A randomized, controlled, single-blinded, multicenter evaluation of the efficacy and safety of a once weekly two dose otic gel containing florfenicol, terbinafine and betamethasone administered for the treatment of canine otitis externa.

BACKGROUND: Otitis externa is a common problem in small animal practice. Compliance with daily treatment is a major cause of treatment failure. The hypothesis tested is that a novel otic gel applied to the ear canal twice with a one-week interval is as efficacious as a daily otic suspension in the treatment of canine otitis externa. The study included 286 privately owned dogs with otitis externa. In this single blinded randomized study, enrolled dogs received either an otic gel containing 1% florfenicol, 1% terbinafine and 0.1% betamethasone acetate twice with a one-week interval or a suspension containing hydrocortisone aceponate, miconazole and gentamicin daily for 5 days. Ears were cleaned with saline prior to administration of the first dose of medication. Dogs were evaluated at day (D) 0, 7, 28 and 56 with an otitis index score (OTIS-3), otic culture and cytology, pain and pruritus, and overall response to treatment (owner and investigator evaluation). Outcome measures were improvement of the OTIS-3 and number of dogs in clinical remission at each time point. RESULTS: OTIS-3 decreased significantly (p < 0.0001) by 63 and 64% for the otic gel and by 63 and 61% for the suspension on D28 and D56 respectively. There was no significant difference between groups at any time point with regard to clinical success, pain, pruritus, overall assessments or otic cytology and culture. The treatment response was considered excellent or good by approximately three quarters of both the clinicians and Owners. Otitis recurrence at D56 was seen in 11% of both groups. Adverse events attributable to the ear medications were not noted. CONCLUSIONS: Administering an otic gel twice at a one-week interval is an effective, safe and convenient way to treat canine otitis externa.

A randomized placebo-controlled trial of the efficacy and safety of a terbinafine, florfenicol and betamethasone topical ear formulation in dogs for the treatment of bacterial and/or fungal otitis externa.

BACKGROUND: Treatment of infected otitis externa (OE) relies on the topical application of specific formulations that most often contain an antibiotic, an antifungal and a glucocorticoid. This study is to report the results of a randomized, placebo-controlled field trial evaluating the efficacy and safety of OSURNIA™ (Elanco Animal Health, a division of Eli Lilly and Company, Greenfield, IN), a novel topical ear medication containing florfenicol, terbinafine and betamethasone acetate in an adaptable gel. The study includes 284 dogs with bacterial and/or fungal OE who were randomly assigned to receive two doses of Osurnia or its vehicle, one week apart. Dogs were evaluated at various time points through Day 45, and a total clinical score (TCS) was calculated based on pain, erythema, exudate, swelling, odor and ulceration. The primary outcome measure was the rate of treatment success (RTS), defined as a TCS of 0, 1 or 2 on Day 45. Before and after treatment, a "clap test" was performed to subjectively assess hearing, and blood and urine were collected for routine clinical pathology. RESULTS: The RTS was significantly higher in ears treated with Osurnia (64.78%) than with placebo (43.42%). There was no significant interaction between efficacy and duration of history, recurrence of otitis or body weight. Adverse events were similar between groups. All dogs treated with Osurnia maintained their hearing, and there were no relevant clinical pathology changes. CONCLUSIONS: The application of two doses of Osurnia, one week apart, is effective and safe to treat microbial otitis externa in dogs.

Stoichiometries of calcium and strontium transport coupled to ATP and acetyl phosphate hydrolysis by skeletal sarcoplasmic reticulum.

