Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Peripheral Artery Disease (STOP-PAD) Trial: Six-Month Results.

Purpose: To present the 6-month results of the Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Peripheral Artery Disease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. Materials and Methods: The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial (ClinicalTrials.gov identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid-based treatment vs placebo (n=34). The primary efficacy outcome was the 6-month wound healing score evaluated by an independent wound core laboratory; the primary safety endpoint was major adverse limb events (MALE), a composite of major amputation plus clinically-driven target lesion revascularization at 6 months. Results: Only one-third of the patients had complete wound healing at 6 months in the placebo (31%), 8-mg injection (33%), and 16-mg injection (33%) groups. In addition, the observed increase in the toe-brachial index from baseline to 6 months was statistically significant in each group; however, this did not result in lower rates of MALE at 6 months (24% in the placebo, 29% in the 8-mg injection, and 11% in the 16-mg injection groups). During the 6-month period, 6 patients (6%) died, and 24 patients (23%) had an amputation [only 4 (4%) major]. Conclusion: Combining revascularization and biological therapy failed to improve outcomes in CLTI at 6 months. STOP-PAD has provided insights for future trials to evaluate biological therapy.

SDF-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD): Randomized, double-blind, placebo-controlled clinical trial.

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 - a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe-brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients' mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204.

Clopidogrel: the data, the experience, and the controversies.

Dual antiplatelet therapy with acetylsalicylic acid (aspirin) and clopidogrel is a guideline-recommended standard of care for patients with acute coronary syndromes (ACS) and those who undergo percutaneous coronary intervention (PCI). Despite a large body of clinical evidence obtained from randomized clinical trials and patient registries supporting the efficacy and safety of aspirin plus clopidogrel therapy in these patients, questions concerning the optimal use of dual antiplatelet therapy remain. Widely debated topics pertaining to dual antiplatelet therapy in patients with ACS or undergoing PCI include (i) the appropriate clopidogrel loading dose; (ii) the optimal time to initiate the clopidogrel loading dose; (iii) the optimal duration of dual antiplatelet therapy following ACS or PCI; (iv) impact of variability of platelet response on patient outcomes; and (v) the role of other recommended and emerging P2Y12 antagonists. This review discusses these ongoing controversies regarding the optimal use of dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS or those undergoing PCI.

Cardiac events after non-cardiac surgery in patients with previous coronary intervention in the drug-eluting stent era.

The peri-operative risk for patients with coronary drug-eluting stents (DES) who subsequently have non-cardiac surgery (NCS) is unclear. We performed this retrospective study of all patients in our institution who had coronary intervention and subsequent NCS from 2003 through December 2008 to evaluate the incidence of major adverse cardiac events (MACE) in patients who received DES compared to those who received bare-metal stents (BMS) or had percutaneous transluminal coronary angioplasty (PTCA) during the same time period. The main outcome measures were 30-day post-operative myocardial infarction, stent thrombosis, target vessel revascularization (TVR) and cardiac death. During the 6-year study period, 1,770 coronary interventions were performed and 238 patients subsequently had NCS in 8 days to 49 months. Eighteen patients had PTCA, 79 BMS and 141 DES. Acute myocardial infarction occurred in 1 patient who had PTCA, 2 who had BMS and 14 who had DES (p = 0.10). Stent thrombosis occurred in 6 patients who had DES and none who had BMS (p = 0.09). Seven patients who had DES had TVR compared to 1 patient who had BMS and none who had PTCA (p = 0.41). Cardiac mortality occurred in 2 patients who had DES and none who had PTCA or BMS (p = 0.35). In conclusion, the 30-day MACE in patients who received coronary DES and undergone NCS were not significantly different compared to those who received BMS or had PTCA only, with a trend toward higher stent thrombosis in the DES group.

Limitation of fractional flow reserve in evaluating coronary artery myocardial bridge.

Symptomatic myocardial bridge is treated with medical therapy, but in refractory cases, percutaneous revascularization has been used. We describe two cases to highlight differences in coronary compression and flow pattern, which make the luminal narrowing associated with a myocardial bridge anatomically and physiologically different from the fixed stenosis of atherosclerotic epicardial disease. Due to these characteristics, evaluating the functional severity of a myocardial bridge using fractional flow reserve as a guide to revascularization may be of limited value. Furthermore, stenting, including drug-eluting stents, may not be the ideal revascularization strategy secondary to a higher risk of in-stent restenosis.

Early invasive strategy improves outcomes in patients with acute coronary syndrome with previous coronary artery bypass graft surgery: a report from TACTICS-TIMI 18.

