Cardiology Trials

N Engl J Med 2004;350:221-31 [https://www.nejm.org/doi/full/10.1056/NEJMoa032441] Background: For the past year we have been posting reviews of seminal trials in cardiovascular medicine. It is our anticipation that these will ultimately be published in a textbook format that will be indexed by major subject headings and the reviews will be presented in chronological order. However, in curating postings for Substack we have had to jump around in order to maintain some consistency in the topics being presented. We started this year by reviewing medical therapies for patients with acute coronary syndrome. After that we moved to the management of patients with mostly stable coronary artery disease and have completed reviews on trials involving CABG and percutaneous coronary interventions compared to medical therapy and to each other, in the case of patients with left main and multivessel disease. In completing that stream of trials, we intentionally skipped trials that have been instrumental in developing those techniques, especially coronary stenting. While perhaps not that important to general readers, medical trainees, especially in the field of cardiovascular medicine need to be familiar with these trials. They are not intended to address questions involving stenting versus medical care but instead, to address the question of “If you’re going to stent, is it better to use product A or B?” In that vein, we recently reviewed the RAVEL trial that compared sirolimus-eluting stents to bare metal stents. This is an issue of interest because a common problem following PCI is restenosis of the treated area due to the process of neointimal proliferation that involves the migration and proliferation of smooth muscle cells from the injured arterial wall. The idea behind drug coated stents was that the drug coatings would reduce this process locally (at the level of stented arterial wall) by blocking the process of neointimal proliferation and hyperplasia, which is not the same as atherosclerosis. RAVEL was a small trial showing that a sirolimus-eluting stent improved the surrogate endpoint of in-stent luminal loss at 6 months compared to a bare metal stent. The TAXUS-IV trial was undertaken for similar purposes but on a larger scale and sought to test a more clinically relevant endpoint. It sought to test the hypothesis that a paclitaxel-eluting stent would reduce ischemia-driven target-vessel revascularization compared to a bare metal stent. *Note to learners: A common parlance for describing stents in the clinical setting is to refer to them based on generation (e.g., first, second, or third generation). First generation stents are bare metal stents. Second and third generation stents are drug eluting stents with newer generations often featuring improved biocompatibility and drug delivery mechanisms. Sirolimus- and paclitaxel-eluting stents are considered second generation stents. Patients: Patients had to be 18 years of age or older, have stable or unstable angina or provokable ischemia, and were undergoing PCI for a single, previously untreated lesion in a native coronary artery. Angiographic inclusion required a single target lesion with a reference-vessel diameter on visual examination of 2.5 to 3.75 mm and a lesion length of 10 to 28 mm that could be covered by a single study stent. There were many exclusion criteria that can be summarized as follows: acute MI, complex coronary disease (including left main, ostial target lesion or bifurcating target lesion), complex patient and predisposition to bleeding. Baseline characteristics: The average age of patients was 62 years and 72% were men. Approximately 30% of patients had diabetes with nearly a quarter requiring insulin. Over 20% were smokers and 30% had a previous MI. The average LV EF was 55%. The target lesion was located in the LAD in 40%, the circumflex in close to 30% and the right coronary artery in 30%. The reference-vessel diameter was >/=3.0 mm in over 75% of patients. The average lesion length was 13 mm, average reference-vessel diameter was 2.75 mm, average minimal luminal diameter was 0.92 mm, and average % stenosis was 66%. Procedures: Patients were assigned in equal proportions in a double-blind fashion to treatment with either the paclitaxel-eluting stent or a visually indistinguishable bare-metal stent. Unfractionated heparin was administered according to standard practice, and the use of glycoprotein IIb/IIIa inhibitors was at the operator’s discretion. After mandatory balloon dilation, patients received an appropriately-sized stent. A postprocedural electrocardiogram was obtained, and cardiac enzymes were measured every 8 hours for 24 hours. Patients took 325 mg of aspirin daily indefinitely and 75 mg of clopidogrel daily for 6 months. Clinical follow-up was scheduled at 1, 4 and 9 months and yearly thereafter for 5 years. Endpoints: The primary end