Advice
Evidence review
Evidence review
Clinical and technical evidence
Regulatory bodies
The Medicines and Healthcare products Regulatory Agency (MHRA) website reports 1 product recall notice issued on 16 September 2011. The alert advised users that a specific batch of PressureWire Aeris could produce erroneously low fractional flow reserve (FFR) values because of a production fault, and that this batch should not be used.
The USA Food and Drugs Authority (FDA) database, Manufacturer and User Device Facility Experience (MAUDE) reports 54 relevant records. Records in MAUDE are entered from a variety of sources, may contain duplicates and the accuracy has not been verified. Where details were available they included incidents of the wire or tip of the device breaking during use, and dissection or perforation during the procedure. No search was made for information on other guidewire devices.
Systematic reviews
Three systematic reviews in English were identified: Raman et al. (2013), Blue Cross and Blue Shield (2011) and Medical Services Advisory Committee (MSAC, 2005). A further systematic review, Siebert et al. (2008) was excluded as the full text was available only in German. A list of the papers included in each is in table 8. Note that the systematic reviews did not select for named devices and therefore may include data relating to FFR devices other than PressureWire FFR devices.
Raman et al. (2013)
This peer-reviewed comparative effectiveness review was carried out for the Agency for Healthcare Research and Quality (AHRQ) in the USA (Raman et al. 2013). It focused on 5 questions, the first of which was the impact of using an intravascular diagnostic technique with angiography versus angiography alone to make therapeutic decisions, and subsequent intermediate outcomes and patient-centred outcomes. The other questions looked at were not relevant to this briefing.
Evidence included 1 randomised controlled trial (FAME) and 2 non-randomised studies (Muramatsu et al. 2002; Wongpraparut et al. 2005). The DEFER trial was excluded because it 'examined appropriateness of stenting a functionally non-significant stenosis, and did not compare FFR-guided stenting versus stenting guided by angiography alone'. It should be noted that other systematic reviews have included this trial and it is summarised later in this briefing. The FAME II trial was excluded because 'all patients underwent FFR during angiography, and FFR-guided stenting plus optimal medical therapy was compared with optimal medical therapy only.'
The reviewers assessed the risk of bias for the included studies as: FAME: low, Wongpraparut et al. (2005): medium, and Muramatsu et al. (2002): high. Study results were summarised in narrative form only.
The report found a moderate strength of evidence favouring FFR-guided stenting decisions over stent placement decisions guided by angiography alone, in patients with intermediate coronary lesions.
Blue Cross and Blue Shield (2011)
This US assessment aimed to review and evaluate available evidence comparing outcomes following FFR-guided percutaneous coronary intervention (PCI) against PCI guided by angiography alone in patients with angina (Blue Cross and Blue Shield Association Technology Evaluation Center 2011).
Evidence included 2 randomised controlled trials (DEFER and FAME) and 4 observational studies (Chamuleau et al. 2002; Legalery et al. 2005; Lindstaedt et al. 2006; Wongpraparut et al. 2005). Excluded studies were not listed.
The authors found that trial data were consistent and that results from the small observational studies were in agreement, although with limitations inherent in observational data. They noted the use of bare metal stents and single target vessels in the DEFER trial. They also noted that there were large numbers of moderate severity lesions in the FAME trial, where PCI in the angiography alone arm was based on physician judgement, including any non-invasive testing.
The authors concluded that the evidence suggested that identifying stenoses is insufficient to determine if revascularisation is likely to be of benefit. For patients with angina for whom revascularisation is considered, evidence suggests that FFR-guided PCI results in better outcomes than strategy guided by angiography alone.
Medical Services Advisory Committee (MSAC, 2005)
This assessment was published by the MSAC in Australia. The scope included the measurement of FFR and coronary flow reserve for single or multi-vessel coronary artery disease, for intermediate lesions (coronary stenosis 30–70%) and post-angioplasty or stenting.
Evidence included:
-
2 randomised controlled trials (Bech et al. 2001a; Leesar et al. 2003)
-
8 non-randomised studies in patients with a range of FFR levels (Bech et al. 2001b; Botman et al. 2004; Jasti et al. 2004; Jimenez-Navarro et al. 2004; Lopez-Palop et al. 2004; Reczuch et al. 2004; Rieber et al. 2002)
-
4 non-randomised studies, in patients with FFR levels considered functionally non-significant (Bech et al. 1998; Hernandez-Garcia et al. 2001; Meuwissen et al. 2003; Ozdemir et al. 2002)
-
1 study comparing FFR to a triple stress test (Pijls et al. 1996).
DEFER (Bech et al. 2001a) is described in full in this briefing.
The report also analysed studies in subgroups.
For single-lesion disease the studies were consistent with the DEFER findings, that for patients with a FFR of 0.75 or more there was with no overall difference in major cardiac events if PCI was carried out or deferred.
For left main coronary artery disease, 3 observational studies found improvements in angina status after FFR measurement regardless of intervention, but this should be treated with caution due to the observational nature of the studies.
For multiple lesion disease 3 observational studies were compared, but no overall conclusions were drawn.
There were no studies restricted to myocardial infarction or unstable angina. Leesar et al. (2003) studied a population with unstable angina or non ST-segment elevated myocardial infarction (NSTEMI), but the 2 groups could not be separated out.
The report's recommendations were accepted by the Australian Minister for Health and Ageing: 'On the strength of evidence relating to safety, effectiveness and cost-effectiveness, the MSAC recommends that public funding be supported for the use of coronary pressure wires to determine whether revascularisation should be performed on intermediate lesions identified on coronary angiography, where previous stress testing has either not been performed or the results are inconclusive'.
Randomised controlled trials
Four randomised controlled trials (10 papers) were identified. Their design is summarised in table 1 and the key findings described in following text and tables.
Table 1: Summary of randomised controlled trial protocols
|
Study component |
Description |
|||
|
DEFER |
FAME |
FAME II |
Dambrink (2010), Ghani (2012) |
|
|
Population |
Stable angina, referred for elective PCI |
Multi-vessel CAD, PCI indicated |
Stable CAD, eligible for PCI |
STEMI, already successfully treated with PCI |
|
Treatment before randomisation |
Randomise first to PCI or defer, then FFR for all |
Angiogram to assess need for PCI, then randomise to receive FFR |
Angiogram to assess need for PCI then FFR for all. Randomise where FFR significant |
All patients had STEMI and successful PCI for culprit lesion in previous 3 weeks |
|
Arm 1 |
Significant + PCI |
FFR guided PCI |
Significant, PCI+medical |
FFR guided PCI |
|
Arm 2 |
Not significant + defer |
Angiogram guided PCI |
Significant, medical |
Conservative treatment |
|
Arm 3 |
Not significant + PCI |
N/A |
Not significant, medical |
N/A |
|
What would have been standard care for these patients? |
All patients would have received PCI |
Patients would have received angiography guided PCI |
Patients would have received angiography guided PCI |
Patients would have received medical treatment |
|
Randomisation |
Yes, but method not stated |
Yes, sealed envelope, blocks of 25. |
Yes, stratified by site, random block sizes |
Yes, computer program, no other detail given |
|
Blinded treatment |
Not stated |
Not stated |
No |
Not stated |
|
Blinded outcomes |
Not stated, Events reviewed by independent committee |
Events adjudicated by independent committee who were unaware of treatment |
Events adjudicated by independent committee who were unaware of treatment |
Blinded for echocardiographic and radio nuclide outcomes. |
|
CAD, coronary artery disease; FFR, fractional flow reserve; PCI, percutaneous coronary intervention; STEMI, myocardial infarction with ST-segment elevation. |
||||
DEFER study
This multicentre randomised controlled trial was carried out in 12 hospitals in Europe and 2 hospitals in Asia between June 1997 and December 1998 (Bech et al. 2001a; Pijls et al. 2007). The pressure wire devices used were from RADI Medical Systems, the previous manufacturer of the PressureWire devices.
The DEFER trial treatment groups, and outcomes, are described in tables 2 and 3.
Event-free survival for all patients with functionally non-significant stenosis (PERFORM plus DEFER) was 76% (p=0.03). For patients with functionally non-significant stenosis, 21% of PERFORM and 27% of DEFER experienced 1 or more events at 5 years. In the reference group this was 39% (p=0.03 compared with the combined PERFORM plus DEFER).
In this trial, for patients with stable chest pain and functionally non-significant stenosis (FFR≥0.75), stenting did not improve outcomes. Measuring FFR could therefore help to identify patients who would not benefit from stenting.
Table 2: Summary of the DEFER trial a
|
Study component |
Description |
|
Objectives/hypotheses |
Is PCI justified in patients with stable chest pain and a functionally non-significant coronary stenosis? |
|
Study design |
Multicentre, prospective randomised controlled trial |
|
Setting |
12 hospitals in Europe and 2 hospitals in Asia between June 1997 and December 1998 Clinical follow-up was at hospital discharge and after 1, 3, 6, 12, 24 and 60 months Patients were randomised to PCI or deferral of PCI. All patients then underwent FFR measurement. In both arms patients with FFR<0.75 received PCI, and these formed the REFERENCE group. In the performance of PCI arm, patients with FFR ≥0.75 received PCI and were labelled the PERFORM group. In the deferral of PCI arm, patients with FFR≥0.75 did not receive PCI and were labelled the DEFER group Stents were bare metal stents |
|
Inclusion / exclusion criteria |
Inclusion criteria Referral for elective PCI of a single angiographically significant stenosis (>50%) in native coronary artery with reference diameter >2.5mm No evidence of reversible ischaemia in last 2 months Exclusion criteria Total occlusion of target artery Acute Q-wave infarction Unstable angina with transient ST-segment abnormality |
|
Variables |
Primary outcome was freedom from adverse cardiac events (MACE) after 2 years of follow-up |
|
Statistical methods |
No sample size calculation was given. Intention to treat analysis Baseline characteristics were compared using chi-square test or unpaired student t-tests Kaplan-Meier survival curves for absence of adverse cardiac events and compared by the log rank test P<0.05 was considered significant. All tests were 2-tailed |
|
Participants |
There were more men than women in the study, and statistically significantly more men in the reference group (80%) than in the FFR≥0.75 group (65% DEFER, 63% PERFORM), p<0.05. Statistically significantly more non-invasive stress tests were performed in the FFR≥0.75 group (67%) than in the reference group (53%), and statistically significantly more negative results were seen (47% DEFER, 50% PERFORM) than in the REFERENCE group (31%). Age, ejection fraction, clinical history and angina class did not show significant differences |
|
Main results |
The primary end point of event-free survival in patients at 2 years was 89% in the DEFER group, and 83% in the PERFORM group (p=0.27). Event free survival of the reference group was 78% (PERFORM p=0.31, DEFER p=0.03) Event free survival at 5 years was 79% in the DEFER group, and 71% in the PERFORM group (p=0.52). Event free survival of the reference group was 61%. (PERFORM p=0.17, DEFER not reported) Event free survival for all patients with functionally non-significant stenosis (PERFORM+DEFER) was 76% (p=0.03) |
|
Conclusions |
For patients with stable chest pain, where FFR≥0.75, stenting did not improve outcomes |
|
CI, confidence interval; FFR, fractional flow reserve; ITT, intention to treat; n, number of patients; PCI, percutaneous interventions; RR, relative risk. a The table contains information from several papers concerning the same DEFER RCT. These are: Bech et al. (2001a, 2 year results), Pijls et al. (2007, 5 year results). |
|
Table 3: Results of the DEFER trial a
|
DEFER Group |
PERFORM group |
REFERENCE group |
Analysis |
|
|
Randomised |
n=91 |
n=90 |
n=144 |
|
|
Efficacy |
n=91 1 lost at 5 year |
n=90 2 lost at 5 year |
n=144 10 lost at 5 year |
ITT |
|
Primary outcome: event-free survival at 2 years |
89.0% (80/91) |
83.3% (75/90) |
78.4% (106/144) |
% and numbers given as reported, but % are not as calculated from numbers. p=0.27, 95% CI −15.7% to 4.6% (DEFER:PERFORM) p=0.31 (REF:PERFOM) p=0.03 (REF:DEFER) |
|
Selected secondary outcomes |
||||
|
Event-free survival at 5 years |
79% (72/91) |
71% (64/90) |
61% (88/144) |
p=0.52 (DEFER:PERFORM) p=0.17 (REF:PERFORM) p=0.03 (REF:DEFER+PERFORM) |
|
Cardiac death |
3.3% (3/91) |
2.3% (2/90) |
6.0% (8/144) |
|
|
Other death |
3.3% (3/91) |
3.4% (3/90) |
3% (4/144) |
|
|
MI (Q wave and non Q wave) |
0 |
6.7% (6/90) |
9.0% (13/144) |
|
|
Freedom from angina |
67% (61/91) |
57% (51/90) |
72% (104/144) |
p=0.028 (REF:DEFER+PERFORM) p=0.015 (Reference:Perform) |
|
Safety |
n=91 |
n=90 |
n=144 |
|
|
Total adverse events |
21 |
30 |
70 |
Reported as 'total events after 5 years'. Patients may have had more than 1 event |
|
Patients with ≥1 event |
21% (19/91) |
27% (24/90) |
39% (52/144) |
p=0.03 (REF:DEFER+PERFORM) |
|
CABG |
1.1% (1/91) |
4.5% (4/90) |
10.4% (14/144) |
|
|
TVR |
8.9% (8/91) |
9.1% (8/90) |
13.4% (18/144) |
|
|
Non-TVR |
6.7% (6/91) |
6.8% (6/90) |
8.2% (11/144) |
% and numbers given as reported, but % are not as calculated from numbers |
|
Other |
0% (0/91) |
1.1% (1/90) |
1.5% (2/144) |
|
|
CABG, coronary artery bypass graft; CI, confidence interval; ITT, intention to treat; MI, myocardial infarction; n, number of patients; RR, relative risk; TVR, tricuspid valve replacement. a The table contains information from several papers concerning the same DEFER randomised controlled trial. These are: Bech et al (2001a), 2 year results), Pijls et al. (2007, 5 year results). |
||||
FAME study
FAME was a multicentre randomised controlled trial across 5 medical centres in the USA and 15 in Europe between January 2006 and September 2007 (Fearon et al. 2007; Fearon et al. 2010; Pijls et al. 2010; Tonino et al. 2009). FAME compared the clinical outcomes and cost effectiveness of treatment based on measurement of FFR using the pressure wire devices from RADI Medical Systems (in addition to angiography) against treatment guided by angiography only, in patients with multi-vessel coronary artery disease for whom PCI was appropriate.
A summary of the trial is presented in tables 4 and 5.
The study showed that measuring FFR in patients with multi-vessel coronary artery disease having PCI with drug-eluting stents significantly reduces myocardial infarction (MI) at 2 years when compared with standard angiography-guided PCI.
Four papers were identified that reported subgroup analyses of the FAME trial (Kim et al. 2012; Nam et al. 2011; Sels et al. 2011; Tonino et al. 2010), 2 of which are relevant to this briefing. A major limitation for any subsequent analysis was that the study was designed and powered to examine the original study question only, so conclusions should be treated with caution.
Sels et al. (2011) reanalysed the trial data to determine if there was a difference in benefit of FFR guidance for PCI for patients with unstable angina or NSTEMI (n=328), compared with stable angina (n=677). The absolute risk reduction from using FFR guidance compared with angiography guidance was similar (5.1% unstable angina or NSTEMI, 3.7% stable angina, p=0.922). The authors noted that FFR measurement can be limited by microvascular obstructions that are often present with MI, but that the FAME study population was defined to minimise this issue.
Kim et al. (2012) considered the impact of sex differences on FFR-guided PCI using data from the FAME study, with 744 men and 261 women. They found that the proportion of functionally significant lesions was lower in women than in men for lesions with 50–70% stenosis (21.1% compared with 39.5% respectively, p<0.001). They also reported that the FFR-guided strategy resulted in no statistically significant difference in relative risk reduction for major adverse cardiac event (MACE) type outcomes for men and women, compared with an angiography-guided approach.
Table 4: Summary of the FAME study a (2 year results)
|
Study component |
Description |
|
Objectives / hypotheses |
To compare the clinical outcomes and cost-effectiveness of treatment based on measurement of FFR in addition to angiography against treatment guided solely by angiography in patients with multi-vessel coronary artery disease for whom PCI is appropriate |
|
Study design |
Multicentre randomised controlled trial |
|
Setting |
5 medical centres in the USA and 15 in Europe between January 2006 and September 2007 Clinical follow-up was at 1 year for primary outcomes, and at 30 days, 6 months, 2 years and 5 years for secondary outcomes The patients were assessed for PCI by using angiogram, then randomised to the FFR or angiogram arm. For the FFR-guided strategy, the clinician could only stent if FFR≤0.8. 96.9% of stents were drug-eluting stents |
|
Inclusion / exclusion criteria |
Inclusion criteria: Multi-vessel coronary artery disease (≥ 50% diameter stenosis in ≥2 major epicardial vessels) and PCI indicated. Age ≥18 years Exclusion criteria: Previous coronary bypass surgery Left main coronary disease Recent ST elevation MI (<5 days) Recent non-ST elevation MI (<5 days) if peak CK is >1000 U per litre Cardiogenic shock Extremely tortuous or calcified coronary vessels Life expectancy <2 years Pregnancy Contraindicated for placement of drug-eluting stent |
|
Variables |
Primary outcome was the rate of major adverse cardiac events at 1 year, defined as a composite of death, MI and repeat revascularisation Secondary outcomes measured at 30 days, 6 months, 2 years and 5 years |
|
Statistical methods |
Sample size based on: 426 patients in each arm, based on alpha level 0.05, statistical power of 0.8 assuming adverse cardiac events at 1 year of 14% for angiography and 8% for FFR. Intention to treat analysis Categorical variables compared using chi-square test, continuous variables compared with unpaired t-test or Mann-Whitney U test. Kaplan-Meier curves for time-to-event distribution of primary end point |
|
Participants |
Baseline characteristics of the 2 groups are reported as similar, as were the number of indicated lesions and angiographic extent and severity of CAD. In both groups there were more men than women (angiography 73% male; FFR 75% male) |
|
Main results |
The primary outcome, MACE at 1 year, occurred in 91 patients (18.3%) in the angiography-guided group, and 62 patients (13.2%) in the FFR group (P=0.02) MACE at 2 years occurred in 111 patients (22.4%) in the angiography-guided group, and 91 patients (17.9%) in the FFR group (p=0.08) |
|
Conclusions |
The primary outcome (MACE) was significantly improved by FFR-guided PCI at 1 year, but the difference was not significant at 2 years. There were significantly fewer MI events in the FFR-guided PCI group at 2 years than in the angiography group |
|
CI, confidence interval; ITT, intention to treat; MACE, major adverse cardiac event; MI, myocardial infarction; n, number of patients; PCI, percutaneous coronary intervention; RR, relative risk. a The table contains information from several papers concerning the same FAME RCT. These are: Fearon et al. (2007, study design, Tonino et al. (2009, 1 year results), Pijls et al. (2010, 2 year results). |
|
Table 5: Results of the FAME study a (2 year results)
|
Angiography |
FFR |
Analysis |
|
|
Randomised |
n=496 |
n=509 |
|
|
Efficacy At 1 year At 2 years |
n=496 11 lost 36 lost |
n=509 8 lost 29 lost |
ITT p=0.45 p=0.31 |
|
Efficacy |
n=496 36 lost |
n=509 29 lost |
ITT p=0.31 |
|
Primary outcome: MACE at 1 year |
18.3% (91/496) |
13.2% (62/509) |
p=0.02, RR=0.72 95% CI 0.54–0.96 |
|
MACE at 2 years |
22.4% (111/496) |
17.9% (91/509) |
p=0.08, RR=0.8 95% CI 0.62–1.02 |
|
Selected secondary outcomes |
All outcomes were at 2 years, unless stated |
||
|
All-cause mortality |
3.8% (19/496) |
2.6% (13/509) |
p=0.25 RR=0.67 95% CI 0.33–1.34 |
|
MI |
9.9% (49/496) |
6.1% (31/509) |
p=0.03 RR=0.62 95% CI 0.40–0.95 |
|
CABG or repeat PCI |
12.7% (63/496) |
10.6% (54/509) |
p=0.3 RR=0.84 95% CI 0.59–1.18 |
|
Periprocedural infarctions (from 1 year results paper) |
3.2% (16/496) |
2.4% (12/509) |
Not stated |
|
Patients without event and free from angina |
64.8% (284) |
68.2% (315) |
p=0.29 Patients without information on angina status excluded, denominator not given |
|
EQ5D score at 1 year |
73.7±16.0 |
74.5±15.7 |
p=0.65 Not reported at 2 years |
|
Total drug-eluting stents used |
1,359 |
980 |
p<0.001 |
|
Safety |
n=496 |
n=509 |
Intention to treat analysis |
|
Total adverse events |
28.6% (142/496) |
20.8% (106/509) |
Reported as 'total events'. This includes MACE, but additional events were not reported in detail. Some patients may have more than one event |
|
CI, confidence interval; EQ5D, EuroQol-5D quality of life measure, ITT, intention to treat; MACE, major adverse cardiac events; n, number of patients; RR, relative risk. a The table contains information from several papers concerning the same FAME RCT. These are: Fearon et al. (2007, study design), Tonino et al. (2009, 1 year results), Pijls et al. (2010, 2 year results). |
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FAME II study
The FAME II multicentre randomised controlled trial was conducted in 28 sites in Europe and North America and enrolled 1220 patients (De Bruyne et al. 2012; Fearon et al. 2013). Recruitment was from May 2010 to January 2012, at which point the trial was stopped because of a highly significant difference in the primary end point between the groups. The objective was to determine whether FFR-guided PCI, using either PressureWire Aeris or PressureWire Certus (with Agile Tip), with drug-eluting stents plus the best available medical therapy was superior to the best available medical therapy alone in reducing adverse cardiac events in patients with stable coronary artery disease.
For patients with functionally significant stenosis, the trial showed those who received PCI had statistically significantly fewer MACE events than those who received medical treatment only. There was no significant difference for these patients in occurrence of death or MI, but there were statistically significantly more urgent revascularisations for patients with functionally significant stenosis who were treated medically rather than receiving PCI. As the study was powered to detect a difference in MACE, non-significant results in the component outcomes may be inconclusive. The difference in urgent revascularisations may have been influenced by healthcare professionals being more likely to recommend PCI for patients who have only received medical treatment to date (Boden 2012).
A summary of the trial is presented in tables 6 and 7.
The patients in this trial were already being considered for PCI, and had at least 1 vessel with 50% or greater stenosis, assessed by angiography. They were randomised to medical treatment or PCI if functionally significant stenosis was identified using FFR measurement. It was not clear how many would have received PCI if not enrolled in the trial.
If normal treatment for this group of patients would have been to give best available medical treatment, FFR measurement could have helped to identify patients who would have benefitted from treatment with PCI.
If normal treatment would have been PCI, then FFR measurement would have helped to identify patients for whom PCI did not provide a benefit in this trial. Outcomes for patients without functionally significant stenosis, treated medically, were not statistically significantly different from outcomes for patients with functionally significant stenosis who received PCI.
Table 6: Summary of the FAME II trial (De Bruyne et al. 2012)
|
Study component |
Description |
|
Objectives / hypotheses |
To determine whether FFR-guided PCI with drug-eluting stents plus the best available medical therapy is superior to the best available medical therapy alone in reducing adverse cardiac events in patients with stable coronary artery disease |
|
Study design |
Multicentre randomised controlled trial |
|
Setting |
28 sites in Europe and North America, with 1220 patients. Recruitment was from May 15 2010 to January 15 2012 at which point the trial was stopped due to a highly significant difference in the primary end point between the PCI and medical therapy groups. All patients underwent FFR. Where FFR>0.8 lesions were included in a register, and 166 were randomly selected for follow-up. Where FFR≤0.8, patients were randomised to PCI and medical treatment, or to medical treatment alone |
|
Inclusion/exclusion criteria |
Inclusion criteria: Stable angina, or atypical / no chest pain but documented ischaemia on non-invasive testing At least one stenosis ≥50% in native coronary artery with diameter ≥2.5mm, supplying viable myocardium Eligible for PCI Exclusion criteria: Preferred treatment is CABG Left main coronary artery disease needing revascularisation Patients with a recent STEMI or non-STEMI (<1 week) Prior CABG, contraindicated to dual anti-platelet therapy LVEF<30%, Severe left ventricular hypertrophy, Planned valve or aortic surgery, tortuous/calcified coronary arteries Life expectancy <2 years, age <21, pregnancy |
|
Variables |
Composite of death from any cause, non-fatal MI or unplanned urgent revascularisation (MACE) at 2 years. |
|
Statistical methods |
Sample size of 816 in each group was calculated to provide 84% power to detect a relative risk reduction with PCI of 30% for the primary end point at 24 months, alpha=0.05. Intention to treat analysis Mantel-Cox to calculate hazard ratios and 95% CI Log rank test for p values Kaplan Meier curves for primary end point. Landmark analyses for events at landmark point of 7 days |
|
Participants |
There were more men than women in the trial (coronary +medical treatment 79.6%, medical therapy 76.6%, registry 68.1%). There were significantly less men in the registry group than in the combined randomised groups, p=0.005 There was less peripheral vascular disease in the registry group than in the combined randomised groups (PCI+medical treatment 9.6%, medical therapy 10.7%, registry group 4.8%), p=0.03, and fewer lesions per patient (PCI+medical treatment 1.87±1.05, medical therapy 1.73±0.94, registry group 1.32±0.59), p<0.001 |
|
Main results |
For the primary end point at 2 years, there was a significant difference between the medical treatment group (12.7%) and the registry group (3.0%), p=0.001, and also between the PCI+medical treatment group (4.3%) and the medical treatment only group (12.7%), p<0.001. The difference between the PCI+medical treatment group and the registry group was not significant, p=0.61. There was a significant difference between the medical treatment only and registry groups, p=0.001 |
|
Conclusions |
In patients with stable coronary artery disease and FFR≤0.8 outcomes were better for FFR-guided PCI than for medical treatment alone |
|
CI, confidence interval; FFR, fractional flow reserve; ITT, intention to treat; LVEF, left ventricular ejection fraction; n, number of patients; PCI, percutaneous intervention; RR, relative risk. |
|
Table 7: Results of the FAME II trial (De Bruyne et al. 2012)
|
PCI plus medical treatment |
Medical treatment only |
Registry |
Analysis For PCI+MT:MT a |
|
|
Randomised |
n=447 |
n=441 |
n=166 |
|
|
Efficacy |
n=447 |
n=441 |
n=166 |
ITT |
|
Primary outcome: MACE at 2 years |
4.3% (19/447) |
12.7% (56/441) |
3.0% (5/166) |
p<0.001 HR=0.32 95%CI 0.19–0.53 |
|
Selected secondary outcomes: |
||||
|
Death (any cause) |
0.2% (1/447) |
0.7% (3/441) |
0% (0/166) |
p=0.31 HR=0.33 95% CI 0.03–3.17 |
|
MI |
3.4% (15/447) |
3.2% (14/441) |
1.8% (3/166) |
p=0.89 HR=1.05 95% CI 0.51–2.19 |
|
Urgent revascularisation |
1.6% (7/447) |
11.1% (49/441) |
2.4% (4/166) |
p<0.001 HR=0.13 95% CI 0.06–0.3 |
|
Safety |
n=447 |
n=441 |
n=166 |
|
|
Serious adverse events |
The events were listed, however the categories overlap and it was not possible to deduce a total number |
|||
|
Any revascularisation |
3.1% (14/447) |
19.5% (86/441) |
3.6% (6/166) |
p<0.001 HR=0.14 95% CI 0.08–0.26 |
|
Stroke |
0.2% (1/447) |
0.5% (2/441) |
0.6% (1/166) |
p=0.56 HR=0.49 95% CI 0.04– 5.50 |
|
Stent thrombosis |
1.1% (5/447) |
0.2% (1/441) |
0.6% (1/166) |
p=0.10 HR=4.98 95% CI 0.59–42.25 |
|
CI, confidence interval; HR, hazard ratio; ITT, intention to treat; n, number of patients; RR, relative risk. a Additional comparisons are given in the supplementary appendix available for De Bruyne (2012). |
||||
Dambrink (2010), Ghani (2012)
This was a randomised controlled trial carried out in a single tertiary referral centre in the Netherlands. It used pressure wire devices from RADI Medical Systems, the previous manufacturer of the PressureWire devices. Patients were recruited between June 2004 and March 2007. The objective was to test the hypothesis that in patients with multi-vessel disease successfully treated with PCI for STEMI, subsequent early FFR-guided PCI would result in improved global left ventricular function and fewer cardiac events during follow-up compared with conservative treatment. The trial is summarised in tables 8 and 9.
The authors concluded that an early ischaemia-guided invasive strategy prevents later PCI procedures but does not result in a reduction in MACE at 6 months.
After 3 years of follow-up the authors concluded that FFR-guided additional revascularisation of early FFR-guided PCI of the 'non-culprit' lesions would result in improved global left ventricular function and fewer cardiac events during follow up compared to conservative treatment. The non-culprit lesions are those that were not treated in the acute STEMI episode.
The strength of these conclusions was limited by the study finishing before recruitment finished, and by combining results (re-infarction and death) in groups that were not originally planned.
Table 8: Summary of the randomised trial reported by Dambrink et al. (2010); Ghani et al. (2012)
|
Study components |
Description |
|
Objectives / hypotheses |
To test the hypothesis that in patients successfully treated with PCI for STEMI and with multi-vessel disease, subsequent early FFR-guided PCI would result in improved global left ventricular function and fewer cardiac events during follow-up compared to conservative treatment |
|
Study design |
Randomised controlled trial. Patients were randomised in 2:1 ratio to invasive treatment: FFR-guided revascularisation within 3 weeks of STEMI, or conservative treatment |
|
Setting |
Single tertiary referral centre in The Netherlands. Patients were recruited between June 2004 and March 2007a. |
|
Inclusion / exclusion criteria |
Inclusion criteria: successful PCI defined by residual diameter stenosis <50% and TIMI 3 flowb. Multi-vessel disease was defined as 1 or more significant stenoses in at least 2 major epicardial coronary arteries, or the combination of a side branch and a main epicardial vessel provided that they supplied different territories. A significant stenosis was defined as a diameter stenosis of at least 50% in luminal diameter. The reference diameter adjacent to the lesion had to be ≥2.5 mm. Exclusion criteria: urgent indication for additional revascularisation, age >80 years, chronic occlusion of one of the non-infarct related arteries, prior CABG, left main stenosis of 50% or more, restenotic lesions in non-infarcted arteries, chronic atrial fibrillation, limited life expectancy, or other factors that made complete follow-up unlikely |
|
Variables |
Primary outcome: Ejection fraction assessed by radionuclide ventriculography at 6 months Secondary outcomes: Change in ejection fraction (baseline to six months) Wall motion score, left ventricular end-systolic and end-diastolic volume and ejection fraction at 6 months by echocardiography MACE |
|
Statistical methods |
A 2-sided p value of <0.05 was considered statistically significant. A difference of 5% in ejection fraction was considered clinically relevant. With a standard deviation of 12%, a power of 80% and alpha of 0.05, 92 patients in both groups were needed to detect a significant difference at the p<0.05 level. A 10% drop-out rate was taken into account. It was anticipated that 50% of lesions, when assessed by FFR, would warrant revascularisation, hence the 2:1 randomisation ratio and target of 300 patients. Students t-test was used for continuous variables. Chi-square was used for proportions |
|
Results |
The study by Dambrink et al. 2010 recruited 121 patients successfully treated with PCI for STEMI and with multi-vessel disease and randomised them to either early (within 3 weeks of STEMI) FFR-guided PCI or conservative treatment. 6 month follow-up: Ejection fraction was comparable between groups (invasively treated group: 59±9% versus conservative group: 57±9%, p=0.362), and there was no difference in MACE between invasively and conservatively treated patients (21 versus 22%, p=0.929) 3-year follow-up: There was no significant difference in all-cause mortality between the invasive treatment and conservative treatment groups; 4 patients (3.4%) died in the invasive treatment group (p=0.29). Re-infarction occurred in 14 patients (11.8%) in the invasive treatment group compared with none in the conservative treatment group (p=0.002). Re-PCI was performed in 7 patients (8.9%) in the invasive treatment group and in 13 patients (32.5%) in the conservative treatment group (p=0.001). There was no difference in MACE between the 2 strategies (35.4 versus 35.0%, p=0.96 |
|
Participants |
Patients successfully treated with PCI for STEMI and with multi-vessel disease. In the invasive treatment group, PCI was performed if FFR<0.75. PCI was performed for all severe lesions (>90% stenosis). In the conservative treatment group, PCI was discouraged but if symptoms occurred, ischaemia-guided revascularisation was performed based on exercise test, dobutamine stress echocardiography or myocardial scintigraphy |
|
Main results |
The study by Dambrink et al. 2010 recruited 121 patients successfully treated with PCI for STEMI and with multi-vessel disease and randomised them to either early (within 3 weeks of STEMI) invasive FFR-guided PCI or conservative treatment. The outcome measures were global left ventricular function and cardiac events. At 6 months follow-up, there were no statistically significant differences between groups for ejection fraction or MACE, but there was a higher rate of death and MI in the invasively treated group than the conservatively treated group by ITT. At 3 years' follow-up, there were more deaths and reinfarctions in the invasively treated group compared to the conservatively treated group, but no difference between groups for MACE |
|
Conclusions |
Authors' conclusions: an early ischaemia-guided invasive strategy prevents later PCI procedures but does not result in a reduction of total major adverse cardiac events at 6 months. These findings support a conservative strategy as currently advocated by the guidelines. After 3 years of follow-up the authors concluded that FFR-guided additional revascularisation of non-culprit lesions early after primary PCI resulted in more deaths and/or re-infarctions compared with a more conservative strategy of ischaemia-guided revascularisation at a later stage |
|
CI, confidence interval; FFR, fractional flow reserve; ITT, intention to treat; MACE, major adverse cardiac event; MI, myocardial infarction; n, number of patients; PCI, percutaneous coronary intervention; RR, relative risk; TIMI, thrombolysis in myocardial infarction. a The trial was stopped before the target accrual of 300 patients was reached because of slow recruitment and in clinical practice over time that could create an inhomogeneous study population. It was therefore underpowered. b Ghani et al. (2012) publication states a TIMI ≥2. |
|
Table 9: Results of the randomised controlled trial reported by Dambrink et al. (2010) and Ghani et al. (2012)
|
Invasive treatment group |
Conservative treatment group |
Analysis |
|
|
Randomised |
n=80 |
n=41 |
Randomised at 2:1 ratio because an anticipated 50% of FFR assessed lesions would warrant revascularisation |
|
Efficacy |
n=80 |
n=41 |
|
|
Primary outcome: ejection fraction assessed by radionuclide ventriculography at 6 months |
EF=58.9% ±9.4% |
EF=56.9% ±9.3% |
Assessed in 90/121 (74%) of all patients Difference=2%, p=0.362 |
|
Selected secondary outcomes |
|||
|
Change in ejection fraction (baseline to 6 months) |
-0.2±6.7% |
+0.1±7% |
Assessed in 90/121 (74%) of all patients No p value reported |
|
Wall motion score index at 6 months |
n=80 Index=1.20±0.20 |
n=41 Index=1.22±0.27 |
p=0.607 Measure of spread not reported (presumably a mean for a continuous variable) |
|
End-systolic volume at 6 months |
n=80 41.4±16.3 |
n=41 45.9±35.7 |
Units not reported p=0.448 |
|
End-diastolic volume at 6 months |
n=80 92.7±29.5 |
n=41 98.9±44.1 |
p=0.482 |
|
Ejection fraction (echocardiographic) at 6 months |
n=80 55.7±8.2 |
n=41 56.3±11.8 |
p=0.784 |
|
MACE (6 months) |
21% |
22% |
p=0.929 ITT analysis |
|
Death (6 months) |
2.5% |
0% |
p=0.015 ITT analysis |
|
MI (6 months) |
14% |
0% |
p=0.015 ITT analysis |
|
PCI (6 months) |
13% |
22% |
p=NS ITT analysis |
|
CABG (6 months) |
6.3% |
0% |
p=NS ITT analysis |
|
Non-culprit-related PCI |
n=65a Rate=6% |
n=40 Rate=22% |
p=0.017 Per protocol analysisa |
|
Non culprit related MACE |
16% |
22% |
|
|
Death and MI (6 months) |
n=65a Rate=9% |
n=40 Rate=0% |
p=0.079 Per protocol analysisa |
|
MACE (6 months) |
n=65a 14% |
n=40 22% |
p=0.295 Per protocol analysisa |
|
Death (6 months) |
n=65a 3% |
n=40 0% |
p=0.079 Per protocol analysisa |
|
MI (6 months) |
n=65a 9% |
n=40 0% |
p=0.079 Per protocol analysisa |
|
PCI (6 months) |
n=65a 9% |
n=40 22% |
p=0.072 Per protocol analysisa |
|
CABG (6 months) |
n=65a 1.6% |
n=40 0% |
p=NS Per protocol analysisa |
|
All-cause mortality (3 years) |
n=79 4/79 (3.4%) |
n=40 0/40 (0%) |
n=119/121=98.3% p=0.30 |
|
Re-PCI |
15/79 (19%) |
13/40 (32.5%) |
p=0.10 |
|
Re-PCI NCL |
7/79 (8.9%) |
13/40 (32.5%) |
p=0.001 |
|
Re-PCI CL |
8/79 (10.1%) |
0/40 (0%) |
p=0.05 |
|
CABG |
12/79 (15.2%) |
1/40 (2.5%) |
p=0.05 |
|
Re-MI |
14/79 (17.7%) |
0/40 (0%) |
p=0.002 |
|
MACE |
28/79 (35.4%) |
14/40 (35%) |
p=0.96 |
|
Death and/or MI |
16/79 (20.3%) |
0/40 (0%) |
p=0.002 |
|
Safety |
n=80 |
n=41 |
|
|
Coronary dissection |
n=1 |
- |
Coronary dissection caused by FFR wire |
|
Acute vessel closure |
n=1 |
- |
Acute vessel closure after FFR but before PCI leading to CABG and death within several days |
|
non-STEMI |
n=2 |
- |
non-STEMI after FFR-guided PCI due to side branch occlusion |
|
Major bleeding |
n=5 |
n=1 |
Defined by needing transfusion or surgery |
|
Subacute stent thrombosis |
n=3 |
- |
Subacute stent thrombosis within 30 days |
|
CI, confidence interval; EF, ejection fraction; ITT, intention to treat; n, number of patients; NS, non-standardised; PCI-ICL, percutaneous coronary intervention, culprit lesion; PCI-NCL, percutaneous coronary intervention, non-culprit lesion; RR, relative risk; STEMI, ST-segment elevated myocardial infarction. a The 65 patients are those who underwent at least one FFR measurement. |
|||
Register data
Li et al. (2013)
This retrospective cohort study included 7358 consecutive patients referred for PCI at the Mayo Clinic, Rochester, USA between October 2002 and December 2009. It aimed to study the long-term outcomes of FFR-guided PCI compared with PCI procedures performed without FFR. FFR measurement used both PressureWire FFR devices and competitor products. Generally, FFR-guided treatment proceeded to PCI if the FFR was less than 0.75, and PCI was deferred if the FFR was greater than 0.8. For FFR values between 0.75 and 0.8, treatment was left to the operator's judgement.
The study is summarised in tables 10 and 11.
Unadjusted analyses showed improved outcomes at 7 years for all combinations of MACE-related outcomes for FFR-guided PCI compared with PCI without prior FFR measurement. When analyses were adjusted for multiple risk factors there were no differences between the groups at 7 years for any MACE-related outcome.
Unadjusted analyses of patients in the FFR-guided strategy found that patients who proceeded to PCI had a significantly higher rate of MI at 7 years than those who did not (p=0.007). Adjusting for multiple risk factors did not change these findings.
The authors concluded that the study supports the use of FFR for decision-making in patients undergoing cardiac catheterisation.
