane Collaboration's statistical software, Review Manager 2012, for data synthesis. Data will be pooled using both the random-effects model and the fixed-effect model to ensure robustness. In the event that there is disagreement between the two models, both results will be reported and the disparity will be addressed in the 'Discussion' section.

Zero-event trials

Review Manager 2012 is unable to handle trials with zero events in both intervention groups when meta-analyses are performed as relative risk or odds ratios. It seems unjustified and unreasonable to exclude zero event trials (Sweeting 2004), and the exclusion may inflate the magnitude of the pooled treatment effects. We will therefore also perform a random-effects meta-analysis with empirical continuity correction of 0.01 in zero-events studies.

Trial sequential analysis

Trial sequential analysis will be applied as cumulative meta-analyses are at risk of producing random errors because of sparse data and repetitive testing on accumulating data (Wetterslev 2008; Wetterslev 2009). To minimise random errors we will calculate the required information size (i.e., the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) (Wetterslev 2008; Wetterslev 2009). Information size calculation should also account for the heterogeneity present in the meta-analysis. In our meta-analysis, information size will be based on the assumption of a plausible RR reduction of 20% or on the RR reduction observed in the included trials with low risk of bias (Wetterslev 2008). The underlying assumption of trial sequential analysis is that significance testing may be performed each time a new trial is added to the meta-analysis. We will add the trials according to the year of publication and if more than one trial was published in a year, trials will be added alphabetically according to the last name of the first author. On the basis of the required information size and risk for type I (5%) and type II (20%) errors trial sequential monitoring boundaries will be constructed (Wetterslev 2008; Wetterslev 2009). These boundaries will determine the statistical inference one may draw regarding the cumulative meta-analysis that has not reached the required information size; if the cumulative Z score crosses the trial sequential monitoring boundary before the required information size is reached in a cumulative meta-analysis, firm evidence may have been established and further trials superfluous. On the other hand, if the boundaries are not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect. We will use as default a type I error of 5%, type II error of 20%, and adjusted information size for diversity unless otherwise stated (Wetterslev 2008; Wetterslev 2009; Thorlund 2011; Trial Sequential Analysis 2011).

Subgroup analysis and investigation of heterogeneity

Subgroup analyses will be performed for:

  1. trials with low-risk of bias compared to trials with high-risk of bias;

  2. age;

  3. sex (if possible);

  4. the predicted postintervention mortality risk score according to the best available scoring system (e.g., STS-PROM score < 4% (low-risk) compared to 4% to 10% (moderate-risk) compared to > 10% (high-risk));

  5. the type of prosthesis and deployment system used in the TAVI group (e.g., Edwards SAPIEN compared to CoreValve System);

  6. the type of access route used in the TAVI group (e.g., transapical compared to transarterial);

  7. co-intervention with PCI or CABG for CAD in both groups (e.g., with compared to without co-intervention);

  8. the use of AV balloon valvuloplasty in the optimal medical therapy group (e.g., with compared to without);

  9. the type of post-procedure antithrombotics used in both groups (e.g., with compared to without warfarin);

  10. the length of follow-up (e.g., one year compared to five years).

Test of subgroup difference will be evaluated with the implemented test in Review Manager 2012.

Sensitivity analysis

We will assess the effect of missing outcome data on all-cause mortality by applying a number of different scenarios to the intention-to-treat analyses. These scenarios will be defined as the following for the primary outcome:

  1. good outcome analysis: assuming that none of the participants with missing data were dead;

  2. poor outcome analysis: assuming that all of the participants with missing data were dead.;

  3. extreme-case favouring TAVI: assuming that none of the participants with missing data in the TAVI group were dead, whereas all of those in the optimal medical therapy group or SAVR group were dead;

  4. extreme-case favouring optimal medical therapy or SAVR: assuming that none of the participants with missing data in the optimal medical therapy group or SAVR group were dead, whereas all of those in the TAVI group were dead.

Further sensitivity analyses could become relevant during the course of the review process. Such post-hoc analyses will be reported and discussed with an appropriate degree of caution.


We thank the Cochrane Heart Group for their support in preparing this protocol and the referees for their comments and feedback during the preparation of this protocol.


Appendix 1. MEDLINE search strategy

1. exp Aortic Valve Stenosis/

2. Heart Valve Diseases/

3. (aortic adj2 stenos?s).tw.

4. ((heart or aortic) adj2 valv* adj2 disease*).tw.

5. (bicuspid adj2 calcification).tw.

6. (tricuspid adj2 calcification).tw.

7. ((aortic or valve) adj2 calcification).tw.

8. (bicuspid adj2 valve*).tw.

9. (tricuspid adj2 valve*).tw.

10. calcinos?

11. (calci* adj3 stenos?s).tw.

12. or/1-11

13. Heart Valve Prosthesis Implantation/


15. (transcatheter adj3 implantation).tw.

16. percutaneous aortic valve

17. valve

18. or/13-17

19. 12 and 18

20. randomized controlled

21. controlled clinical

22. randomized.ab.

23. placebo.ab.

24. drug therapy.fs.

25. randomly.ab.

26. trial.ab.

27. groups.ab.

28. 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27

29. exp animals/ not

30. 28 not 29

31. 19 and 30

Appendix 2. Risk of bias assessment tool

Potential source of bias and assessment criteria

Was there adequate sequence generation?

Yes (low risk of bias): Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).

No (high risk of bias): Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.

Unclear: Insufficient information about the sequence generation process to permit judgement.

Was allocation adequately concealed?

Yes (low risk of bias): Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).

No (high risk of bias): Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear: Randomisation stated but no information on method used is available.

Was knowledge of the allocated interventions adequately prevented during the study?

Yes (low risk of bias): No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken; either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias.

No (high risk of bias): No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken; either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias.

Unclear: Insufficient information to permit judgement of 'Yes' or 'No'.

Were incomplete outcome data adequately addressed?

Yes (low risk of bias): No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.

No (high risk of bias): Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; 'as-treated' analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Unclear: Insufficient information to permit judgement of 'Yes' or 'No'.

Are reports of the study free of suggestion of selective outcome reporting?

Yes (low risk of bias): The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

No (high risk of bias): Not all of the study's pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear: Insufficient information to permit judgement of 'Yes' or 'No'.

Was there vested interest bias?

No risk of vested interest bias, if the trial's source of funding did not come from parties that might have a conflicting interest or if the authors had not previously published studies on similar interventions.

Unclear, if the source of funding was not clear.

Risk of vested interest bias, if the trial was funded by a drug manufacturer or the authors had previously published studies on similar interventions.

Contributions of authors

  1. Conceiving the protocol: HGHT, CG, DAS

  2. Designing the protocol: HGHT, CHM, LS, CG, DAS

  3. Writing the protocol: HGHT, CHM, LS, CG, DAS

  4. Providing general advice on the protocol: CHM, CG, DAS

  5. Securing funding for the protocol: HGHT, LS, DAS

  6. Performing previous work that was the foundation of the current protocol: CHM, CG, DAS

  7. Final approval of the protocol version to be published: HGHT, CHM, LS, CG, DAS

First author HGHT is the guarantor of the protocol.

Declarations of interest

LS serves as a physician proctor for Medtronic Inc. This role implies supervising other centres in implementing the TAVI device and implantation system. He has received consulting and lecture fees, grant support, and reimbursement for travel expenses from Medtronic Inc.

No other author has any known conflict of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • The Danish Heart Foundation, Denmark.

    The Danish Heart Foundation ( is a private organization and relies largely on donations from individuals and companies supplemented by governmental funding for specific projects. No medical companies are involved in the distribution of grants.

    HGHT has received a one-year research grant to cover general salary expenses as a clinical research fellow.