point was the 9 month incidence of ischemia-driven target-vessel revascularization. It was considered to be “ischemia driven” if the stenosis of the target vessel was at least 50% of the luminal diameter on the basis of quantitative analysis with either: 1) ECG changes while the patient was at rest or 2) a functional study indicating ischemia in the distribution of the target vessel. It was also considered “ischemia driven” if there was a 70% stenosis in conjunction with recurrent symptoms alone. *It should be noted that in this case “ischemia driven” does not necessarily mean symptom driven. Major adverse cardiac events were defined as death from cardiac causes, MI, or ischemia-driven target-vessel revascularization. Target-vessel failure was defined as death, MI or ischemia-driven target vessel revascularization related to the target vessel. Analysis was based on the intention-to-treat principle. A total of 1172 patients were needed to detect a 40% relative reduction (6% absolute reduction) in the primary endpoint based on an anticipated event rate of 15% in the bare-metal stent group. This sample size would have 85% power with an alpha level of 0.05 to detect the difference described above while allowing for a drop out rate of 10%. Results: A total of 1,326 patients were enrolled over a 3 month period from 73 US centers and 1,314 were included in the final analysis with 662 in the paclitaxel-eluting stent group and 652 in the bare-metal stent group. The initial angiographic results were similar in the 2 groups. At 9 months, paclitaxel-eluting stents reduced the primary endpoint of ischemia-driven target vessel revascularization by 61% (4.7% vs 12.0%; RR 0.39; 95% CI 0.26-0.59). There were no differences in death from cardiac causes (1.4% vs 1.1%), MI (3.5% vs 3.7%), or stent thrombosis (0.6% vs 0.8%). In a prespecified subset of patients who underwent coronary angiography at 9 months, paclitaxel-eluting stents were associated with better angiographic features compared to bare-metal stents. Conclusions: In patients with stable and unstable angina (not acute MI), paclitaxel-eluting stents significantly reduced ischemia-driven target vessel revascularization at 9 months of follow-up with a number needed to treat of approximately 14 patients. There were no differences in any hard endpoints. While some would hail this as a remarkably positive trial we have reservations. Firstly, the primary endpoint is not symptom-driven and it should be regarded as a surrogate endpoint. At the time this trial was undertaken it was routine practice for patients to undergo surveillance testing with ECG’s and functional tests following coronary revascularization and this is likely how the majority of patients came to undergo revascularization (not via a symptom-driven route). Had these elective revascularizations not occurred, it is unknown whether it would have resulted in any deleterious consequences. Second, patients enrolled in the trial were highly selected and no information is provided in the main manuscript on how many underwent screening. Commonly-occurring angiographic features of coronary lesions, for which patients undergo PCI, were excluded (i.e., ostial and bifurcating lesions, lesions in vessels with reference vessel diameters <2.5 mm, etc.). Third, there were no differences in hard outcomes like death from cardiac causes, MI or stent thrombosis but the trial was not powered for these events. It cannot be determined from this study whether target-vessel revascularization even improved symptoms or any other proxy measure of quality of life. In conclusion, the TAXUS-IV trial demonstrated that paclitaxel-eluting stents reduced the surrogate endpoint of target lesion revascularization at 9 months compared to bare-metal stents in highly selected patients with stable coronary disease. Whether this translates into improvements in hard endpoints or even patient-centered endpoints cannot be answered by this study. 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 [https://cardiologytrials.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]

N Engl J Med 2002;346:1773-1780 [https://www.nejm.org/doi/full/10.1056/NEJMoa012843] Background: Percutaneous revascularization of the coronary arteries is frequently performed for patients with stable and unstable angina. By the late 1990s and early 2000s, most percutaneous coronary interventions (PCI) were performed with intracoronary stent placement rather than balloon angioplasty alone given lower rates of angiographic detected restenosis with stent placement. However, stent restenosis was a common cause of repeat revascularization. Unlike the process of atherosclerotic plaque development, stent restenosis is caused by a distinct process of neointimal proliferation. When a blood vessel is injured during a procedure like coronary stenting, the body's natural healing response triggers the migration and proliferation of smooth muscle cells from the vessel wall into the inner lining (intima), creating a new tissue layer called neointima. If the neointima grows excessively, it can narrow the blood vessel lumen, leading to restenosis, which can cause symptoms like angina. Early coronary stenting was performed using bare-metal stents that were prone to neointimal proliferation. Animal studies and a small clinical study at the time suggested that the systemic or local administration of the drug sirolimus could reduce neointimal proliferation. Sirolimus is a macrocyclic lactone that inhibits cytokine-mediated and growth-factor–mediated proliferation of lymphocytes and smooth-muscle cells. The RAVEL trial [https://www.nejm.org/doi/full/10.1056/NEJMoa012843] sought to assess the performance of stents coated with sirolimus (drug-eluting stents ”DES”) compared to uncoated stents (bare-metal stents “BMS”). Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Patients: Eligible patients had stable angina, unstable angina, or silent ischemia. Only patients with single target lesions in a native coronary artery were included. The stenosis had to be 51-99% and could be covered by an 18 mm stent. The coronary artery had to be 2.5 – 3.5 mm in diameter. Patients were excluded if they had evolving myocardial infarction, left main disease unprotected by a graft, ostial lesions, calcified lesions that couldn’t be completely dilated, angiographically visible coronary thrombus, ejection fraction <30% or intolerance to antiplatelets. Baseline characteristics: The trial randomized 238 patients – 120 randomized to receive a sirolimus DES and 118 to receive a BMS. The average age of patients was 61 years and 76% were men. Approximately 61% had hypertension, 36% had prior myocardial infarction, 19% had diabetes, 40% had hyperlipidemia, and 30% were current smokers. Approximately 50% had unstable angina, 39% had stable angina, and 11% had silent ischemia. The target lesion was left anterior descending artery in 50% of the patients, left circumflex artery in 23% and right coronary artery in 27%. The average target vessel diameter was 2.6 mm. Procedures: Stenting without pre-dilation was not allowed. After pre-dilation, patients were assigned in a 1:1 ratio to either of the stents. The trial was double-blinded and the two types of stents were indistinguishable except under the microscope. Coronary angiograms before dilation, after PCI and at six months were assessed by a core laboratory to determine the luminal diameter of the coronary artery and the degree of stenosis. Dual antiplatelets were continued for eight weeks. Endpoints: The primary outcome was in-stent luminal loss at six months, defined as the difference between the minimal luminal diameter immediately after PCI and the diameter at six months. Restenosis defined as a luminal stenosis of 50% or more was assessed as a secondary endpoint. The study also assessed a clinical endpoint at 12 months. This endpoint included death, myocardial infarction, coronary artery bypass grafting and PCI of the target lesion. Analysis was performed based on the intention-to-treat principle. A total of 207 patients were needed to have 90% power with a two sided alpha of 0.05, to detect a difference in the mean late luminal loss of 0.25 mm between the two treatment groups. Results: Successful stent placement was 97% in the sirolimus DES arm and 93% in the BMS arm. Angiographic data at six months were available from 89% of the patients. At six months, the primary outcome of in-stent luminal loss was significantly lower in the sirolimus DES arm (-0.01 mm vs 0.80 mm; p< 0.001). Luminal restenosis of 50% or more was also significantly lower with the sirolimus DES (0.0% vs 26.6%; p< 0.001). At one year, the clinical endpoint of death, myocardial infarction, coronary artery bypass grafting and PCI of the target lesion was lower with the sirolimus DES (5.8% vs 28.8%; p< 0.001). This was driven by lower repeat revascularization in the sirolimus DES arm (0.0% vs 22.9%). There were four patients who died; two in each group. Conclusion: Sirolimus drug-eluting stents reduced neointimal proliferation and in-stent restenosis compared to bare-metal stents. These findings are very promising as in-stent restenosis is a major concern with the use of bare-metal stents. The study focused on single lesions in coronary arteries measuring 2.5 – 3.5 mm in diameter and more validation is required. Additionally, the study was not adequately powered to evaluate clinical outcomes and these findings need to be confirmed in larger studies. Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. 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The Lancet Volume 403, Issue 10438 p1753-1765May 04, 2024 [https://doi.org/10.1016/S0140-6736(24)00413-6] Background Cardiologist have long been taught that acute plaque rupture leading to myocardial infarction is more likely to come from non-flow-limiting lipid-rich atherosclerotic plaques. The concept of the vulnerable plaque is surely one of the reasons that revascularization of high-grade stable coronary artery disease does not reduce myocardial infraction or death over optimal medical therapy. The search for and treatment of the vulnerable plaque remains one of the important research areas in modern cardiology. South Korean investigators set out to test whether PCI of non-flow-limiting, high-risk vulnerable plaques identified by intracoronary imaging would reduce major adverse cardiac outcomes over medical therapy in the Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT [10.1016/S0140-6736(24)00413-6]). Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Patients Patients were recruited in the cardiac catheterization lab. Both ACS and stable CAD patients were included. FFR was done to exclude significant flow limitations. Clinically relevant lesions with an FFR ≤ 0.80 underwent PCI with a drug-eluting stent before randomization. All untreated, non-culprit lesions (ie, those that were clearly not responsible for the presenting clinical syndrome) with an angiographic diameter stenosis of 50% or more by site visual estimation were functionally assessed by fractional flow reserve. Then, intermediate non-flow-limiting lesions (FFR >0.80) were assessed by intra-coronary imaging—with one of four techniques (at the discretion of the operator). These included grey-scale intravascular ultrasonography (IVUS), radiofrequency intravascular ultrasonography, a combination of grey-scale intravascular ultrasonography and near-infrared spectroscopy, or optical coherence tomography (OCT). Vulnerable plaques were defined as lesions possessing at least two of the following four characteristics: a minimal lumen area of less than 4·0 mm2 by IVUS or OCT; a plaque burden of more than 70% by IVUS; a lipid-rich plaque by near-infrared spectroscopy (defined as maximum lipid core burden index within any 4 mm pullback length [maxLCBI4mm] >315); or a thin-cap fibroatheroma detected by radiofrequency intravascular ultrasonography or optical coherence tomography (defined as a ≥10% confluent necrotic core with >30° abutting the lumen in three consecutive frames on radiofrequency intravascular ultrasonography or as a lipid plaque with arc >90° and fibrous cap thickness <65 μm on optical coherence tomography). Major exclusion criteria included previous coronary-artery bypass grafting, target-lesions previously stented, patients with three and more target lesions or two target lesions in the same coronary artery, heavily calcified or angulated lesions, or bifurcation lesions requiring two-stent techniques. Baseline Characteristics Trialists screened 5627 patients and randomized 1606 in 1:1 fashion. Approximately 2000 patients were excluded because all lesions had FFR ≤ 0.80 and were referred for PCI. Another 2000 were excluded for not meeting the imaging criteria of a vulnerable plaque. The median age was 65 years, 73% were men and about a third had diabetes. More patients had stable CAD (84%) then unstable syndromes. PCI of non-target lesions was performed in 36% of patients while 64% had PCI of only target lesions. The mean left ventricular ejection fraction was 63% in both groups. The median fractional flow reserve of the 1672 target lesions was 0·86 (IQR 0·83–0·90) and their mean diameter stenosis was 54·5%. For the predefined criteria for plaque vulnerability per patient, 1562 (97%) of 1606 patients qualified with minimal luminal area less than 4·0 mm2, 1533 (96%) qualified with plaque burden greater than 70%, 186 (11%) qualified with maxLCBI4mm greater than 315, and 77 (5%) qualified as thin-cap fibroatheromas. PCI of non-flow-limiting lesions was performed in 729 (91%) of the 803 patients assigned to preventive PCI, with bioresorbable vascular scaffolds (in 237 [33%] of 729 patients) or cobalt–chromium everolimus-eluting metallic stents (in 491 [67%]. In the preventive PCI group, 74 (9%) patients crossed over to medical therapy alone. In the medical therapy group, 791 (99%) received medical therapy alone and 12 (1%) patients crossed over to percutaneous coronary intervention. The most common reason for cross-over was patient or physician preference. Use of dual antiplatelet therapy was greater in the percutaneous coronary intervention group than the optimal medical therapy alone group. More than half of patients in both groups were taking high-intensity statins or moderate-intensity statins plus ezetimibe during the entire follow-up period Procedures Initially, patients in the PCI arm had bioresorbable vascular scaffolds, but when these were withdrawn from the market, PCI was done with cobalt–chromium everolimus-eluting metallic stents (Xience; Abbott, Santa Clara, CA, USA) were used. Intravascular imaging of all target lesions in enrolled patients was performed to guide