Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease (The FAME 2 Study) Final results Cost-effectiveness analysis

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1 Clinical Summary Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease (The FAME 2 Study) Final results Cost-effectiveness analysis This study is sponsored by St. Jude Medical. Coordinating clinical investigators: Bernard De Bruyne, OLV Ziekenhuis, Aalst, Belgium Nico H.J. Pijls, Catharina Hospital, Eindhoven, the Netherlands William F. Fearon, Stanford University Medical Center, Stanford, CA, USA Results of Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease (The FAME 2 Study) were published in The New England Journal of Medicine 2012;367(11): Cost-effectiveness analysis was presented as a late breaking trial at Transcatheter Cardiovascular Therapeutics (TCT) 2012 by William F. Fearon

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3 SUMMARY OF KEY FINDINGS FFR-guided PCI is a cost-effective strategy that improves outcomes and quality of life The results of FAME 2, a St. Jude Medical sponsored clinical study, show a significant benefit in using FFRguided intervention. In patients with stable coronary artery disease undergoing PressureWire -guided intervention, PCI plus medical therapy was found to improve outcomes compared to medical therapy alone. For patients with one or more significant lesions, there was an 86% relative reduction in the risk for unplanned hospital readmission with urgent revascularization for patients who received FFR-guided PCI plus medical therapy. Patients also experienced greater relief of angina and improved quality of life. A cost-effectiveness analysis indicates that FFR-guided PCI is a cost-effective strategy compared to medical therapy alone, at approximately $32,000 per quality-adjusted life year (QALY). These findings support using FFR-guided PCI compared to medical management alone to improve outcomes in the treatment of stable patients with single-vessel or multivessel coronary artery disease. FFR-Guided PCI Is a Cost-Effective Strategy in Stable Patients with CAD that Improves Patient Outcomes, Quality of Life and Significantly Reduces the Risk for ACS Requiring Unplanned Hospital Readmission Leading to Urgent Revascularization Compared to Medical Therapy Alone. Background In patients with clinically stable coronary disease, PCI has not been shown to affect clinical outcomes such as death, nonfatal myocardial infarction and the need for urgent revascularization. In previous studies on revascularization, treatment has been guided by the angiographic appearance of the lesions. It is likely that in all previous studies dealing with patients with nonacute coronary artery disease (CAD), a sizable proportion of patients did not have ischemia. Objectives The overall purpose of the FAME 2 study was to compare the clinical outcomes, safety and cost-effectiveness of FFR-guided contemporary PCI plus medical therapy versus medical treatment alone in patients with stable coronary artery disease. Methods The FAME 2 study is a prospective, multicenter, randomized clinical study with an all-comers design. All consecutive patients with stable clinical condition and angiographically defined one-, two- or three-vessel coronary artery disease and amenable for PCI were screened and considered for participation in the study. Patients with at least one hemodynamically significant lesion were randomized into PCI (drug-eluting stents [DES] were recommended) plus medical therapy or medical therapy alone. It was expected that in approximately 20% of patients no stenoses would be hemodynamically significant. Patients without hemodynamically significant lesions were enrolled in the registry portion of the study and treated with medical therapy. For prospectively collected data in the randomized study and the registry, an independent clinical events committee (CEC) adjudicated all clinical endpoints. Key Exclusion Criteria Prior coronary artery bypass grafting (CABG) Left ventricular ejection fraction (LVEF) < 30% Left main (LM) stenosis

4 Study Endpoints Primary Endpoint Composite of: All-cause death Nonfatal myocardial infarction Unplanned hospitalization with urgent revascularization As adjudicated by an independent CEC. Secondary Endpoints Individual components of the primary endpoint* Cardiac death* Nonurgent revascularization procedures* Cost and cost-effectiveness Angina class *As adjudicated by an independent CEC. Original FAME 2 Study Flow Chart Stable patients scheduled for 1, 2 or 3 vessel DES stenting FFR in all target lesions RANDOMIZED TRIAL REGISTRY At least 1 stenosis with FFR 0.80 When all FFR > 0.80 Randomization 1:1 PCI + medical therapy medical therapy medical therapy Follow-up after 1, 6 months, 1, 2, 3, 4 and 5 years Medical Therapy Aspirin Beta blocker Calcium blocker and/or nitrate as necessary Statin ACE inhibitor (or ARB) Diabetes treatment guided by a specialist FFR-guided PCI FFR measured during hyperemia PCI only if FFR 0.80 and randomized to PCI 2nd-generation drug-eluting stents (recommended) Fractional Flow Reserve Measurements Intracoronary pressure measurements were obtained with a guiding catheter (fluid-filled) and the St. Jude Medical PressureWire Certus or Aeris guidewire. Cost-Effectiveness Analysis The aim of the cost-effectiveness analysis was to describe the economic and quality of life implications of the FFRguided PCI strategy in the FAME 2 trial. Direct medical costs of the index procedure and hospitalization were calculated from actual resource consumption. Follow-up events were assigned costs based on Medicare s reimbursement rate per diagnosis related group. Cumulative costs over 12 months were calculated monthly using an incremental approach. Angina was assessed at baseline, 1, 6 and 12 months. Patient utility (quality of life) was assessed using the EQ-5D with U.S. weights at baseline and 1 month. As only 11% of patients had 12-month utility measure, quality-adjusted life years (QALYs) were calculated by projection of 1-month EQ-5D change scores. Incremental cost-effectiveness ratios (ICERs) were estimated based on in-trial results and on extrapolation to 3 years of follow-up. One-year cost differences were assumed to persist in subsequent follow-up. The following utility differences were estimated: Improved by PCI (in both arms), lasted 1 year One-month difference declined linearly over 3 years The cost-effectiveness ratio was calculated as: (Cost FFR-PCI Cost ) (Δ QALY FFR-PCI Δ QALY )

5 Results The independent Data and Safety Monitoring Board recommended halting patient recruitment due to a significantly increased patient risk of major adverse cardiac events among patients randomized to medical therapy alone compared to patients randomized to medical therapy plus PCI. The enrollment goal in FAME 2 was approximately 1,800 patients (randomized study and registry combined). The data sample presented here is the same data on which the decision to halt enrollment was based (January 15, 2012). A total of 888 (73%) patients with ischemic lesions had been successfully randomized, and an additional 332 (27%) patients were enrolled in the registry because no ischemic lesions were detected. In total, 1,220 patients were enrolled in the FAME 2 trial, including 1,054 who were assigned to follow-up. Actual FAME 2 Study Flow Chart Underwent FFR (n = 1220) FFR >0.80 in all lesions included in registry (n = 332)* Randomized (n = 888) Allocated to PCI+medical therapy (n = 447) Received allocated intervention (n = 435) Did not receive allocated intervention (n = 12) Treated with balloon angioplasty (n = 3) Underwent CABG rather than PCI (n = 4) Received medical therapy, planned for staged procedure (n = 3) Received medical therapy, unsuccessful PCI (n = 1) Received medical therapy, FFR >0.8 (n = 1) Allocated to medical therapy alone (n = 441) Received allocated intervention (n = 439) Did not receive allocated intervention (n = 2) Erroneously received DES (n = 2) Randomly selected to receive follow-up (n = 166) Received medical therapy alone (n = 165) Received DES (n = 1) Follow-up information for primary endpoint available until Jan 15, 2012 (n = 446) Followed up and alive (n = 445) Deceased (n = 1) Follow-up at Jan 15, 2012 unavailable (n = 1) Withdrew (n = 1) Lost to follow-up (n = 0) Follow-up information for primary endpoint available until Jan 15, 2012 (n = 439) Followed up and alive (n = 436) Deceased (n = 3) Follow-up at Jan 15, 2012 unavailable (n = 2) Withdrew (n = 2) Lost to follow-up (n = 0) Follow-up information for primary endpoint available until Jan 15, 2012 (n = 163) Followed up and alive (n = 163) Deceased (n = 0) Follow-up at Jan 15, 2012 unavailable (n = 3) Withdrew (n = 1) Lost to follow-up (n = 2) Analyzed on primary clinical endpoint (n = 447) Censored at time of lost to follow-up or withdrawal (n = 1) Analyzed on primary clinical endpoint (n = 441) Censored at time of lost to follow-up or withdrawal (n = 2) Analyzed on primary clinical endpoint (n = 166) Censored at time of lost to follow-up or withdrawal (n = 3) * Note that 6 patients had total occlusions supplying akinetic myocardium and were therefore not considered for PCI; 1 patient had 2 FFR negative lesions and was therefore included in the registry; however, a subsequently detected total occlusion was eventually treated with DES.

6 Baseline Characteristics I* PCI+medical therapy Randomized Trial p-value for Trial vs. medical therapy alone Patients n = 447 n = 441 n = 166 Age in years, mean±sd ± ± ± Men, n (%) 356 (79.6) 338 (76.6) 113 (68.1) BMI, mean±sd ± ± ± Family history of coronary artery disease, n (%) 216 (48.3) 207 (46.9) 76 (45.8) 0.65 Current smoking, n (%) 89 (19.9) 90 (20.4) 35 (21.1) 0.79 Hypertension, n (%) 347 (77.6) 343 (77.8) 136 (81.9) 0.23 Hypercholesterolemia, n (%) 330 (73.8) 348 (78.9) 118 (71.1) 0.15 Diabetes mellitus, n (%) 123 (27.5) 117 (26.5) 42 (25.3) 0.65 Insulin requiring diabetes, n (%) 39 (8.7) 39 (8.8) 10 (6.0) 0.24 Renal insufficiency (Creatinine > 2.0 mg/dl), n (%) 8 (1.8) 12 (2.7) 7 (4.2) 0.14 Peripheral vascular disease, n (%) 43 (9.6) 47 (10.7) 8 (4.8) 0.03 History of stroke/tia, n (%) 33 (7.4) 28 (6.3) 10 (6.0) 0.69 History of MI, n (%) 164 (37.1) 165 (37.8) 60 (36.6) 0.83 History of PCI in target vessel, n (%) 80 (17.9) 76 (17.2) 34 (20.5) 0.37 Angina Class, n (%) 0.64 Asymptomatic 53 (11.9) 46 (10.5) 17 (10.2). CCS class I 82 (18.3) 98 (22.3) 42 (25.3). CCS class II 204 (45.6) 197 (44.8) 74 (44.6). CCS class III 80 (17.9) 65 (14.8) 23 (13.9). CCS IV, stabilized 28 (6.3) 34 (7.7) 10 (6.0). Silent Ischemia, n (%) 73 (16.3) 73 (16.6) 27 (16.3) 0.96 Left ventricular ejection fraction<50%, n (%) 83 (19.6) 56 (13.7) 27 (18.0) 0.69 Classification of patients according to angiography No. of significant lesions per patient, mean±sd 1.87 ± ± ± 0.59 <0.001 No. of vessels per patient with at least one significant lesion, n (%) < (56.2) 261 (59.2) 136 (81.9) (34.9) 146 (33.1) 26 (15.7) (8.9) 34 (7.7) 4 (2.4). Proximal or mid LAD stenosis (%) <0.001 Classification of patients according to FFR No. of significant lesions per patient according to FFR, mean±sd 1.52 ± ± ± 0.17 <0.001 No. of vessels with significant lesions by FFR, n (%) < (74.0) 343 (77.8) 5 (3.0) (22.8) 85 (19.3) 0 (0) 3 14 (3.1) 13 (2.9) 0 (0) Proximal or mid LAD stenosis (%) <0.001 Lesions n = 890 n = 815 n = 241 Classification of lesions according to angiography No. of significant lesions (diameter stenosis>50%), n (%) 837 (94.0) 764 (93.7) 219 (90.9) 0.13 Percent diameter stenosis, n (%) <0.001 <50% 53 (6.0) 51 (6.3) 22 (9.1) 50-69% 317 (35.6) 331 (40.6) 176 (73.0) 70-90% 383 (43.0) 331 (40.6) 38 (15.8) >90% 101 (11.3) 80 (9.8) 0 (0) Total occlusions 36 (4.0) 22 (2.7) 5 (2.1) Classification of lesions according to FFR No. of significant lesions (FFR 0.80), n (%) 679 (76.3) 625 (76.7) 5** (2.1) <0.001 FFR in significant lesions, mean±sd 0.68 ± ± ± * Differences between the two randomized groups were not significant with the exception of left ventricular ejection fraction<50% (p<0.04). Data are mean±sd or number of patients assessed (%). P-value using chi square test; when cells are small Fisher s test is used. Data for ejection fraction were available for 423 in PCI&medical therapy, 410 in medical therapy and 150 in registry. Data for history of MI were available for 442 in PCI&medical therapy, 436 in medical therapy and 295 in registry. CCS=Canadian Cardiovascular Society functional classification of angina pectoris; Data available in 447 in PCI&medical therapy, 440 in medical therapy, and 166 in registry. ** Five totally occluded arteries supplied infarcted areas and therefore not considered for revascularization using PCI. In patient level analysis p-value calculated using chi-square test, in case of cells <15 Fisher s test. In lesion level analysis, mixed maximum-likelihood logistic regression models were used for comparisons between groups for dichotomous variables and mixed maximum-likelihood linear regression models for continuous variables to account for the correlation of multiple lesions within patients..

7 Death or MI or Urgent Revascularization Cumulative incidence (%) No. at risk 5 0 vs. : HR 0.32 ( ); p<0.001 vs. : HR 1.29 ( ); p=0.61 vs. : HR 4.32 ( ); p< Months after randomization Death Cumulative incidence (%) No. at risk 5 0 vs. : HR 0.33 ( ); p=0.31 vs. : HR 1.12 ( ); p=0.54 vs. : HR 2.66 ( ); p= Months after randomization

8 Urgent Revascularization Cumulative incidence (%) No. at risk 5 0 vs. : vs. : HR 0.13 ( ); p<0.001 vs. : HR 0.63 ( ); p=0.43 HR 4.65 ( ); p= Months after randomization Myocardial Infarction Cumulative incidence (%) No. at risk 5 0 vs. : vs. : HR 1.61 ( ); p=0.41 vs. : HR 1.05 ( ); p=0.89 HR 1.65 ( ); p= Months after randomization

9 Percentage of patients with angina class II IV and corresponding risk ratios in randomized and registry patients at the different time points Randomized Trial Trial vs. n/n RR (95% CI) P RR (95% CI) P Baseline 312/ ( ) ( ) /440 Reference 1.04 ( ) /166 - Reference 30 days 46/ ( ) < ( ) /412 Reference 1.87 ( ) /149 - Reference 6 months 21/ ( ) ( ) /239 Reference 1.36 ( ) /92 - Reference 12 months 1/ ( ) ( ) /37 Reference 1.14 ( ) /7 - Reference Percentage of patients with CCS II to IV, % Reasons for urgent revascularization Unstable angina only 51.8% N= % N= % N=15 Myocardial infarction Unstable angina plus evidence of ischemia on ECG 21.4% MI 26.8% ECG changes Only urgent revascularization triggered by MI or UA 83% relative risk reduction P<0.001 If you only count the urgent revascularizations triggered by MI or UA with evidence of ischemia on ECG, the difference between FFR-guided PCI and alone is still statistically significant, and the relative risk reduction is still 83%. Reasons for urgent revascularization MI UA and ischemia on ECG UA only* N = 12 (21.4%) N = 15 (26.8%) N = 29 (51.8%) * Resting symptoms (i.e., unstable) that were refractory to medication and therefore required hospitalization. Fulfilled criteria of ACS based on the judgement of the blinded CEC, who adjudicated each case. Only urgent revascularization triggered by MI or UA PCI group group N = 4 (0.9%) N = 23 (5.2%) UNEQUIVOCAL EVIDENCE OF ACS Urgent revascularization triggered by MI or unstable angina with evidence of ischemia on ECG: 0.9% (PCI) vs. 5.2% (). Hazard ratio with PCI, 0.13; 95% CI, 0.04 to 0.43; P<0.001

10 Cost-Effectiveness Analysis Results Cost Estimates FFR-guided PCI P-value Baseline $8,790 $3,305 <0.001 Drug-Eluting Stent(s) $4,304 $48 < Year Follow-up $2,584 $5,561 <0.001 Revascularization $442 $3,928 <0.001 TOTAL $11,374 $8,866 <0.001 At baseline, 1-year cost estimates per patient were significantly higher for FFR-guided PCI vs. medical therapy, driven mainly by the cost of drug-eluting stents. There was, however, a catch-up effect during follow-up, where the cost of revascularization, which was more frequent in the group, caused cost estimates for to be significantly higher than for FFR-guided PCI. In addition to a relative risk reduction for developing acute coronary syndromes leading to unplanned hospital readmission and urgent revascularization, patients in the FFR-guided PCI group experienced significantly improved quality of life, including lower angina class, at 1 month as compared to the patients in the -only group. Mean Cumulative Cost, $ Cumulative Costs over 12 Months 0 2,000 4,000 6,000 8,000 10,000 $5,485 Quality of Life at 1 Month $2,508 FFR-Guided PCI % of study population 100% 56% 11% Month FFR-guided PCI P-value Angina (%) Class <0.001 Class <0.001 Utility Change <0.001 FFR-Guided PCI Incremental Cost-Effectiveness Ratio In-trial results $2,500 / QALY = $53,000 / QALY 3-Year Projection $2,500 / QALY = $32,000 / QALY FFR-guided PCI was shown to be cost-effective compared with medical therapy alone. Due to the study being stopped early, the in-trial results showed $53,000 per QALY gained. This is in line with the common QALY threshold of $50,000. In addition, a 3-year projection was completed to determine a more realistic QALY calculation. The results of this analysis showed $32,000 per QALY gained, well below the $50,000 QALY threshold. FAME 2 shows that the addition of FFR guidance makes PCI a cost-effective strategy compared to medical therapy alone. Interventions with ICERs between $50,000 (hemodialysis standard) and $150,000 (WHO GDP standard) are generally considered to be cost-effective. The COURAGE study did not include FFR and did not show PCI to be a cost-effective strategy. FAME 1 showed FFR-guided PCI to be not only cost effective, but cost saving (reduced costs while also improving clinical outcomes) in patients with multivessel disease. FAME 2 clearly shows that PCI guided by FFR not only improves outcomes but is economically attractive. CE Benchmarks: Hemodialysis = $50,000 / QALY WHO GDP standard $150,000 / QALY Study Comparators CE Ratio COURAGE Angio-Guided PCI vs. $168,000+ / QALY FAME 1 Angio-Guided PCI vs. FFR-Guided PCI FFR-Guided PCI is Dominant ( $ / QALY) FAME 2 FFR-Guided PCI vs. $32,000 / QALY Note: Courage showed ICERs of $168,000 and higher.

11 Limitations The cost-effectiveness analysis is limited by the short time horizon, and cost-effectiveness estimates have wide confidence limits due to: Model assumptions Parameter uncertainty Statistical uncertainty Conclusions FAME 2 demonstrated that FFR-guided PCI using PressureWire is a cost-effective strategy in stable patients with CAD that significantly reduces the risk for ACS requiring urgent revascularization compared to medical therapy alone. The new data support the paradigm of Functionally Complete Revascularization, that is, stenting of ischemic lesions and medical treatment of nonischemic ones. FFR-Guided PCI Is a Cost-Effective Strategy in Stable Patients with CAD that Improves Patient Outcomes, Quality of Life and Significantly Reduces the Risk for ACS Requiring Unplanned Hospital Readmission Leading to Urgent Revascularization Compared to Medical Therapy Alone.

12 St. Jude Medical is focused on reducing risk by continuously finding ways to put more control into the hands of those who save and enhance lives. The content of this clinical summary is based on: De Bruyne B, Pijls N, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11): ; published online ahead of print August 28, Grosse SD. Assessing cost-effectiveness in healthcare: History of the $50,000 per QALY threshold. Expert Rev Pharmacoecon Outcomes Res. 2008;8(2): St. Jude Medical. Data on File. FAME 2 study protocol. World Health Organization. CHOosing Interventions that are Cost Effective (WHO-CHOICE). Last accessed October 23, FAME 2 Study Identifier: NCT ATRIAL FIBRILLATION CARDIAC RHYTHM MANAGEMENT CARDIOVASCULAR NEUROMODULATION Global Headquarters One St. Jude Medical Drive St. Paul, Minnesota USA Fax Cardiovascular Division 177 East County Road B St. Paul, Minnesota USA Fax U.S. Division 6300 Bee Cave Road Building Two, Suite 100 Austin, Texas USA Fax St. Jude Medical Systems AB Box 6350 SE Uppsala Sweden Fax SJM Coordination Center BVBA The Corporate Village Da Vincilaan 11 Box F Zaventem, Belgium Fax St. Jude Medical Japan Co., Ltd. Shiodome City Center 15F 1-5-2, Higashi-Shinbashi Minato-ku Tokyo Japan Fax St. Jude Medical (Hong Kong) Ltd. Suite 1608, 16/F Exchange Tower 33 Wang Chiu Road Kowloon Bay, Kowloon Hong Kong SAR Fax St. Jude Medical Brasil Ltda. Rua Itapeva, 538 5º ao 8º andar São Paulo SP Brazil Fax St. Jude Medical Australia Pty. Ltd. 17 Orion Road Lane Cove NSW 2066 Australia Fax SJMprofessional.com SJMknowledgecenter.com Rx Only Brief Summary: Please review the Instructions for Use prior to using these devices for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use. Product referenced is approved for CE Mark. PressureWire Aeris and PressureWire Certus are designed, developed and manufactured by St. Jude Medical Systems AB. PressureWire, Aeris, Certus, ST. JUDE MEDICAL, the nine-squares symbol and MORE CONTROL. LESS RISK. are registered and unregistered trademarks and service marks of St. Jude Medical, Inc. and its related companies St. Jude Medical, Inc. All rights reserved. IPN GMVASC467EN