Table 10 Summary of the cohort study reported by Li et al. [2013]
|
Study component |
Description |
|
Objectives / hypotheses |
To study the long term outcomes of FFR guided PCI in general clinical practice, comparing outcomes after FFR-guided PCI with outcomes after angiography-guided PCI |
|
Study design |
Retrospective cohort study of 7358 patients at 1 site |
|
Setting |
Consecutive patients referred for PCI at the Mayo Clinic, Rochester, USA between October 2002 and December 2009 |
|
Inclusion / exclusion criteria |
A register of all patients referred for coronary revascularisation at the Mayo Clinic started in October 2002. Exclusion criteria included presentation with ST-segment elevation MI (STEMI) or cardiogenic shock, referral for coronary artery bypass surgery, or lack of consent From 8942 procedures performed, 220 were excluded due to denial of research authorisation, 1360 met exclusion criteria, and 7358 were eligible for analysis Patients were followed up by telephone at 3 months, 6 months, 12 months and then annually. Information was retrieved from medical records. For patients with deferred PCI, follow-up was by a single questionnaire and history review Follow-up information was available in 7050 (95.8%) of patients. The median follow-up duration was 44.9 months for PCI only, 52.5 months for FFR PERFORM, and 48.7 months for FFR DEFER. |
|
Variables |
There was no clearly stated primary outcome. Reported outcomes included MACE, death, MI and emergency revascularisation |
|
Statistical methods |
Students' 2-sample t-test for most continuous variables Rank sum test for FFR comparisons Pearson's x2 test for discrete data Kaplan-Meier estimates to estimate survival curves, and the log-rank test to test differences between groups Cox proportional hazards multiple regression models to estimate association between FFR use versus deferral on long-term outcomes All significance tests were 2-tailed with a 0.05 significance level Analyses were conducted using SAS 9.2 |
|
Participants |
Of the included 7358 patients, 6268 (85.2%) underwent PCI without FFR assessment. In the remaining 1090 (14.8%) patients, FFR was performed. From these 369 (33.9% of FFR) patients received PCI, and in 721 (66.1% of FFR) PCI was deferred. In 115 (10.5% of FFR) patients PCI was performed where FFR>0.8, and in 39 (3.6%) of patients no PCI was performed where FFR<0.75 |
|
Main results |
1. Unadjusted analyses: FFR (and PCI only if indicated by FFR) strategy versus straight to PCI strategy: the FFR group had better outcomes at 7 years for all combinations of cardiac event outcomes. This could be due to better selection of patients for PCI due to FFR, or it could reflect those in the FFR group being fitter at baseline2. Unadjusted analyses: of patients who received FFR, those who underwent PCI in response to FFR had poorer outcome at 7 years than those who had no PCI – in terms of MI only. There was no difference for other cardiac events 3. Adjusted analyses: FFR (and PCI only if indicated by FFR) strategy versus straight to PCI strategy: there were no longer differences between groups at 7 years for any MACE-related outcome 4. Adjusted analyses: of patients who received FFR, those who underwent PCI in response to FFR had a poorer outcome at 7 years in terms of MI than those in whom PCI was deferred. There was no difference in other MACE related outcomes |
|
Conclusions |
Authors' conclusions: In current practice, FFR-guided treatment is associated with a favourable long-term outcome. The study supports the use of the FFR for decision-making in patients undergoing cardiac catheterisation. |
|
CI, confidence interval; ITT, intention to treat; n, number of patients; RR, relative risk; SAS, supra-regional assay service. The study was retrospective, so treatment decisions, including those based on FFR diagnostic information, were made without a trial protocol. FFR may have been selectively used in 'fitter' patients for whom a decision about whether to do PCI was more difficult. Baseline risk factor data appear to support this. |
|
Table 11: Results of the cohort study reported by Li et al. (2013)
|
PCI only |
All FFR |
FFR Perform |
FFR Defer |
Analysis |
|
|
Randomised |
n=6268 |
n=1090 |
n=369 |
n=721 |
|
|
Efficacy |
n=6268 193 (3.1%) lost |
n=369 17 (4.6%) lost |
n=721 108 (15.0) lost |
ITT |
|
|
Primary outcome: MACE |
57% |
50% |
p=0.016 |
||
|
Selected secondary outcomes: Mortality |
32% |
21% |
p<0.001 7 year follow-up. Unadjusted Kaplan-Meier analysis |
||
|
MI |
15% |
8% |
p<0.001 7 year follow-up. Unadjusted Kaplan-Meier analysis |
||
|
Mortality or MI |
41% |
26% |
- |
- |
p<0.001 7 year follow-up. Unadjusted Kaplan-Meier analysis |
|
Repeat revascularisation |
36% |
35% |
- |
- |
p=0.97 7 year follow-up. Unadjusted Kaplan-Meier analysis |
|
MI |
- |
- |
12% |
6% |
7 year follow-up. Unadjusted Kaplan-Meier analysis |
|
7 year follow-up. Adjustedb Cox multivariable model |
|||||
|
Analysis |
|||||
|
MACE |
HR (All FFR:PCI) 1.01 (95% CI 0.89–1.14), p=0.93 |
||||
|
Death |
HR (All FFR:PCI) 0.89 (95% CI 0.73–1.10), p=0.28 |
||||
|
MI |
HR (All FFR:PCI) 0.79 (95% CI 0.26–0.82), p=0.12 |
||||
|
Death / revascularisation |
HR (All FFR:PCI) 1.003 (95% CI 0.88–1.14), p=0.96 |
||||
|
Death / MI |
HR (All FFR:PCI) 0.85 (95% CI 0.711.01), p=0.06 |
||||
|
MACE |
HR (FFR-DEFER:FFR-PERFORM) 0.97 (95% CI 0.77-1.23), p=0.81 |
||||
|
Death |
HR (FFR-DEFER:FFR-PERFORM) 0.84 (95% CI 0.56–1.24), p=0.37 |
||||
|
MI |
HR (FFR-DEFER:FFR-PERFORM) 0.46 (95% CI 0.26–0.82), p=0.008 |
||||
|
Death / revascularisation |
HR (FFR-DEFER:FFR-PERFORM) 1.002 (95% CI 0.78–1.27), p=0.98 |
||||
|
Death / MI |
HR (FFR-DEFER:FFR-PERFORM) 0.73 (95% CI 0.52–1.01), p=0.06 |
||||
|
Safety |
n=6268 |
n=369 |
n=721 |
||
|
CI, confidence interval; FFR, fractional flow reserve; ITT, intention to treat; n, number of patients; RR, relative risk. a This was the only outcome between FFR-PERFORM and FFR-DEFER that reported significance. b Adjusted for age, sex, body mass index, smoking history, chronic heart failure on presentation, diabetes, hypertension, hypercholesterolaemia, primary symptom, recent MI, prior PCI, prior CABG, history of MI, heart failure, cerebral vascular disease, peripheral artery disease, chronic obstructive pulmonary disease, renal dysfunction, presence of tumour/lymphoma/leukaemia, metastatic cancer, ejection fraction ≤40%, ejection fraction unknown, level of stenosis in each coronary vessel (right coronary artery, left anterior descending, left circumflex, left main coronary artery). Most of the results are presented in the paper graphically, and without the information needed to present them numerically. |
|||||
Ongoing clinical trials
Ten ongoing or in-development studies using FFR as a decision tool for treatment of coronary artery disease were identified, including the UK-based RIPCORD trial, in the preparation of this briefing (NCT01764334; NCT01835808; NCT01175863; NCT01132495; NCT01399736; NCT01366404; NCT01881555; NCT01810224; NCT01070771; NCT01960933).
Costs and resource consequences
In a 2012 audit carried out by the British Cardiovascular Interventional Society, it was reported that FFR was used in 113 centres in the UK out of a total of 178 (118 that carry out PCI, 60 that do diagnostic angiography only). Of 241,240 diagnostic angiography procedures, 7630 included FFR measurement (3.1%). There were also 92,445 PCI procedures, of which 6132 included FFR (6.6%), although there was significant variation in these proportions between centres (Ludman 2013a). In a UK regional cardiology centre, 6.2% of patients (100/1621) with NSTEMI had FFR measured over a 15 month period in 2009–10 (Carrick et al. 2011; Carrick et al. 2013). It is not known what proportion of these procedures used either of the 2 PressureWire FFR devices.
Many centres already use devices that measure FFR, but for others (for example, diagnostic-only centres) additional training and new protocols would be needed. Competency-based training for interventional cardiologists and support staff is provided by the manufacturer. This is included in the cost of the device and depends on the needs of the centre.
The PressureWire Aeris is claimed to be compatible with 'all major hemodynamic recording systems' so it should be suitable for most cardiac catheterisation laboratories with systems that have FFR capability. Proprietary monitoring systems are needed for the PressureWire Certus (with Agile tip).
Measuring FFR takes an additional 5–20 minutes during angiography or PCI.
FFR measurements during PCI are reimbursed in the NHS in England via the Payment by Results tariff and are covered by Health Resource Group (HRG) code EA49Z. In the 2013–14 tariff, this is £3262 for elective procedures and £4440 for non-elective procedures. In the 2014–15 tariff, FFR when used with arteriography only will be covered by HRG code EA35Z. The tariff values for EA35 in 2014–15 will be £2092 for elective procedures and £3393 for non-elective procedures.
Four published economic analyses have been identified, all of which used PressureWire FFR devices.
Fearon et al. (2003)
Fearon et al. (2003) created a decision tree model for patients with chest pain in whom intermediate lesions were detected during angiography. The authors reported that FFR-guided stenting during angiography was US $3830 cheaper than stenting all patients and US $1795 cheaper than deferring PCI until a nuclear perfusion stress test is conducted. All 3 strategies had a similar quality-adjusted survival, although the quality-adjusted life year (QALY) for the stenting strategy was slightly lower than that for the FFR strategy. Although the authors state that in the US, PCI is often delayed for non-invasive testing after intermediate lesions are detected, it is not known whether this represents current practice in the UK. It is also unlikely that a strategy of stenting all intermediate lesions would be ethical because of the additional risk of implanting a stent.
Fearon et al. (2010), FAME
Fearon et al. (2010) conducted an economic analysis using resource data and outcomes from the FAME international multicentre randomised controlled trial. This study used international data but was conducted in the context of the US healthcare system. A population of 1005 patients with multi-vessel coronary artery disease who were indicated for PCI were randomised to either angiography-guided PCI or FFR-guided PCI. Patient utility was determined using survival and quality of life measures at 1 month and 1 year. FFR-guided PCI was reported to be less costly than angiography-guided PCI for both the index procedure (US $13,182 ±US $9667 versus US$ 14,878 ±US $9509) and the total 1 year costs (US$14315 ±US $11,109 compared with US $16,700 ±US $11,868). Despite the wide variation in values these differences were highly statistically significant (p<0.0001) and robust to bootstrap simulations (cost saving in 91% of simulations). Ninety per cent of the costs were incurred during the index procedure and were primarily dependent on the costs of drug-eluting stents, cardiac unit bed days and the FFR devices (US $650 each).
Baseline utility was slightly higher in the FFR-guided group (significance not reported) and this difference was corrected for by offsetting (half the difference was added to the angiography-guided group and half was subtracted from the FFR-guided group). Offset utility increased at 1 month and remained stable at 1 year for both groups and was not statistically significantly different between the groups (p=0.2 at 1 year). These results should be interpreted with caution given that the patient population was pre-determined to receive PCI for 2 or 3 lesions. The use of FFR-guided PCI was highly likely to reduce the number of stents used and the cost of the PressureWire FFR devices is US $1450 less than the cost of the drug-eluting stent (Hoole et al. 2011).
The PressureWire device was cost effective for the group of patients in whom 2 or more lesions were already determined by angiography to be treated with PCI. The cost saved by reducing the number of stents in some patients was greater than the cost incurred by using PressureWire FFR devices on all of the patients.
Hoole et al. (2011)
Hoole et al. (2011) conducted a retrospective analysis of 100 intermediate lesions, of which 50 had an FFR of greater than 0.80, in a Canadian general hospital. Three independent interventional cardiologists blinded to the FFR value and actual treatment provided a theoretical treatment plan. 7 fewer stents were used with an angiography-guided decision compared with FFR values. The authors indicated that this reduction in the number of stents plus the additional cost of the PressureWire FFR device would result in the FFR-guided strategy being cost-incurring with respect to angiography guidance. However, this is a simplistic analysis only comparing the technology costs during the index procedure and ignoring any health and resource outcomes from not using stents.
Fearon et al. (2013), FAME II
Fearon et al. (2013) conducted an economic analysis from a US perspective using resource data and outcomes from the FAME II trial. A population of 888 patients with stable angina and coronary artery disease for whom PCI was appropriate and who had an FFR of less than 0.80 were randomised to either FFR-guided PCI plus medical therapy or medical therapy only. Patient utility was determined using quality of life measures at 1 month and projected assuming a linear decline to baseline over 3 years (as the trial was stopped early). FFR-guided PCI incurred costs with respect to medical therapy for the initial hospitalisation (US $9927 compared with US $3900, p<0.001), primarily as a result of the PCI procedure. The cost difference reduced over the following year, primarily as a result of a higher rate of revascularisations in the medical therapy arm, but were still significantly higher in the FFR strategy arm (US $12,646 compared with US $9763, p<0.001).
Change in patient utility from baseline to 1 month was significantly higher in the FFR arm compared with medical treatment (0.054 compared with 0.001 respectively, p<0.0001). If these utility differences declined linearly over 3 years and costs beyond 1 year did not change, the incremental cost-effectiveness ratio (ICER) of FFR compared with medical therapy was determined to be US $36,000/QALY. This value was below a maximum acceptable ICER of US $50,000/QALY in 80% of bootstrap simulations.
These results should be interpreted with caution as the patient population was defined as patients with 'significant myocardial ischaemia caused by a coronary lesion amenable to PCI'. NICE clinical guideline 126 states that, for patients whose angina symptoms are not controlled by medical treatment, angiography and additional functional testing should be considered. It is not clear if the patients in this study had poorly controlled symptoms, although they did have angiographically demonstrated stenosis and PCI was considered appropriate for them. A possible interpretation is that some patients randomised to medical treatment were undertreated, as they would have received PCI if not in the trial.
Economic analyses relevant to NHS use
Bornstein et al. (2011), Siebert et al. (2011a) and Siebert et al. (2011b) conducted economic analyses using data from the FAME study in the context of the healthcare systems of several European countries, including the UK. These studies were only reported as conference abstracts and so provide only a small amount of information. Cost savings in Germany, UK and Italy are reported as ranging from 300–600 Euros per patient if an FFR-guided strategy was used in comparison to angiography-guided PCI in patients already indicated for PCI. As in Fearon et al. (2010) these figures do not necessarily represent the use of FFR-guided decision-making in patients with angina whose stenosis status is unknown and in whom suitability for PCI is undetermined.
No published economic analyses based in the UK were identified.
Strengths and limitations of the evidence
The evidence comes from 3 large multicentre randomised controlled trials, 1 single centre randomised controlled trial and 1 large registry. This is a strong evidence level compared with many other medical technologies.
In all of the randomised controlled trials neither clinicians nor patients were blinded to treatment, although in some an adjudication panel that considered adverse events was blinded to treatment. Blinding is frequently very difficult to achieve in trials of medical devices. The single-centre trial did not recruit the full number of patients and was underpowered, meaning that a finding of no significant difference was inconclusive.
In some instances, differences between the treatment arms did not reach statistical significance (at p<0.05) when data were analysed using the planned method. When outcomes are re-defined, differences may appear to reach statistical significance. There is an increased likelihood of detecting a difference between the arms purely by chance (type I error) associated with carrying out multiple statistical tests on the same data, but the authors did not correct for this. As such, results for redefined outcomes that appear to reach statistical significance (at p<0.05) should be interpreted with caution.
A key consideration for all the trials is to understand the context of current care pathways in the NHS and the setting for the trial. The interpretation of the results depends on the assumptions about the treatment the patients would have received had they not been participating in a trial, and if the same patients would have received that treatment within the NHS.
There were many more men recruited to the trials than women, reflecting disease prevalence. However, Kim et al. (2012) addressed this in a reanalysis of the FAME data.
The register data included information from procedures carried out with both PressureWire FFR devices and other guidewire devices with FFR capability.