percutaneous coronary intervention. After percutaneous coronary intervention, patients received dual antiplatelet therapy for at least 6 or 12 months according to clinical presentation and anatomical complexity. Optimal medical therapy in both groups included lifestyle modification, and intensive pharmacological therapy per guidelines. Clinical follow-up was done at 1, 6, 12, and 24 months after randomization and every year thereafter. Follow-up continued annually in all enrolled patients until the last enrolled patient reached 2 years after randomization. Trialists assumed an incidence of the primary outcome at 2 years of 8·5% for the preventive percutaneous coronary intervention group and 12·0% for the medical therapy alone group, which corresponds to a 30% relative risk reduction. A sample size of 1600 patients provided 80% power at a two-sided significance level of 5%, assuming a 7% loss to follow-up and crossover rate. Endpoints The primary outcome was a composite of cardiovascular (CV) death, target-vessel myocardial infarction (MI), ischemia-driven revascularization or hospitalization for unstable or progressive angina. Secondary outcomes included all the original components of the primary composite, as well as, death from any cause, any MI, any revascularization, definite stent thrombosis, stroke, bleeding events, angina status, procedural complications, and the composite all-cause death, all MI, or any repeat revascularizations. Results The trial median follow-up was 4.3 years, but the primary outcome was measured at 2 years. The primary outcome occurred in three (0·4%) patients in the preventive percutaneous coronary intervention group and in 27 (3·4%) patients in the optimal medical therapy group (absolute difference –3·0 percentage points [95% CI –4·4 to –1·8] p=0·0003. The primary endpoint hazard curves favoring percutaneous coronary intervention diverged through 2 years of follow-up and were thereafter parallel. All components of the primary outcome favored PCI as did the secondary composite endpoint of death, MI, or any revascularization (3 vs 5.2% at 2 years; HR 0·69 (0·50 to 0·95). Procedural safety included the observation that 4 of 741 patients had a total of 5 acute adverse events.The benefit of PCI were similar in most subgroups though there was a stronger effect with cobalt stents over bioresorbable scaffold as well as when the median diameter stenosis was more than 55% vs less than 55%. Conclusion The trialists concluded that In patients with non-flow-limiting vulnerable coronary plaques, preventive percutaneous coronary intervention reduced major adverse cardiac events arising from high-risk vulnerable plaques, compared with optimal medical therapy alone. They then added this sentence: Given that PREVENT is the first large trial to show the potential effect of the focal treatment for vulnerable plaques, these findings support consideration to expand indications for percutaneous coronary intervention to include non-flow-limiting, high-risk vulnerable. Our conclusions are different. We laud the authors for testing a unique method of identifying high-risk plaques. But offer this list of our concerns: This was a highly select group of patients. More than 5600 patients were screened and only 1600 patients were randomized. There were small numbers of events 3 vs 27, mostly non-fatal events. In a trial of 1600. Note that all-cause MI rates were only 3.5% in the control arm at 7 years. This does not suggest that vulnerable plaques were that vulnerable (or, alternatively, medical therapy was quite good.) The significant results at 2 years did not remain significant at 4 and 7 years. You’d think that if this intervention was effective, the accrual of more events would strengthen not weaken the effect size. The other issue is the open-label design. Two of the endpoints are susceptible to human decision making. Namely, subtraction anxiety. Those patients who did not receive a stent (or get fixed) may have been more apt to be admitted for UA, or have a ‘target vessel revascularization.’ There were also more patients taking P2Y12 inhibitors in the PCI arm. Another reason they may have had fewer events. There was missing data in 50 patients; that’s not a small number given that the delta was only 24 events. Finally, and perhaps most importantly, there is the matter of translating this data to real life. Imaging of coronary lesions is not as common in some geographies. What’s more, 2 of the 4 imaging techniques that they used involve complicated devices, that are not universally available to many IC. In sum, PREVENT is a start. We would want to see imaging-guided identification and treatment of vulnerable plaques replicated in other studies. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe [https://cardiologytrials.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4]

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