BACKGROUND: Patients with previous coronary artery bypass graft surgery (CABG) have been classified as a high-risk subset of patients who experience non-ST elevation acute coronary syndrome (ACS). Recent studies suggest that an early invasive strategy is beneficial in moderate- and high-risk patients with non-ST elevation ACS. We hypothesized that an early invasive strategy is associated with improved outcomes in patients with non-ST elevation ACS with prior CABG. METHODS AND RESULTS: In the Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 trial (TACTICS-TIMI 18), 2220 patients with non-ST segment elevation ACS were randomized to an early invasive or conservative (selectively invasive) strategy. All patients were treated with aspirin, heparin, and tirofiban. Four hundred eighty-four (22%) of these patients had undergone CABG before enrollment. We analyzed whether patients with previous CABG had different 6-month outcomes and whether an early invasive strategy was associated with an improvement in long-term outcomes. Prior CABG was associated with a higher risk of adverse outcomes by 6 months, including a higher rate of readmission for ACS (17.4% vs 11.0%, P < 0.001) and a higher incidence of the composite end point of death, myocardial infarction, or rehospitalization for ACS (22.3% vs 16.4%, P = 0.002). There was a trend toward a higher incidence of myocardial infarction (7.1% vs 5.3%, P = 0.051). An early invasive strategy was associated with a reduction in the composite of death or myocardial infarction (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.31-1.0; P = 0.089) and a significant reduction in the incidence of myocardial infarction at 6 months (OR, 0.44; 95% CI, 0.21-0.93; P=0.032). CONCLUSIONS: Patients with non-ST segment elevation ACS who have had previous CABG are a high-risk subset. An early invasive strategy reduces risk of myocardial infarction in this high-risk group.

Association of elevated B-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non-ST-segment elevation myocardial infarction.

OBJECTIVES: We hypothesized that elevated B-type natriuretic peptide (BNP) levels would be associated with a greater severity of angiographic disease and a greater extent of myocardium at risk. BACKGROUND: Elevations of BNP have been associated with increased risk of adverse outcomes in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). METHODS: Of the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction-18 (TACTICS-TIMI-18) trial, 276 randomized to the invasive arm had both baseline BNP levels and angiographic core laboratory data. Patients were categorized according to their baseline BNP levels as < or =80 or >80 pg/ml. RESULTS: A total of 233 patients (84%) had BNP levels >80 pg/ml, and 43 (16%) had admission BNP levels >80 pg/ml. Patients with BNP >80 pg/ml had tighter culprit vessel stenosis on quantitative coronary angiography (median stenosis 76% vs. 67%, p = 0.004) and a higher (slower) corrected TIMI frame count (median CTFC 43 vs. 30, p = 0.018) in the culprit vessel. The median BNP level was higher in patients with a left anterior descending coronary artery (LAD) versus non-LAD culprit lesion location (median BNP level 40 vs. 24 pg/ml, p = 0.005), and the culprit artery was more often the LAD in patients with BNP >80 pg/ml compared with < or =80 pg/ml (44% vs. 30%, p = 0.06). CONCLUSIONS: Among patients with UA/NSTEMI, elevated BNP levels are associated with tighter culprit stenosis, higher CTFC, and LAD involvement. These findings suggest that elevated BNP may be associated with a greater severity and extent of myocardial ischemic territory during the index event and may partly explain the association between elevated BNP and adverse outcomes.

A risk score to estimate the likelihood of coronary artery bypass surgery during the index hospitalization among patients with unstable angina and non-ST-segment elevation myocardial infarction.

OBJECTIVES: A simple risk score on admission to estimate the likelihood of in-hospital coronary artery bypass graft surgery (CABG) might be useful in selecting patients for early clopidogrel therapy. BACKGROUND: Routine early use of clopidogrel in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) is associated with increased risk of bleeding in patients who undergo early CABG. METHODS: The test cohort utilized to derive the score was the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction-18 (TACTICS-TIMI-18) trial. Patients who underwent CABG after randomization during index hospitalization were identified and were compared with patients who did not undergo in-hospital CABG. RESULTS: Overall, 362 patients (16.3%) underwent CABG during the index hospitalization. Patients with a history of prior CABG (n = 484) were significantly less likely to undergo in-hospital CABG (odds ratio [OR], 0.34). Five additional variables independently associated with CABG were identified: elevated troponin (OR, 3.9), prior stable angina (OR, 1.8), ST-segment deviation >or=0.5 mm (OR, 1.7), male gender (OR, 1.6), and history of peripheral arterial disease (OR, 1.6). A CABG risk score was generated by assigning numerical values to each of the variables based upon these odds ratios. Coronary artery bypass surgery rates increased significantly with increasing risk scores (6.2% for a risk score <3.0, 21.9% for 3 to 5, and 54.6% for >5.0). The association of the risk score with CABG was highly significant (p < 0.0001, c-statistic 0.72). The association remained significant in the validation cohorts from TIMI-11B trial and TIMI-III registry. CONCLUSIONS: Among patients with UA/NSTEMI, a novel risk score based on admission clinical variables can be used to estimate the likelihood of CABG. These data may assist in the identification of patients who might derive optimal benefit from early initiation of clopidogrel therapy.

Incidence and time course of thrombocytopenia with abciximab and eptifibatide in patients undergoing percutaneous coronary intervention.

Thrombocytopenia is recognized as a potential adverse effect in patients treated with glycoprotein IIb/IIIa inhibitors. We monitored platelet counts at baseline and at 10 minutes and at 1, 8, and 24 hours after initiation of therapy with either abciximab (n = 74) or eptifibatide (n = 26) in a series of 100 consecutive patients who underwent percutaneous coronary intervention. Thrombocytopenia (platelet count <100,000 m(3) occurred in 11 patients treated with abciximab (15%) and in none of those treated with eptifibatide. The inhibition of platelet adhesion to fibrinogen-coated material by abciximab and eptifibatide was similar, indicating that the reduction in platelet count with abciximab is unrelated to inhibition of platelet function.

Clinical and angiographic characteristics of patients with combined anterior and inferior ST-segment elevation on the initial electrocardiogram during acute myocardial infarction.

OBJECTIVE: We evaluated the significance of combined anterior and inferior ST-segment elevation on the initial electrocardiogram (EKG) in patients with acute myocardial infarction (AMI) and correlated it with AMI size and left ventricular (LV) function. METHODS: We analyzed admission EKGs of 2996 patients with AMI from the GUSTO-I angiographic substudy and the GUSTO-IIb angioplasty substudy who underwent immediate angiography. In all, we identified 1046 patients with anterior ST elevation (ST-segment elevation in > or =2 of leads V1-V4) and divided them into 3 groups: Group 1, anterior + inferior ST elevation (ST elevation in > or =2 of leads II, III, aVF, n =179); Group 2, anterior ST elevation only (<2 of leads II, III, aVF with ST elevation or depression, n = 447); Group 3, anterior ST elevation + superior ST elevation (ST depression in > or =2 of leads II, III, aVF, n = 420). RESULTS: Cardiac risk factors, prior AMI, prior percutaneous transluminal coronary angioplasty or coronary artery bypass graft, Killip class, and thrombolytic therapy assignment did not differ among the 3 groups. Group 1 patients had greater number of leads with ST elevation compared to Groups 2 and 3 (ST elevation in > or =6 leads 83% vs 22% vs 49%, P =.001). Despite greater ST-segment elevation, Group 1 patients had a lower peak CK level (median baseline peak CK 1370 vs 1670 vs 2381 IU, P =.0001) and less LV dysfunction (median ejection fraction 0.53 vs 0.49 vs 0.45, P =.0001; median number of abnormal chords 21 vs 32 vs 40, P =.0001). Angiographically, Group 1 had 2 distinct subsets of patients with either right coronary artery (RCA) (59%) or left anterior descending coronary artery (LAD) (36%) occlusion. In contrast, the infarct-related artery (IRA) was almost entirely the LAD in Groups 2 and 3 (97%). Further, the site of IRA occlusion in Group 1 was mostly proximal RCA (67%) in the RCA subgroup and mid or distal LAD (70%) in the LAD subgroup. ST-segment elevation in lead V1 > or = V3 and absence of progression of ST elevation from lead V1 to V3 on the EKG differentiated IRA-RCA from IRA-LAD in patients with combined anterior and inferior ST elevation. CONCLUSIONS: The AMI size and LV dysfunction in patients with anterior ST elevation is directly related to the direction of ST segment deviation in the leads II, III, aVF; least with inferior ST elevation, intermediate with no ST deviation, and maximal with superior ST elevation (inferior ST depression). Despite greater ST-segment elevation, patients with combined anterior and inferior ST elevation have limited AMI size and preserved LV function. Angiographically, they comprise 2 distinct subsets with either proximal RCA or mid to distal LAD occlusion. A predominant right ventricular and limited inferior LV AMI from a proximal RCA occlusion, or a smaller anterior AMI from a more distal occlusion of LAD may explain their limited AMI size despite greater ST elevation.

Primary PCI for ST-segment elevation myocardial infarction in a patient treated with subcutaneous enoxaparin utilizing point-of-care Enox test.

The superiority of enoxaparin compared with unfractionated heparin in the medical management of patients with non-ST elevation acute coronary syndromes (NSTE ACS) has been demonstrated in clinical trials. Further, enoxaparin has been shown to be safe and effective during PCI, including in combination with glycoprotein IIb/IIIa inhibitors. Whether enoxaparin is superior to unfractionated heparin in patients with NSTE ACS under-going early invasive strategy is currently being tested in a large clinical trial. Data on the use of enoxaparin in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction are limited. Unlike patients who present to the catheterization laboratory after several doses of enoxaparin where in a steady state anticoagulation might have been achieved, patients who present early after administration of a single dose of subcutaneous enoxaparin may not have an adequate level of anticoagulation for PCI. The ability to monitor activity of enoxaparin in such patients using a point-of-care test might be useful. This report describes a patient with ST-segment elevation myocardial infarction who presented for primary angioplasty 75 minutes after administration of subcutaneous enoxaparin. The Rapidpoint Enox test measured 135 seconds and the patient's corresponding serum anti-Xa level was 0.12 IU/mL indicating a suboptimal level of anticoagulation for PCI. Procedural success was attained using additional 0.3-mg/kg intravenous enoxaparin.