Effect of Alcohol-Mediated Renal Denervation on Blood Pressure in the Presence of Antihypertensive Medications: Primary Results From the TARGET BP I Randomized Clinical Trial.

BACKGROUND: Renal denervation (RDN) has demonstrated clinically relevant reductions in blood pressure (BP) among individuals with uncontrolled hypertension despite lifestyle intervention and medications. The safety and effectiveness of alcohol-mediated RDN have not been formally studied in this indication. METHODS: TARGET BP I is a prospective, international, sham-controlled, randomized, patient- and assessor-blinded trial investigating the safety and efficacy of alcohol-mediated RDN. Patients with office systolic BP (SBP) ≥150 and ≤180 mm Hg, office diastolic BP ≥90 mm Hg, and mean 24-hour ambulatory SBP ≥135 and ≤170 mm Hg despite prescription of 2 to 5 antihypertensive medications were enrolled. The primary end point was the baseline-adjusted change in mean 24-hour ambulatory SBP 3 months after the procedure. Secondary end points included mean between-group differences in office and ambulatory BP at additional time points. RESULTS: Among 301 patients randomized 1:1 to RDN or sham control, RDN was associated with a significant reduction in 24-hour ambulatory SBP at 3 months (mean±SD, -10.0±14.2 mm Hg versus -6.8±12.1 mm Hg; treatment difference, -3.2 mm Hg [95% CI, -6.3 to 0.0]; P=0.0487). Subgroup analysis of the primary end point revealed no significant interaction across predefined subgroups. At 3 months, the mean change in office SBP was -12.7±18.3 and -9.7±17.3 mm Hg (difference, -3.0 [95% CI, -7.0 to 1.0]; P=0.173) for RDN and sham, respectively. No significant differences in ambulatory or office diastolic BP were observed. Adverse safety events through 6 months were uncommon, with one instance of accessory renal artery dissection in the RDN group (0.7%). No significant between-group differences in medication changes or patient adherence were identified. CONCLUSIONS: Alcohol-mediated RDN was associated with a modest but statistically significant reduction in 24-hour ambulatory SBP compared with sham control. No significant differences between groups in office BP or 6-month major adverse events were observed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02910414.

Novel Supreme Drug-Eluting Stents With Early Synchronized Antiproliferative Drug Delivery to Inhibit Smooth Muscle Cell Proliferation After Drug-Eluting Stents Implantation in Coronary Artery Disease: Results of the PIONEER III Randomized Clinical Trial.

BACKGROUND: Accelerated endothelial healing after targeted antiproliferative drug delivery may limit the long-term inflammatory response of drug-eluting stents (DESs). The novel Supreme DES is designed to synchronize early drug delivery within 4 to 6 weeks of implantation, leaving behind a prohealing permanent base layer. Whether the Supreme DES is safe and effective in the short term and can improve long-term clinical outcomes is not known. METHODS: In an international, 2:1 randomized, single-blind trial, we compared treatment with Supreme DES to durable polymer everolimus-eluting stents (DP-EES) in patients with acute and chronic coronary syndromes. The primary end point was target lesion failure-a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. The trial was designed to demonstrate noninferiority (margin of 3.58%) of the Supreme DES at 12 months compared with DP-EES (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03168776). RESULTS: From October 2017 to July 2019, a total of 1629 patients were randomly assigned (2:1) to the Supreme DES (N=1086) or DP-EES (N=543). At 12 months, target lesion failure occurred in 57 of 1057 patients (5.4%) in the Supreme DES group and in 27 of 532 patients (5.1%) in the DP-EES group (absolute risk difference, 0.32% [95% CI, -1.87 to 2.5]; Pnoninferiority=0.002]. There were no significant differences in rates of device success, clinically driven target lesion revascularization, or stent thrombosis at 12 months, and the safety composite of cardiovascular death and target vessel myocardial infarction was 3.5% versus 4.6% (hazard ratio, 0.76 [95% CI, 0.46-1.25]) with Supreme DES compared with DP-EES, although rates of combined clinically and non-clinically driven target lesion revascularization at 12 months were higher with Supreme DES. CONCLUSIONS: Among patients with acute and chronic coronary syndromes undergoing percutaneous coronary intervention, the Supreme DES proved to be noninferior to the standard DP-EES. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03168776.

The Supreme Biodegradable Polymer DES in Acute and Chronic Coronary Syndromes: A PIONEER III Substudy.

Background: The PIONEER III trial demonstrated noninferiority of 12-month target lesion failure (TLF) with the Supreme DES (Sinomed), a thin-strut cobalt-chromium, biodegradable polymer, sirolimus-eluting stent, compared with a durable polymer, everolimus-eluting (XIENCE/PROMUS) stent (DP-EES). The relative safety and effectiveness of the Supreme DES in patients with acute coronary syndromes (ACS) and those with chronic coronary syndromes (CCS) is not known. Methods: PIONEER III was a prospective, multicenter, international, 2:1 randomized trial stratified by clinical presentation. The primary end point was TLF at 12 months (a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization). Results: A total of 1628 patients were enrolled, including 41% of patients with ACS (unstable angina and non-ST-elevation myocardial infarction) randomized to Supreme DES (n = 441) versus DP-EES (n = 232) and 59% of patients with CCS randomized to Supreme DES (n = 645) versus DP-EES (n = 310). Patients with ACS were younger, fewer presented with less diabetes, hypertension, and previous revascularization, but more were current smokers. The primary end point of TLF (6.4% vs 4.4%; P = .1), major adverse cardiac events (8.5% vs 6.5%; P = .16), and stent thrombosis (0.4% vs 0.9%; P = .25) at 12 months were similar in the ACS and CCS groups. There was no difference in TLF at 12 months between Supreme DES and DP-EES among patients with ACS (6.6% vs 6.0%; P = .89) and those with CCS (4.5% vs 4.3%; P = .83); interaction P = .51 for TLF by clinical presentation. Conclusions: Compared with the DP-EES, the Supreme DES seemed safe and effective with a similar TLF at 12 months in both patients with ACS and those with CCS.

Geographic Variations on the Safety and Efficacy of the Supreme Biodegradable Polymer DES: Results From PIONEER III.

Background: The PIONEER III trial showed the 12-month safety and efficacy of the Supreme drug-eluting stent (DES) vs the durable polymer everolimus-eluting stent. We sought to assess whether the characteristics and clinical outcomes of the Supreme DES in PIONEER III were consistent among patients by enrollment location. Methods: This subgroup analysis of the PIONEER III trial compared the characteristics and outcomes of patients recruited from North America, Europe, and Japan and the relative differences in patient outcomes according to the site recruitment volume. Results: From October 2017 to July 2019, 1629 patients were recruited in North America (816, 50.1%), Europe (650, 39.9%), and Japan (163, 10%). Procedural success was achieved in 1556 of 1611 procedures (96.6%), with no difference by the geographic location. Target lesion failure at 12 months for combined groups was observed in 84 of 1629 patients (5.2%), with no significant geographic differences (4.7%, 6.5%, and 2.5%, respectively; P =.08), with similar results in the Supreme DES group alone (4.4%, 6.8%, and 3.7%, respectively, P =.20). Cardiac death at 12 months occurred in 0.4%, 0.2%, and 0.0% (P =.79), target vessel-related myocardial infarction occurred in 2.2%, 4.7%, and 3.7%, (P =.10), and clinically driven target lesion revascularization was required in 2.1%, 3.1%, and 0%, respectively (P =.15). Compared with those from high-recruiting sites, results from low-recruiting sites were similar for target lesion failure, major adverse cardiac events, stent thrombosis, and mortality, with a nonsignificant trend for higher rates of myocardial infarction. Conclusions: Despite regional differences in patient characteristics, the clinical outcomes between Supreme DES and durable polymer everolimus-eluting stent in the PIONEER III trial were not different, supporting the generalizability and robustness of the findings from this multicenter controlled trial.

Safety and Efficacy of the Supreme Biodegradable Polymer Sirolimus-Eluting Stent in Patients With Diabetes Mellitus.

Background: Patients with diabetes mellitus (DM) have worse outcomes following percutaneous coronary intervention than nondiabetic patients. The novel Supreme DES is a biodegradable polymer sirolimus-eluting stent designed to synchronize early drug delivery, limiting the potential for long-term inflammatory response. The purpose of this study was to evaluate the safety and efficacy of the Supreme DES in patients with DM. Methods: This is a prespecified analysis of the diabetic subgroup from the PIONEER III randomized (2:1), controlled trial, comparing the Supreme DES with a durable polymer everolimus-eluting stent (DP-EES). The primary safety and efficacy composite endpoint was target lesion failure at 1 year, a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Results: The PIONEER III trial randomized 1629 patients, of which 494 (30.3%) had DM with 331 (398 lesions) randomly assigned to Supreme DES and 163 (208 lesions) to DP-EES. Among patients with DM, target lesion failure at 1 year was 6.1% (20/331) with Supreme DES vs 3.7% (6/163) with DP-EES (hazard ratio = 1.65; 95% confidence interval = 0.66-4.10, P = .28). The composite of cardiac death or target vessel myocardial infarction was 3.3% (11/331) with Supreme DES and 3.7% (6/163) with DP-EES (hazard ratio = 0.90; 95% confidence interval = 0.33-2.44, P = .83). There were no significant differences in other secondary endpoints. Conclusions: This prespecified substudy of the PIONEER III trial demonstrated the relative safety and efficacy of the novel Supreme DES when compared with commercially available DP-EES in diabetics at 1 year. Longer term follow-up will be required to ensure continued safety and efficacy of the Supreme DES.

Outcomes of the Novel Supreme Drug-Eluting Stent in Complex Coronary Lesions: A PIONEER III Substudy.

Background: The Supreme healing-targeted drug-eluting stent (DES) is designed to promote endothelial healing to reduce stent-related adverse events. This may be particularly relevant among complex lesions that have a higher rate of adverse events. We sought to compare 1-year outcomes of percutaneous coronary intervention in complex lesions between the Supreme DES and contemporary durable-polymer, everolimus-eluting stents (DP-EES). Methods: PIONEER III was a multicenter, prospective, single-blind clinical trial, randomizing 1629 patients with either an acute or chronic coronary syndrome in a 2:1 ratio to the Supreme DES or DP-EES. Complex lesions (American College of Cardiology/American Heart Association type B2/C) were found in 1137 patients. Outcomes were also compared for specific parameters of lesion complexity: severe calcification, long length (>20 â€‹mm), and severe tortuosity. The primary end point was target lesion failure at 1 â€‹year. Results: At 1 â€‹year, there was no difference in target lesion failure between the Supreme DES and DP-EES: (5.7% vs 5.6%; hazard ratio 1.00, 95% confidence interval 0.59-1.68, P = .99). Similarly, there were no differences in the secondary end points of lesion success (99.7% vs 99.4%, P = .41), device success (97.0% vs 98.5%, P = .14), target vessel failure (6.5% vs 7.4%, P = .50), major adverse cardiac events (7.8% vs 8.5%, P = .64), or stent thrombosis (0.7% vs 1.1%, P = .48). A trend was observed toward a higher rate of target lesion revascularization with the Supreme DES (2.5% vs 0.9%, P = .06). Conclusions: This study suggests that the Supreme DES is as effective and safe at 1 â€‹year compared with the standard DP-EES across a broad spectrum of lesion complexity.

Safety and Effectiveness of the SVELTE Fixed-Wire and Rapid Exchange Bioresorbable-Polymer Sirolimus-Eluting Coronary Stent Systems for the Treatment of Atherosclerotic Lesions: Results of the OPTIMIZE Randomized Study.

[Figure: see text].

Clinical Conference Proceedings: 15th Biennial International Andreas Gruentzig Society Meeting.

The International Andreas Gruentzig Society is an educational society of physicians and scientists interested in cardiovascular and related fields. Members cooperate in the advancement of knowledge and education through research, publication, study, and teaching in the fields of cardiovascular disease. This summary reflects the proceedings from the recent scientific meeting to assess current clinical problems and propose future directions and possible solutions.

The State of the Absorb Bioresorbable Scaffold: Consensus From an Expert Panel.

Significant progress has been made in the percutaneous coronary intervention technique from the days of balloon angioplasty to modern-day metallic drug-eluting stents (DES). Although metallic stents solve a temporary problem of acute recoil following balloon angioplasty, they leave behind a permanent problem implicated in very late events (in addition to neoatherosclerosis). BRS were developed as a potential solution to this permanent problem, but the promise of these devices has been tempered by clinical trials showing increased risk of safety outcomes, both early and late. This is not too dissimilar to the challenges seen with first-generation DES in which refinement of deployment technique, prolongation of dual antiplatelet therapy, and technical iteration mitigated excess risk of very late stent thrombosis, making DES the treatment of choice for coronary artery disease. This white paper discusses the factors potentially implicated in the excess risks, including the scaffold consideration and deployment technique, and outlines patient and lesion selection, implantation technique, and dual antiplatelet therapy considerations to potentially mitigate this excess risk with the first-generation thick strut Absorb scaffold (Abbott Vascular, Abbott Park, Illinois). It remains to be seen whether these considerations together with technical iterations will ultimately close the gap between scaffolds and metal stents for short-term events while at the same time preserving options for future revascularization once the scaffold bioresorbs.

Comparison of long-term (seven year) outcomes among patients undergoing percutaneous coronary revascularization with versus without stenting.

Coronary stents have markedly improved the short- and intermediate-term safety and efficacy of percutaneous coronary intervention by improving acute gains in luminal dimensions, decreasing abrupt vessel occlusion, and decreasing restenosis, yet the long-term benefit of coronary stenting remains uncertain. We examined long-term clinical outcomes of death, myocardial infarction, and repeat target vessel revascularization (TVR) among patients enrolled in the Duke Database for Cardiovascular Disease who underwent revascularization with percutaneous transluminal coronary angioplasty alone or stent placement from 1990 to 2002. Among 6,956 patients who underwent percutaneous revascularization, propensity modeling was applied to identify 1,288 matched patients with a similar likelihood to receive coronary stents according to clinical, angiographic, and demographic characteristics. Significant (p <0.05) predictors of stent placement included multivessel disease, diabetes, hypertension, recent myocardial infarction, decreased ejection fraction, and year of study entry. At a median follow-up of 7 years, although treatment with coronary stenting was associated with a significant and sustained decrease in repeat TVR (18.0% vs 28.1%, p = 0.0002) and the occurrence of death, myocardial infarction or TVR (39.2% vs 45.8%, p = 0.004), long-term survival did not significantly differ between treatment groups (19.9% vs 20.5%, p = 0.72). Outcomes of death and myocardial infarction did not significantly differ between patients who did and did not undergo repeat TVR. In conclusion, compared with angioplasty alone, revascularization with coronary stents provides a significant early and sustained decrease in the need for repeat revascularization, but stents do not influence long-term survival.

Peripheral arterial disease: an overview of endovascular therapies and contemporary treatment strategies.

Even in the absence of symptoms, peripheral arterial disease carries with it a significant risk of morbidity and mortality; thus, screening with the use of the ankle-brachial index is important in identifying patients at risk. Endovascular therapy in the lower extremities is continually evolving for treatment of patients with claudication symptoms or limb-threatening ischemia. Alternative treatments such as cryotherapy and the use of laser-assisted angioplasty hold much promise but need further investigation. In the case of renal artery stenosis and resulting hypertension, supportive clinical evidence is limited for renal revascularization despite the rationale for reducing cardiovascular risk. The current standard of care for significant carotid artery stenosis can include carotid stenting and carotid endarterectomy, but medical therapy may have a role also.

Cost-effectiveness of sirolimus-eluting stents for treatment of complex coronary stenoses: results from the Sirolimus-Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SIRIUS) trial.

BACKGROUND: Recently, sirolimus-eluting stents (SESs) have been shown to dramatically reduce the risk of angiographic and clinical restenosis compared with bare metal stent (BMS) implantation. However, the overall cost-effectiveness of this strategy is unknown. METHODS AND RESULTS: Between February and August 2001, 1058 patients with complex coronary stenoses were enrolled in the SIRIUS trial and randomized to percutaneous coronary revascularization with either a SES or BMS. Clinical outcomes, resource use, and costs were assessed prospectively for all patients over a 1-year follow-up period. Initial hospital costs were increased by 2881 dollars per patient with SESs. Over the 1-year follow-up period, use of SESs led to substantial reductions in the need for repeat revascularization, including repeat percutaneous coronary intervention and bypass surgery. Although follow-up costs were reduced by 2571 dollars per patient with SESs, aggregate 1-year costs remained 309 dollars per patient higher. The incremental cost-effectiveness ratio for SES was 1650 dollars per repeat revascularization event avoided or 27,540 dollars per quality-adjusted year of life gained, values that compare reasonably with other accepted medical interventions. Under updated treatment assumptions regarding available stent lengths and duration of antiplatelet therapy, use of SESs was projected to reduce total 1-year costs compared with BMSs. CONCLUSIONS: Although use of SESs was not cost-saving compared with BMS implantation, for patients undergoing percutaneous coronary intervention of complex coronary stenoses, their use appears to be reasonably cost-effective within the context of the US healthcare system.

Randomized COMparison of platelet inhibition with abciximab, tiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide.

BACKGROUND: The relative anti-aggregatory effects of currently prescribed platelet glycoprotein IIb/IIIa receptor antagonists during and after percutaneous coronary intervention for acute coronary syndromes have not been established. METHODS AND RESULTS: We randomized 70 acute coronary syndrome patients undergoing percutaneous coronary intervention to receive abciximab, eptifibatide, or tirofiban at doses used in the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT), Platelet glycoprotein IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)/Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trials, respectively. Platelet aggregation (PA) in response to 20 micro mol/L of adenosine diphosphate was measured with turbidimetric aggregometry in both D-phenylalanyl-L-prolyl-L-arginine chloromethylketone and citrate-anticoagulated blood early (15 and 30 minutes) and late (4, 12, and 18 to 24 hours) after drug initiation. At 15 and 30 minutes, PA was significantly less inhibited by the tirofiban-RESTORE regimen compared with abciximab (P=0.028) and eptifibatide regimens (P=0.0001). The abciximab regimen, however, showed increasingly varied anti-aggregatory effects during continued infusion for > or =4 hours. Citrate exaggerated ex vivo platelet inhibition after eptifibatide and tirofiban, but had the opposite effect on abciximab. Of all regimens evaluated, the eptifibatide regimen inhibited PA most consistently throughout both the early and late periods. CONCLUSIONS: Currently recommended drug regimens to inhibit the platelet glycoprotein IIb/IIIa receptor have distinct pharmacodynamic profiles that might affect their relative efficacy in acute coronary syndromes and percutaneous coronary intervention.

Safety and efficacy of only 2 weeks of ticlopidine therapy in patients at increased risk of coronary stent thrombosis: results from the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial.

BACKGROUND: Controversy exists regarding the frequency of late stent thrombosis among patients treated with intracoronary stents and the most appropriate duration of treatment with a thienopyridine that is required to prevent this complication. METHODS: We analyzed the frequency of stent thrombosis and other ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial. In the ATLAST trial, 1102 patients at increased risk of stent thrombosis (ST-elevation myocardial infarction within 48 hours, diffuse distal disease, a large amount of thrombus, acute closure, residual dissection, etc) were randomly assigned to receive either enoxaparin (40 or 60 mg given every 12 hours for 14 days) or placebo; all patients received aspirin (325 mg daily) and ticlopidine (250 mg twice daily) for only 14 days. RESULTS: The primary end point, the 30-day combined incidence of death, nonfatal myocardial infarction, and urgent revascularization, was reached in 2.3% of patients (1.8% of patients taking enoxaparin vs 2.7% of patients taking placebo; P =.295). However, during the 15th through 30th days, the frequency of ischemic events was only 0.73%, and only 0.27% (3/1102) of patients had possible stent thrombosis (95% CI 0.06, 0.77). CONCLUSION: The frequency of stent thrombosis and other adverse ischemic events in the 15th through 30th days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low whether or not enoxaparin is administered.

Economic impact of drug-eluting stents on hospital systems: a disease-state model.

BACKGROUND: Drug-eluting intracoronary stents decrease restenosis and later revascularization. The US Department of Health and Human Services (HHS), recognizing the financial and clinical impact of this technology, recently proposed accelerated reimbursement to hospitals. METHODS AND RESULTS: A disease state-transition computer model simulated the clinical and economic consequences to hospitals of drug-eluting stents over 5 years. Model parameters combined information from a longitudinal clinical database, a hospital cost-accounting system, and a survey instrument. Simulations were repeated 1000 times for each set of parameters. With 85% of stent procedures shifted to drug-eluting stents in the first year of availability, the mean number of repeat revascularizations dropped by 60.4% at year 5. With no changes in reimbursement policy, a hospital with a catheterization laboratory volume of 3112 patients yearly converted from a 2.01 million dollars (M) annual profit to an 8.10 M dollars loss in the first year (95% CI 8.09 M dollars to 8.12 M dollars) and 8.7 M dollars annual losses in later years. This represented an overall change in cash flow of 55.71 M dollars (95% CI 55.66 M dollars to 55.76 M dollars) away from the hospital over 5 years. The incremental reimbursement proposed by HHS reduced this loss to 4.75 M dollars in the first year and to 5.6 M dollars annually thereafter. In sensitivity analyses, the conversion of patients from bypass surgery to drug-eluting stents was the largest driver of overall cash flow shifts. CONCLUSIONS: Although Medicare has proposed to increase reimbursement to ease the impact of drug-eluting stents on hospitals, this increase will not totally offset the costs.

Role of target vessel size and body surface area on outcomes after percutaneous coronary interventions in women.

BACKGROUND: Women have higher mortality rates than men after coronary angioplasty. Differences in target vessel size may partially account for these differences. We set out to explore the effects of sex, body surface area (BSA), and target coronary vessel size on clinical outcomes after angioplasty. METHODS: Data from 5 interventional trials and 1 registry were pooled for analysis (n = 3982). RESULTS: Compared with men, women undergoing angioplasty were older, had lower weights and BSA, more coronary risk factors, and slightly smaller target coronary vessel size (as assessed by reference vessel diameter). The correlation between target vessel size and BSA was poor (r = 0.13). At 6 months, women had higher mortality rates (1.7% vs 0.8%, P =.03) but similar rates of myocardial infarction and repeat revascularization. On univariate analysis, advanced age, smaller BSA, and female sex were associated with increased mortality, but target vessel size was not. Advanced age was the only significant multivariate predictor of mortality. Target vessel size and diabetes were independent predictors of repeat revascularization. CONCLUSIONS: Women have higher unadjusted 6-month mortality rates after angioplasty, owing largely to their more advanced age at the time of intervention. Smaller target vessel size is associated with increased risk of restenosis and repeat revascularization; however, it does not appear to be a predictor for downstream mortality. As such, the fact that women have smaller vessels does not account for their higher 6-month mortality after coronary angioplasty.