The stoichiometries of Ca2+ and of Sr2+ transport by the Ca2(+)-ATPase of skeletal muscle sarcoplasmic reticulum have been previously reported to be 2 and 1, respectively, when determined by flux ratio methods (Mermier, P. and Hasselbach, W. (1976) Eur. J. Biochem. 69, 79-86; Holguin, J.A. (1986) Arch. Biochem. Biophys. 251, 9-16). We have measured transport of Ca2+ and Sr2+ by the pulsed pH-stat method, when supported by ATP or the pseudo-substrate acetyl phosphate (AcP). The stoichiometry of ATP-supported Ca2+ transport, Ca2+/ATP, was pH dependent and varied from 2.0 at pH 6.5 to 1.0 at pH 8.0. Sr2+/ATP ratios showed a similar pH dependence and were approx. 7-18% lower. Ca2+/AcP ratios showed little pH dependence and varied from 2.0 to 1.7 in the pH range 6.5 to 8.0. Sr2+/AcP ratios were 17-34% lower, with maximum differences at the pH extremes. Ruthenium red, which blocks calcium efflux from calcium release channels, increased measured stoichiometries by less than 10%. It is concluded that the transport of both Ca2+ and Sr2+, when supported by either ATP or a pseudo-substrate, have similar stoichiometrics and occurs via identical mechanisms. The relatively low Sr2+ transport ratios have been related to uncoupled reverse flux through the Ca2(+)-ATPase cation transport channel. Subintegral M2+/substrate ratios appear to be an intrinsic feature of active transport by the Ca2+ pump of skeletal muscle sarcoplasmic reticulum.

Time resolved absorption study of the reaction of hydroxyurea with sickle cell hemoglobin.

Hydroxyurea has been mixed with hemoglobin S and the reaction was studied using electronic absorption spectroscopy as a function of time and wavelength. The rate of conversion of oxyhemoglobin S to other species was determined and the nature of the reaction products was studied. We also report the formation of methemoglobin (and other reaction products) when deoxyhemoglobin S is combined with hydroxyurea. The probable increase in the formation of methemoglobin, and other potential reaction products such as nitric oxide-hemoglobin, in patients with sickle cell anemia who are taking hydroxyurea as a therapeutic drug is discussed in terms of the pathophysiology of the disease. It is proposed that methemoglobin and possibly nitric oxide-hemoglobin formation may partially explain beneficial effects observed in these patients before their levels of fetal hemoglobin have increased.

Nitric oxide binding to oxygenated hemoglobin under physiological conditions.

We have added nitric oxide (NO) to hemoglobin in 0.1 M and 0.01 M phosphate buffers as well as to whole blood, all as a function of hemoglobin oxygen saturation. We found that in all these conditions, the amount of nitrosyl hemoglobin (HbNO) formed follows a model where the rates of HbNO formation and methemoglobin (metHb) formation (via hemoglobin oxidation) are independent of oxygen saturation. These results contradict those of an earlier report where, at least in 0.01 M phosphate, an elevated amount of HbNO was formed at high oxygen saturations. A radical rethink of the reaction of oxyhemoglobin with NO under physiological conditions was called for based on this previous proposition that the primary product is HbNO rather than metHb and nitrate. Our results indicate that no such radical rethink is called for.

The reaction of deoxy-sickle cell hemoglobin with hydroxyurea.

In addition to its capacity to increase fetal hemoglobin levels, other mechanisms are implicated in hydroxyurea's ability to provide beneficial effects to patients with sickle cell disease. We hypothesize that the reaction of hemoglobin with hydroxyurea may play a role. It is shown that hydroxyurea reacts with deoxy-sickle cell hemoglobin (Hb) to form methemoglobin (metHb) and nitrosyl hemoglobin (HbNO). The products of the reaction as well as the kinetics are followed by absorption spectroscopy and electron paramagnetic resonance (EPR) spectroscopy. Analysis of the kinetics shows that the reaction can be approximated by a pseudo-first order rate constant of 3.7x10(-4) (1/(s.M)) for the disappearance of deoxy-sickle cell hemoglobin. Further analysis shows that HbNO is formed at an observed average rate of 5.25x10(-5) (1/s), three to four times slower than the rate of formation of metHb. EPR spectroscopy is used to show that the formation of HbNO involves the specific transfer of NO from the NHOH group of hydroxyurea. The potential importance of this reaction is discussed in the context of metHb and HbNO being able to increase the delay time for sickle cell hemoglobin polymerization and HbNO's vasodilating capabilities through conversion to S-nitrosohemoglobin.

The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries.

BACKGROUND: Endovascular irradiation (EI) inhibits balloon-induced neointima formation in animals and is now in clinical trials for restenosis prevention. However, little is known of the effect of EI on vessel thrombogenicity due to delayed arterial healing. We investigated EI effects on platelet recruitment in pig coronary arteries. METHODS AND RESULTS: EI was performed using (90)Sr/Y at 0 Gray (Gy), 15Gy, or 30Gy at 2 mm after balloon overstretch injury. At 1 day, 1 week, and 1 month, platelet recruitment and thrombus formation were assessed using autologous (111)In-oxine-platelet labeling and light and scanning electron microscopy. In balloon-injured nonirradiated vessels, there was complete reendothelialization at 1 month, and platelet recruitment was similar to normal uninjured arteries. In irradiated vessels, scanning electron microscopy showed incomplete reendothelialization at 1 month, and these areas demonstrated attachment of activated platelets. Light microscopy of irradiated coronaries showed adherent partially organized thrombi and incomplete resolution of intramural hemorrhages. There was a significant increase in platelet recruitment at 1 month in arteries receiving EI at 15Gy (5.1+/-2. 8x10(6), P=0.02) or 30Gy (12.5+/-9.9x10(6), P=0.005) compared with nonirradiated controls (2.7+/-1.5x10(6)); 30Gy was also higher than 15Gy (P=0.05). Platelet recruitment was also increased for 30Gy compared with control at 1 day. CONCLUSIONS: Endovascular irradiation at 15Gy or 30Gy after balloon angioplasty results in incomplete endothelial recovery, impaired resolution of intramural hemorrhage, and a dose-dependent increase in platelet recruitment at 1 month.

Intracoronary beta-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries.

BACKGROUND: Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. We examined late arterial responses 6 months after balloon angioplasty and beta-radiation in normal pig coronary arteries. METHODS AND RESULTS: Coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of (186)Re beta-radiation or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analyzed histopathologically at 6 months. beta-Radiation decreased lumen area (20 Gy, 1.55+/-0.99 mm(2); 30 Gy, 1.03+/-0.82 mm(2); and 0 Gy, 2.05+/-0.80 mm(2); P<0.05) but not overall vessel area. The neointimal area was significantly larger within the injured segment with beta-radiation (20 Gy, 1.92+/-1.23 mm(2); 30 Gy, 1.51+/-0.97 mm(2); and 0 Gy, 0.89+/-0.31 mm(2); 0 Gy versus 20 Gy, P<0.05), and a significant increase of edge stenosis was observed with beta-radiation. Irradiated vessels also had larger thrombus areas within the neointima (30 Gy, 0.24+/-0.61 mm(2); 20 Gy, 0.98+/-1.57 mm2; and 0 Gy, 0.00+/-0.01 mm(2); P<0.05) and larger adventitial areas (20 Gy, 2.25+/-0.75 mm(2); 30 Gy, 2.38+/-0.98 mm(2); and 0 Gy, 1.23+/-0.29 mm(2); 0 Gy versus 20 or 30 Gy, P<0.05) that showed substantial collagen accumulation. CONCLUSIONS: Intracoronary beta-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries 6 months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary beta-radiation.

Percutaneous coronary intervention in the current era compared with 1985-1986: the National Heart, Lung, and Blood Institute Registries.

BACKGROUND: Although refinements have occurred in coronary angioplasty over the past decade, little is known about whether these changes have affected outcomes. METHODS AND RESULTS: Baseline features and in-hospital and 1-year outcomes of 1559 consecutive patients in the 1997-1998 Dynamic Registry who were having first coronary intervention were compared with 2431 patients in the 1985-1986 National Heart, Lung, and Blood Institute Registry. Compared with patients in the 1985-1986 Registry, Dynamic Registry patients were older (mean age, 62 versus 58 years; P:<0.001) and more often female (32.1% versus 25.5%; P:<0.001). In the Dynamic Registry, procedures were more often performed for acute myocardial infarction (22.9% versus 9.9%; P:<0.001) and treated lesions were more severe (84.5% versus 82.5% diameter reduction; P:<0.001), thrombotic (22.1% versus 11.3%; P:<0.001) or calcified (29.5% versus 10.8%; P:<0.001). Stents were used in 70.5% of Dynamic Registry patients, whereas 1985-1986 patients received balloon angioplasty alone. Procedural success was higher in the Dynamic Registry (92.0% versus 81.8%; P:<0.001) and the rate of in-hospital death, myocardial infarction, and emergency coronary bypass surgery combined was lower (4.9% versus 7.9%; P:=0.001) than in the 1985-1986 Registry. The 1-year rate for CABG was lower in the Dynamic Registry (6.9% versus 12.6%; P:<0.001). CONCLUSIONS: Although Dynamic Registry patients had more unstable and complex coronary disease than those in the 1985-1986 Registry, their rate of procedural success was higher whereas rates of complications and subsequent CABG were lower. Results of percutaneous coronary intervention have improved substantially over the past decade.

Ten-year completed follow-up of percutaneous transluminal coronary angioplasty: the early Zurich experience.

OBJECTIVES: The objective of this communication was to report the long-term follow-up of all the patients treated by Dr. Andreas Gruentzig in Zurich, Switzerland. BACKGROUND: The first patients to undergo percutaneous transluminal coronary angioplasty had the procedure performed by Andreas Gruentzig in Zurich between 1977 and 1980. The method of angioplasty has changed little, and the patients undergoing these first procedures were similar to many patients undergoing angioplasty today; therefore, their long-term outcome is of significant interest. METHODS: All 169 patients with attempted angioplasty during Gruentzig's years in Zurich have now been completely followed up at 10 years. All surviving patients were contacted directly or by telephone interview, and the occurrence of each cardiac procedure and coronary event was analyzed. RESULTS: One hundred thirty-three of the 169 patients underwent successful angioplasty. Ten-year follow-up of this group revealed an overall survival rate of 89.5%. The survival rate was 95% among patients with single-vessel disease and 81% among those with multivessel disease. Patients undergoing unsuccessful dilation and those with failed angioplasty and subsequent bypass surgery had a similar 10-year survival rate. Angiographic restenosis was present in 31% at 6 months. Late restenosis between 6 months and 10 years occurred in eight patients; however, progression of disease in undilated segments occurred in 31 patients. In addition to a better survival rate, patients with single-vessel disease were less likely to have had bypass surgery and were more likely to be angina free at the 10-year follow-up than were patients with multivessel disease (79% vs. 67%). CONCLUSIONS: This earliest angioplasty experience was also the first to demonstrate a difference in outcome between patients with single-vessel and multivessel disease treated with angioplasty. Although angioplasty is now performed in more complex patient subsets, the long-term outcome of these "classic" angioplasty patients should be applicable to similar patients treated today.

Percutaneous transluminal coronary angioplasty as a first revascularization procedure in single-, double- and triple-vessel coronary artery disease.

OBJECTIVES: We sought to compare in-hospital and long-term outcome after angioplasty in patients with single-, double- and triple-vessel disease. BACKGROUND: Coronary angioplasty is increasingly used in patients with multivessel disease. METHODS: The source of data was the clinical data base at Emory University. Patients who had previous coronary revascularization or who underwent angioplasty in the setting of acute myocardial infarction were excluded. RESULTS: Of 10,783 patients, 71% had one-vessel, 24% two-vessel and 5% three-vessel disease. Age, male gender, diabetes, hypertension, history of previous myocardial infarction, Canadian Cardiovascular Society class III or IV angina and congestive failure all increased with severity of disease. Complete revascularization was achieved in most patients with one-vessel disease, in a minority with two-vessel disease and rarely in those with three-vessel disease. Emergency coronary bypass surgery increased from 1.7% with one-vessel disease to 3.2% with three-vessel disease. Q wave myocardial infarctions could not be shown to vary significantly with severity of disease. The mortality rate increased from 0.2% with one-vessel disease to 1.2% with three-vessel disease. The number of vessels diseased was a multivariate correlate of in-hospital and long-term mortality. The 1-, 5- and 10-year survival was 0.99, 0.93 and 0.86 for one-vessel disease and 0.97, 0.89 and 0.76 for two-vessel disease, respectively. The 1-, 5- and 9-year survival was 0.95, 0.85 and 0.70 in three-vessel disease, respectively. Freedom from myocardial infarction, coronary bypass surgery and repeat angioplasty was also lower with more severe disease. CONCLUSIONS: Patients have increasing in-hospital and long-term mortality as the severity of disease increases. There is also an increased incidence of myocardial infarction and revascularization procedures with more severe disease.

Can restenosis after coronary angioplasty be predicted from clinical variables?

OBJECTIVES: The purpose of this study was to determine whether variables shown to correlate with restenosis in one group (learning group) could be shown to predict recurrent stenosis in a second group (validation group). BACKGROUND: Restenosis remains a critical limitation after percutaneous transluminal coronary angioplasty. Although several clinical variables have been shown to correlate with restenosis, there are few data concerning attempts to predict recurrent stenosis. METHODS: The source of data was the clinical data base at Emory University. Patients who had had previous coronary surgery and patients who underwent coronary angioplasty in the setting of acute myocardial infarction were excluded. A total of 4,006 patients with angiographic restudy after successful angioplasty were identified. They were classified into a learning group of 2,500 patients and a validation group of 1,506 patients. The correlates of restenosis in the learning group were determined by stepwise logistic regression, and a model was developed to predict the probability of restenosis and was tested in the validation group. By using various cut points for the predicted probability of restenosis, a receiver operating characteristic curve was created. Goodness of fit of the model was evaluated by comparing average predicted probabilities with average observed probabilities within subgroups on the basis of risk level determined by linear regression analysis. RESULTS: In the learning group 1,145 patients had restenosis and 1,355 did not. Correlates of restenosis were severe angina, severe diameter stenosis before angioplasty, left anterior descending coronary artery dilation, diabetes, greater diameter stenosis after angioplasty, hypertension, absence of an intimal tear, eccentric morphology and older patient age. The model derived from the learning group was used to predict restenosis in the validation group. By varying the cut point for the predicted probability of restenosis above which restenosis is diagnosed and below which it is not, a receiver operating characteristic curve was created. The curve was close to the line of identity, reflecting a poor predictive ability. However, the model was shown to fit well with the predicted probability of restenosis correlating well with the observed probability (r = 0.98, p = 0.0001). CONCLUSIONS: Clinical variables provide limited ability to predict definitively whether a particular patient will have restenosis. However, the current model may be used to predict the probability of restenosis, with some uncertainty, at least in well characterized patients who have already had angioplasty.

Coronary aneurysms after stent placement: a suggestion of altered vessel wall healing in the presence of anti-inflammatory agents.

Coronary aneurysms are rare after conventional angioplasty and have not been reported after coronary stenting. Coronary artery stent sites were examined by follow-up angiography at a median of 4 months in 29 patients who received the Cook stent (Gianturco-Roubin) for acute coronary closure. Nineteen patients were treated with glucocorticoids administered intravenously or orally, or both, with or without colchicine and results were compared with those in 10 patients who were treated with neither agent. Standard therapy for all patients included routine administration of aspirin and heparin before and warfarin sodium (Coumadin) and aspirin after stent placement. Most patients also received dipyridamole and lovastatin during the follow-up period. Compliance with medications was confirmed by telephone conversation with each patient. Six (32%) of the 19 stented arteries showed evidence of coronary artery aneurysm, defined as expansion of the lumen outside the margins of the stent. None of the patients in the control group (who did not receive steroids or colchicine) developed aneurysm. This pattern of altered vascular healing in stented coronary segments appears to be due to the addition of multiple anti-inflammatory drugs rather than to stent presence alone. This observation demonstrates the possibility of medical impairment of normal vascular remodeling after acute injury and stent placement, which may be of benefit in designing future trials on restenosis.

Efficacy of a new angioplasty catheter for severely narrowed coronary lesions.

Conventional over the wire dilation catheters may be unsuccessful in crossing coronary lesions that are severely narrowed. Hence, a new, extremely low profile coronary angioplasty catheter specifically designed to dilate such lesions was investigated. The catheter features a 2.0, 2.5 or 3.0 mm (inflated diameter) balloon mounted on a guide wire. The deflated profile of the 2.0 mm balloon measures 0.020 +/- 0.001 in. (0.51 +/- 0.03 mm). The catheter can be used in conjunction with 7F angiographic or 8F guide catheters. The catheter was used in 61 patients, aged 43 to 86 years, with predominantly Canadian Cardiovascular Society class III-IV angina. Dilation was attempted in 77 lesions. Lesion length averaged 5.7 +/- 3.1 mm (mean +/- 1 SD), minimal diameter 0.51 +/- 0.25 mm and internal vessel diameter 2.27 +/- 0.43 mm. Sixty lesions (78%) were successfully dilated to less than 50% residual stenosis with this catheter alone; nine lesions were further dilated with a larger balloon catheter. The new catheter was unable to cross 13 lesions (17%); only 2 of these lesions were subsequently crossed with a conventional over the wire system. On the other hand, the catheter was used after failure of conventional dilating catheters in 21 lesions and was successful in 16. The new catheter was particularly valuable for distal lesions and those demonstrating 90 to 99% diameter reduction. For all lesions crossed, stenosis decreased from 76 +/- 11 to 29 +/- 12% after 2.9 +/- 2.7 inflations and peak inflation pressure of 8.0 +/- 2.9 bar. Complications were rare; coronary occlusion occurred in two lesions (3%) and dissection in three lesions (4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary artery spasm at the site of angioplasty in the first 2 months after successful percutaneous transluminal coronary angioplasty.

The clinical course of five patients manifesting coronary artery spasm at the site of previous successful percutaneous coronary angioplasty is reviewed. All patients showed this spasm on hemodynamically insignificant (less than 50% diameter narrowing) obstruction. Four patients did not respond to therapy with calcium channel antagonists and nitrates and subsequently developed recurrent stenosis. One patient died 2 months after angioplasty and 1 day after coronary bypass surgery. Pathologic study at the site of angioplasty revealed new artherosclerotic disease. Coronary spasm may occur during the healing period after coronary angioplasty and should be distinguished from fixed obstruction.

Eight-year mortality in the Emory Angioplasty versus Surgery Trial (EAST)

OBJECTIVES: To evaluate the long-term outcome of patients randomized to coronary bypass surgery or coronary angioplasty. BACKGROUND: The Emory Angioplasty versus Surgery Trial (EAST) is a single center randomized comparison of a strategy of initial coronary angioplasty (n = 198) or coronary bypass surgery (n = 194) for patients with multivessel coronary artery disease. The primary end point (death, myocardial infarction or a large ischemic defect at 3 years) was not different, and repeat revascularization was significantly greater in the angioplasty group. Subsequently, the National Heart, Lung and Blood Institute supported a five-year extension of the trial. METHODS: After the three year anniversary visit, annual questionnaires, telephone contact and examination of medical records were accomplished until death or the eight year anniversary in 100% of the patients surviving at 3 years. RESULTS: Survival at 8 years is 79.3% in the angioplasty group and 82.7% in the surgical group (p = 0.40). Patients with proximal left anterior descending stenosis and those with diabetes tended to have better late survival with surgical intervention although not reaching statistical significance. After the first 3 years, repeat interventions remained relatively equal for both treatment groups. CONCLUSIONS: Long-term survival is not significantly different between angioplasty and surgery, and late (three to eight year) revascularization procedures were infrequent. Patients without treated diabetes had similar survival in both groups.

Local delivery of a synthetic antithrombin with a hydrogel-coated angioplasty balloon catheter inhibits platelet-dependent thrombosis.

OBJECTIVES: This study evaluated the efficacy of local administration of an antithrombin agent with a hydrogel-coated percutaneous transluminal coronary angioplasty balloon catheter. BACKGROUND: Intravenous infusion of antithrombin compounds has been shown to inhibit platelet-dependent thrombosis. However, hemorrhage is a common side effect associated with the systemic administration of antithrombin compounds. METHODS: The potent, irreversible thrombin inhibitor D-Phe-L-Pro-L-Arginyl chloromethyl ketone (PPACK) was used to inhibit thrombus formation in chronic porcine arteriovenous shunts. Platelet deposition was quantitated with gamma camera imaging of 111In-labeled platelets. RESULTS: Intravenous administration of PPACK in swine, in doses sufficient to maximally inhibit thrombus formation, was associated with prolongation of bleeding parameters. The inhibition of thrombosis associated with intravenous PPACK was dose related. The amount of intravenous PPACK necessary for maximal inhibition of thrombus formation for a period of 45 min was 16.9 mg. In contrast, local delivery of PPACK with a hydrogel-coated angioplasty balloon deployed at the site of the thrombus inhibited platelet deposition for at least 45 min after the balloon was removed. Using 3H-labeled PPACK, the calculated amount of PPACK delivered was 33.5 micrograms. There was no change in bleeding time or activated partial thromboplastin time when swine received an intravenous bolus greater than the total amount of PPACK adsorbed onto the balloon (70 micrograms). CONCLUSIONS: These results suggest that in this model, a hydrogel-coated coronary angioplasty balloon catheter can be used to deliver enough antithrombin agent to inhibit platelet-dependent thrombosis for at least 45 min at doses that are several orders of magnitude less than those required for systemic administration. In addition, local delivery can provide effective inhibition of thrombus formation without alteration of bleeding parameters.

Percutaneous transluminal coronary angioplasty in women compared with men.

OBJECTIVES: This study compares in-hospital and long-term outcome after angioplasty in women and men. BACKGROUND: The recognition that coronary artery disease is the most common cause of death in women has increased interest in outcome studies of coronary artery disease in women. METHODS: Patients who had previous coronary revascularization and those who underwent angioplasty in the setting of acute myocardial infarction were excluded. Angioplasty was performed with standard methods. Clinical data were retrieved from a clinical data base and analyzed with standard statistical methods. RESULTS: There were 2,845 women and 7,940 men. The women were older (62 +/- 11 vs. 57 +/- 10 years) and had more hypertension (54.5% vs. 40.1%), diabetes (19.3% vs. 11.7%), grade III to IV angina (71.5% vs. 58.4%) and congestive failure (4.3% vs. 2.1%) than men (all p < 0.0001). More men had a previous myocardial infarction (35.4% vs. 31.0%) and were taller and weighed more (all p < 0.0001). The men had lower ejection fractions and more multivessel disease (31.0% vs. 25.2%) (both p < 0.0001). In women there was a trend toward more Q wave myocardial infarctions (1.1% vs. 0.75%, p = 0.10), and hospital mortality was higher (0.7% vs. 0.1%, p < 0.0001). Angina at follow-up was more common in women 40.2% vs. 26.7%, p < 0.0001). The multivariate correlates of in-hospital death were short stature, reduced ejection fraction and multivessel disease, with trends for older age and female gender. Five-year survival was 95% in men and 92% in women (p = 0.0002). However, female gender was not a multivariate correlate of long-term survival and was accounted for by other characteristics, primarily age. The multivariate correlates of long-term survival were older age, congestive failure, reduced ejection fraction, multivessel disease, diabetes, hypertension and a trend for severe angina. No difference between women and men was noted in long-term freedom from myocardial infarction. There were more additional procedures in men than in women. CONCLUSIONS: Despite higher in-hospital mortality, long-term mortality and clinical outcome were similar in both genders when age and body habitus were accounted for.

Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronary angioplasty.

This double-blind, randomized study evaluated the effect of nifedipine on restenosis after coronary angioplasty. Two hundred forty-one patients with dilation of 271 coronary sites were randomized at the time of hospital discharge to receive nifedipine, 10 mg (123 patients), or placebo (118 patients) four times daily for 6 months. No patient was known to have coronary artery spasm. The mean duration of therapy was 4.4 +/- 2 (mean +/- SD) months for nifedipine and 4.3 +/- 2 months for placebo. A restudy angiogram was available in 100 patients (81%) in the nifedipine group and 98 patients (83%) in the placebo group. A recurrent coronary stenosis was noted in 28% of patients in the nifedipine group and in 29.5% of those in the placebo group (p = NS). The mean diameter stenosis was 36.4 +/- 23% for the nifedipine group and 36.7 +/- 23% for the placebo group (p = NS). By pill count, 78% of patients receiving nifedipine and 82% of those receiving placebo complied with the study drug regimen. Coronary stenosis recurred in 33% of patients in the placebo group and in 29% of patients in the nifedipine group who complied with the regimen and had angiograms (p = NS). In conclusion, the study did not demonstrate a significant beneficial effect of nifedipine on the incidence of recurrent stenosis after successful percutaneous transluminal coronary angioplasty.

Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis.

OBJECTIVES: This study was designed to compare the proliferative response in coronary arteries after tantalum stent placement or balloon injury in a normolipemic swine model of restenosis. BACKGROUND: Restenosis remains a significant complication of percutaneous transluminal coronary angioplasty. Efforts to study restenosis have been hampered by the lack of a suitable animal model. METHODS: In an attempt to create lesions resembling those of human restenosis, normolipemic swine underwent injury of either the left anterior descending or the left circumflex coronary artery with either balloon inflation or deployment of a tantalum stent. At 4 weeks, they were killed and the injured vessels processed for histopathologic analysis. Intimal area, lumen area and maximal intimal thickness were measured. The degree of stenosis was expressed as residual lumen area (lumen area/intimal area ratio). RESULTS: Vessels injured by either method demonstrated significant intimal smooth muscle proliferation leading to reduction in lumen area. In the 18 stented vessels residual lumen area measured 0.64 +/- 0.18 and maximal intimal thickness measured 0.6 +/- 0.3 mm; in the 15 balloon-injured vessels these values were 0.75 +/- 0.18 and 0.4 +/- 0.3 mm, respectively (p less than 0.05). In addition, most stented vessels had reactive inflammatory infiltrates surrounding the stent wires composed of lymphocytes, histiocytes and many eosinophils. CONCLUSIONS: These data indicate that coronary artery injury in swine with either balloon inflation or stenting leads to intimal smooth muscle cell proliferation similar to that seen in human restenosis. The degree of intimal proliferation appears to be greater after stenting than after balloon injury. Intracoronary stenting in swine is associated with a marked inflammatory reaction around the stent wires. These models may be helpful in planning systemic and local antirestenosis strategies.