Efficacy and Safety of Proton-Pump Inhibitors in High-Risk Cardiovascular Subsets of the COGENT Trial.

BACKGROUND: Proton-pump inhibitors (PPIs) have been demonstrated to reduce rates of gastrointestinal events in patients requiring dual antiplatelet therapy (DAPT). Data are limited regarding the efficacy and safety of PPIs in high-risk cardiovascular subsets after acute coronary syndrome or percutaneous coronary intervention. METHODS: All patients enrolled in COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) were initiated on DAPT (with aspirin and clopidogrel) for various indications within the prior 21 days. These post hoc analyses of the COGENT trial evaluated the efficacy and safety of omeprazole compared with placebo in subsets of patients requiring DAPT for the 2 most frequent indications: 1) patients undergoing percutaneous coronary intervention (for any indication) within 14 days of randomization (n = 2676; 71.2%); and 2) patients presenting with acute coronary syndrome managed with or without percutaneous coronary intervention (n = 1573; 41.8%). Unadjusted Cox proportional hazards models were used to estimate effect sizes through final follow-up. RESULTS: Median follow-up duration was 110 days (interquartile range 55-167). In percutaneous coronary intervention-treated patients, omeprazole significantly reduced rates of composite gastrointestinal events at 180 days (1.2% vs 2.7%; hazard ratio [HR] 0.43; 95% confidence interval [CI], 0.22-0.85; P = .02) without increasing composite cardiovascular events (5.4% vs 6.3%; HR 1.00; 95% CI, 0.67-1.50; P = 1.00). Similarly, omeprazole lowered risk of the primary gastrointestinal endpoint at 180 days in patients presenting with acute coronary syndrome (1.1% vs 2.7%; HR 0.37; 95% CI, 0.13-1.01; P = .05) without a significant excess in cardiovascular events (5.6% vs 4.5%; HR 1.40; 95% CI, 0.77-2.53; P = .27). CONCLUSIONS: PPI therapy attenuates gastrointestinal bleeding risk without significant excess in major cardiovascular events in high-risk cardiovascular subsets, regardless of indication for DAPT. Future studies will be needed to clarify optimal gastroprotective strategies for higher-intensity and longer durations of DAPT.

Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy.

BACKGROUND: The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. OBJECTIVES: The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. METHODS: Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into "low-dose" (≤ 100 mg) and "high-dose" (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. RESULTS: Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. CONCLUSIONS: Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921).

Clopidogrel with or without omeprazole in coronary artery disease.

BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Rescue percutaneous coronary intervention for failed thrombolysis.

BACKGROUND: Previous studies of rescue percutaneous coronary intervention (PCI) for failed thrombolysis yielded conflicting results. In the current era of newer thrombolytic agents, coronary stents, glycoprotein IIb/IIIa inhibitors, and aggressive hemodynamic support, the outcome of this high-risk patient group has not been characterized. METHODS: From January 2000 to October 2004, 214 consecutive patients were transferred and underwent emergent coronary angiography following failed thrombolysis. One hundred and fifty five (72%) underwent immediate PCI, 23 (11%) underwent delayed PCI, and 36 (17%) received surgical revascularization or medical therapy. Medical records and angiograms for the entire PCI cohort (n=178) were reviewed for in-hospital events including bleeding complications, stroke, recurrent ischemia or myocardial infarction (MI), target vessel revascularization (TVR), and death. RESULTS: Time from symptom onset to thrombolysis (mean +/- standard deviation) was 5.6 +/- 11.9 hr, and time from thrombolysis to angiography was 7.0 +/- 5.5 hr. The study cohort was critically ill, with 9.6% experiencing cardiac arrest, 21% in cardiogenic shock, and 12% intubated prior to transfer. Coronary stents were placed in 88%, Rheolytic thrombectomy was used in 21%, an intraaortic balloon pump was placed in 17%, and a glycoprotein IIb/IIIa inhibitor was administered in 92%. Patients receiving delayed PCI had higher TIMI 3 flow grade at initial angiography than those receiving immediate PCI (83% vs. 34%, respectively, P < 0.0001). Angiographic success was 90% for the entire PCI cohort, 89% for the immediate PCI group, and 100% for the delayed PCI group. Clinical success (angiographic success and freedom from major adverse cardiac events) was 85% for the entire PCI cohort, 83% for the immediate PCI group, and 100% for the delayed PCI group. Severe and moderate bleeding complications occurred in 7.3%, stroke in 1.7%, recurrent ischemia or MI in 7.3%, and TVR in 3.4%. Overall, in-hospital mortality for the entire PCI cohort was 3.4%. CONCLUSIONS: This observational, consecutive, real-world study of contemporary rescue PCI for failed thrombolysis shows a high use of coronary stents, Rheolytic thrombectomy, glycoprotein IIb/IIIa inhibitors, and intraaortic balloon pump placement. Angiographic and clinical success was high with low bleeding complications and low in-hospital mortality, suggesting that prospective, randomized trials using contemporary interventional therapy for rescue PCI be considered.

Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.

BACKGROUND: In postmenopausal women with coronary artery disease, conjugated equine estrogen with or without continuous administration of medroxyprogesterone acetate has failed to slow the progression of atherosclerosis. Whether 17beta-estradiol (the endogenous estrogen molecule) alone or administered sequentially with medroxyprogesterone acetate can slow the progression of atherosclerosis is unknown. METHODS: We conducted a double-blind, placebo-controlled trial in 226 postmenopausal women (mean age, 63.5 years) who had at least one coronary-artery lesion. Participants were randomly assigned to usual care (control group), estrogen therapy with micronized 17beta-estradiol alone (estrogen group), or 17beta-estradiol plus sequentially administered medroxyprogesterone acetate (estrogen-progestin group). In all patients the low-density lipoprotein (LDL) cholesterol level was reduced to a target of less than 130 mg per deciliter. The primary outcome was the average per-participant change between base-line and follow-up coronary angiograms in the percent stenosis measured by quantitative coronary angiography. RESULTS: After a median of 3.3 years of follow-up, the mean (+/-SE) change in the percent stenosis in the 169 participants who had a pair of matched angiograms was 1.89+/-0.78 percentage points in the control group, 2.18+/-0.76 in the estrogen group, and 1.24+/-0.80 in the estrogen-progestin group (P=0.66 for the comparison among the three groups). The mean difference in the percent stenosis between the estrogen group and the control group was 0.29 percentage point (95 percent confidence interval, -1.88 to 2.46), and the mean difference between the estrogen-progestin group and the control group was -0.65 (95 percent confidence interval, -2.87 to 1.57). CONCLUSIONS: In older postmenopausal women with established coronary-artery atherosclerosis, 17beta-estradiol either alone or with sequentially administered medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis.