Cardiology Trials

N Engl J Med 2009;360:213-24Lancet 2015;386:1853-60Background: Fractional flow reserve (FFR) is a measure of the physiologic significance of a coronary stenosis that is defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow. It is measured during coronary angiography by calculating the ratio of distal coronary pressure measured with a coronary pressure guidewire to aortic pressure measured simultaneously with the guiding catheter. FFR in a normal coronary artery equals 1.0 whereas a value 90% and is similar to information obtained with stress imaging studies.For patients with multivessel coronary disease, it can be a challenge in the cath lab to differentiate between blockages causing ischemia and those that are not and this may be especially challenging when patients have not undergone stress imaging prior (e.g., patients presenting with acute coronary syndromes without ST segment elevation). The FAME trial sought to test the hypothesis that revascularization guided by FFR would be superior to revascularization guided by angiography alone in a broad cohort of patients with multivessel disease in whom revascularization with PCI was indicated.Patients: Patients with multivessel CAD of at least 50% of the vessel diameter in at least 2 of the 3 major epicardial coronary arteries in whom PCI was indicated. Patients with a STEMI could be included if the infarction occurred at least 5 days before PCI. Patients with a NSTEMI could be included earlier than 5 days. Patients who had undergone previous PCI could be included.Patients were excluded if they had left main coronary disease, previous CABG, cardiogenic shock, extremely tortuous or calcified coronary arteries, a life expectancy less than 2 years, a contraindication to the placement of drug-eluting stents, or if patients were pregnant.Baseline characteristics: Information is not provided on patients screened to enrolled. The average age of patients was 64.5 years and approximately three quarters were men. It is not clear from the main manuscript how many patients presented with acute MI’s. It appears that approximately one third of patients presented with unstable angina and about half of these patients had dynamic ECG changes. More than half of patients in the trial had class 2 angina or below. Approximately 25% of patients had diabetes and over 60% had hypertension. The average EF was 57%.The mean number of lesions per patient was 2.8. About 40% of blockages were estimated to be in the 50-70% range, another 40% were in the 71-90% range, 15% were 91-99% narrowed and 3% were chronic total occlusions. The minimal luminal diameter was 1.0 mm, mean reference vessel diameter was 2.5 mm, mean lesion length was 12.5 mm and the SYNTAX score was 14.5.Procedures: Patients were randomized after they were found to have multivessel disease, meeting the study criteria, and were thought to require PCI. Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions with drug-eluting stents. Those assigned to FFR-guided PCI underwent FFR in each diseased coronary artery and drug-eluting stents were placed in lesions with FFR that was All patients were treated with aspirin and clopidogrel for at least 1 year after PCI and if a patient underwent a repeat procedure during follow-up, the initially assigned strategy was followed in the case of stent placement. After discharge, a follow-up assessment was performed at 1 month, 6 months, and 1 year. Endpoints: The primary endpoint was a composite of all-cause death, myocardial infarction, and any repeat revascularization at 1 year. Procedural MI’s were systematically assessed and included in the MI endpoint. Secondary endpoints included procedure time, contrast use, functional class at 1 year, health-related quality of life, the number of antianginal medications used, and individual components of the primary endpoint at 1 year as well as the rates of major adverse cardiovascular events at 30 days and 6 months. Cost effectiveness was also assessed.A minimum sample size of 426 patients in each group was based on a two-sided chi-square test with an alpha level of 0.05 and a statistical power of 0.80, assuming 1-year rates of the primary endpoint of 14% in the angiography group and 8% in the FFR group, which equals a 6% absolute risk reduction and 43% relative risk reduction. The 14% event rate was based on outcome data in earlier studies of drug-eluting stents that were available in 2005 (RAVEL 2002, TAXUS-IV 2004).Results: A total of 1,005 patients were enrolled in 20 centers in the United States and Europe of whom 496 were assigned to angiography-guided PCI and 509 were assigned to FFR-guided PCI. A total of 2,415 stents were placed with significantly more stents in the angiography-guided group (2.7+/-1.2 vs 1.9+/-1.3; p). In the FFR group, 874 lesions (64%) were ischemic based on FFR measurements and stents were placed, while 513 lesions (37%) were not and stents were not placed. The procedure time was similar between groups but significantly more contrast agent was used in the angiography-guided group.Patients in the FFR-guided group were significantly less likely to experience the primary endpoint at 1-year (13.2% vs 18.3%; RR 0.72; 95% CI 0.54-0.96). This difference was based on 24 events and this translates to a Fragility Index of 4 - meaning, if 4 patients in the experimental group were converted from NOT having the primary endpoint to HAVING the primary endpoint, the study would lose statistical significance (p > 0.05). The number of patients lost to follow up in the FFR-guided group was higher than the fragility index (8 vs 4).No statistically significant differences were noted in the rates of death, MI, repeat revascularization, functional status at 1 year, or the mean length of stay. The mean cost of materials used in the index procedure was $6,007 in the angiography-guided group and $5,332 in the FFR-guided group (p).No subgroup information was provided in the main manuscript.The 5-year results were published in 2016 and there was no difference in the primary endpoint (28% vs 31%, RR 0.91, 95% CI 0.75-1.10) or any major secondary endpoints. Conclusions: In patients with multivessel CAD, in whom PCI is indicated and there is uncertainty regarding the significance of coronary lesions, an FFR-guided approach reduced coronary stent use (approximately 1 stent per patient) and reduced a composite endpoint of death, MI or repeat revascularization at 1 year compared to an angiography-guided approach with a NNT of approximately 20 patients. It should be noted that the treatment effect was associated with a fragility index of 4, which is not clinically robust and event rates in both the experimental and control groups were well above the assumed rates (it is usually the opposite). The results were not statistically significant at 5 years.One design element of this trial, in particular, may have biased the results in favor the FFR-guided strategy and reduces confidence in the results. That was the inclusion of patients with lesions in the 50-70% range. It was NOT standard practice at the time to routinely stent such lesions as they were not felt to be ischemia-inducing. In clinical practice, such lesions may have been stented depending on the clinical circumstances, but to do it in all such cases was well beyond the standard of care. Such lesions accounted for 530 blockages (41%) in the angiography-guided group and 624 (44%) in the FFR-guided group. Ultimately, FFR-guided patients ended up with 379 less stents. A strategy of angiography guided PCI for blockages >70% vs FFR-guided strategy for blockages >50% would have been a better hypothesis test with more direct implications for patient care at the time. The FAME trial provides evidence that PCI itself causes coronary events (at least over short-term follow-up) and the authors acknowledge this in the discussion. More stents equal more coronary events via procedural MI’s, in-stent thrombosis and in-stent restenosis. The authors believed FFR was a useful tool to determine lesions that needed revascularization or not; however, that hypothesis was not directly tested in this trial but was tested several years later in the FAME 2 trial that we have already reviewed. In FAME 2, PCI of FFR positive lesions did NOT reduce death or MI compared to up-front medical treatment alone but did reduce urgent revascularization. That particular endpoint comes with important caveats which we discussed in detail in our post.In conclusion, the FAME trial showed that in select patients with multivessel CAD (based on blockages of >/=50% in 2 of 3 major epicardial coronary arteries) and an indication for PCI, that FFR-guidance may reduce stent use and improve outcomes over short-term follow-up. However, more data is needed to confirm this result and to distinguish patient populations most likely to benefit based on clinical indication for PCI and complexity of coronary anatomy.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

For full review of the trial, please visit https://cardiologytrials.substack.com/ Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2016;375:1242-1252Background: The first drug-eluting stent (DES) was approved by the FDA in 2003 following the publication of the RAVEL trial. Since then, newer generations of DES were developed and were tested in clinical trials. The majority of trials comparing DES to bare-metal stents (BMS) showed reduction in repeat revascularization with DES but no significant reduction in death or myocardial infarction. Following these publications, the use of DES grew rapidly and was used in more than two thirds of percutaneous coronary interventions (PCI) by 2010.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.These trials, however, were very selective, had short follow up time (TAXUS-IV followed patients for 9 months and SPRIT IV followed patients for 12 months), and had limited power to assess hard outcomes.The NORSTENT trial investigators sought to compare DES to BMS in a more pragmatic design and follow patients for longer time.Patients: All patients who were undergoing PCI in Norway were assessed for enrollment. Patients had stable angina or acute coronary syndrome. Lesions were in native coronary arteries or bypass grafts.Patients were excluded if they had prior coronary stents, bifurcating lesions requiring a two-stent technique or life expectancy less than 5 years due to a medical condition other than coronary artery disease. Patients were also excluded if they had contraindications to dual antiplatelets or were taking warfarin.Baseline characteristics: The trial randomized 9,013 patients – 4,504 randomized to receive a DES and 4,509 to receive a BMS.The average age of patients was 63 years and 75% were men. Approximately 42% had hypertension, 54% had hyperlipidemia, 10% had prior myocardial infarction, 7% had prior CABG, 12% had diabetes, and 35% were current smokers.The indication for PCI was stable angina in 29% of the patients, unstable angina in 12% and STEMI or NSTEMI in 58%.Procedures: The study was open-label but outcomes assessment was blinded. Patients were randomly assigned in a 1:1 ratio to receive DES or BMS. Patients could receive several stents as clinically indicated but can only receive the assigned stent type during the index procedure.In all patients, aspirin 75 mg daily was given indefinitely while clopidogrel 75 mg daily was given for 9 months.Follow up visits were done as clinically appropriate without specification from the study protocol. Similarly, no routine follow up coronary angiography was performed.Endpoints: The primary outcome was a composite of all-cause death or spontaneous myocardial infarction. Secondary outcomes included repeat revascularization, stent thrombosis, major bleeding and health status based on the Seattle Angina Questionnaire.Clinical outcomes were collected by linking each patient unique national identification number to the Norwegian national patient registry.Analysis was performed based on the intention-to-treat principle. The study planned to enroll 8,000 patients to be followed for a median of 5 years. Assuming the 5-year event rate of the primary outcome to be 17%, the study would provide 93% power to detect 3% absolute risk difference between the study groups (rate ratio: 1.18). Due to lower than expected mortality, the sample size was increased to 9,000 patientsResults: Among the 20,663 patients who were assessed for eligibility, 12,425 met inclusion criteria. Among patients who met inclusion criteria, 9,013 were randomized. Figure 1 in the manuscript provides details for excluding patients and for not randomizing patients who met eligibility criteria. The most common reason for exclusion was prior PCI.The number of stents implanted per patient was 1.7 and more than 98% received the assigned stent type. The median follow up time was 5 years.The primary composite outcome of all-cause death or nonfatal spontaneous myocardial infarction was not significantly different between both treatment arms (16.6% with DES vs 17.1% with BMS, HR: 0.98; 95% CI: 0.88 - 1.09; p= 0.66).For the secondary outcomes – Hospitalization for unstable angina was similar between treatment groups (5.2% vs. 5.7%; p= 0.21). Stent thrombosis was lower with DES (0.8% vs 1.2%; p= 0.05). Target-lesion revascularization was also lower with DES (5.3% vs 10.3%; pThere was no significant difference in health status based on the Seattle Angina Questionnaire.There were no significant subgroup interactions.Conclusion: In patients undergoing PCI, the use of DES did not reduce the composite endpoint of death or spontaneous myocardial infarction compared to BMS. Target-lesion revascularization was reduced with DES with a number needed to treat of 20 patients.The findings of this study align with the results of other trials comparing DES to BMS. We have reviewed several key trials and included links to additional studies in this field below. Overall, DES significantly reduce target-lesion revascularization without significant effect on all-cause mortality or myocardial infarction.An important consideration in this and other related trials is that both stent types were studied using similar durations of dual antiplatelet therapy (DAPT) following PCI. For patients with stable angina, BMS typically require only one month of DAPT, while DES often necessitate three to twelve months. Since shorter durations of DAPT are generally safer for patients, a trial comparing DES with three to twelve months of DAPT compared to BMS with one month of DAPT would be insightful.A final teaching point is that less than 50% of screened patients were ultimately enrolled in this pragmatic trial, which had minimal exclusion criteria. It’s not uncommon for trials to enroll less than 5% of screened patients which limits their external validity.* Other trials of DES vs BMShttps://pubmed.ncbi.nlm.nih.gov/21080780/https://pubmed.ncbi.nlm.nih.gov/22951305/Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe