Lars I. Thulin

Sodium-Hydrogen Exchange Inhibition by Cariporide to Reduce the Risk of Ischemic Cardiac Events in Patients Undergoing Coronary Artery Bypass Grafting: Results of the EXPEDITION Study

BACKGROUND The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger-mediated calcium overload to reduce infarct size. METHODS High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months. RESULTS At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant. CONCLUSIONS The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.

Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: Results of the CABG surgery cohort of the GUARDIAN study

OBJECTIVES To evaluate the effects of cariporide on all-cause mortality or myocardial infarction at 36 days in patients at risk of myocardial necrosis after coronary artery bypass graft surgery. METHODS In the coronary artery bypass graft cohort of the GUARD During Ischemia Against Necrosis trial, patients > or =18 years who required urgent coronary artery bypass graft, repeat coronary artery bypass graft, or had a history of unstable angina and > or =2 risk factors (age >65 years, female gender, diabetes mellitus, ejection fraction <35%, or left main or 3-vessel disease) were randomized to placebo (n = 743) or cariporide 20 mg (n = 736), 80 mg (n = 705), or 120 mg (n = 734). A 1-hour intravenous infusion was initiated shortly before surgery and administered every 8 hours for 2 to 7 days. Patients were followed up for 6 months. A nonparametric covariance analysis was used to calculate the primary efficacy endpoint. RESULTS Baseline characteristics were similar between treatment groups. The cariporide 20- and 80-mg groups had event rates similar to placebo. The endpoint of all-cause mortality or myocardial infarction at day 36 was significant with cariporide 120 mg versus placebo (event rate 12.2% vs 16.2%; P =.027). The risk reduction was evident on postoperative day 1 (3.3% vs 6.5%; P =.005) and was maintained at 6 months (event rate 15.0% vs 18.6%; P =.033). Cariporide was well tolerated, and most adverse events were mild and transient in this high-risk population. CONCLUSIONS Clinical benefit with cariporide 120 mg was observed early after treatment initiation and continued for 6 months postsurgery, suggesting that sodium-hydrogen exchange inhibition with cariporide is cardioprotective in patients undergoing high-risk coronary artery bypass graft surgery.

Quality of Life in the Very Elderly after Cardiac Surgery: A Comparison of SF-36 between Long-Term Survivors and an Age-Matched Population

Background: Octogenarians are the fastest growing section of the population in Western countries. Since health care resources are limited, there is a need for critical evaluations of the long-term surgical outcome and quality of life in the elderly. Objectives: Our aim was to assess the quality of life and long-term survival after cardiac surgery in the very elderly. Methods: Between 1990 and 1993, 117 octogenarians underwent aortic valve replacement, coronary artery bypass grafting or combined surgery at our department. Forty-one patients were still alive at the time of follow-up (mean 8.3 ± 1.9 years). Thirty-nine of the 41 long-term survivors (95%) answered a quality of life questionnaire (SF-36). The scores were compared with an age-matched population. Results: The overall survival at 1, 5 and 9 years was 92.3 ± 2.5, 65.0 ± 4.4 and 37.9 ± 5.2%, respectively. A significant difference was identified between the scores of our patients and the general Swedish octogenarians in two SF-36 headings (Bodily Pain and Physical Functioning). Our patients indicated lower physical function, but less pain in comparison with the general aged population. There was no significant difference in six of the eight SF-36 headings. Conclusions: The overall long-term survival was similar to Swedish octogenarians. Late postoperative quality of life in our long-term survivors was comparable to an age-matched population. Our findings support the view that a selected population of elderly may undergo open heart surgery with good long-term quality of life.

Perception of Mechanical Heart Valve Sounds

Most currently used mechanical heart valve prostheses generate a distinct sound when they close. This sound is sometimes disturbing to the patient, and may impair quality of life. In a study of 285 patients followed up for a mean of 2.5 years after mechanical heart valve replacement, one-third were sometimes disturbed by sounds emanating from the prosthesis. Older patients were less disturbed than young ones, but whether this could be explained by age-related impairment of hearing ability (presbyacusis) was not possible to determine. Prosthetic size, implantation site, patients weight, body surface area and type of prosthesis did not statistically differ according to experience of prosthetic sounds. Although few patients were seriously disturbed by these sounds, it is hoped that mechanical heart valves of the future will function more quietly.

Heart Valve Replacement with the Björk-Shiley Monostrut Valve: Early Results of a Multicenter Clinical Investigation

To evaluate the clinical performance of the Björk-Shiley Monostrut prosthesis, five centers combined their early experience. Between May, 1982, and June, 1985, 537 prostheses were implanted in 486 patients at these centers: 246 patients had aortic valve replacement (AVR), 163 underwent mitral valve replacement (MVR), and 47 had double-valve replacement (DVR). Thirty patients underwent other, more complex procedures. Concomitant cardiac procedures were performed in altogether 25%. Overall hospital (30 days) mortality was 5.1% (3.6% for AVR, 4.3% for MVR, 8.3% for DVR, and 16.6% for other procedures). The patients were followed up at 6- to 9-month intervals from 6 to 48 months (mean follow-up, 33 months). Follow-up was 99.6% complete. Late mortality was 7.2%. The three-year survival rate was 91.0% for AVR, 92.3% for MVR, and 76.2% for DVR. There was no structural failure of the prosthesis. No instances of valve thrombosis and fatal thromboembolism occurred in anticoagulated patients. The three-year incidence of freedom from thromboembolic events (including TIA) was 89.8% for AVR, 94.9% for MVR, and 90.2% for DVR. Preoperative and postoperative data for the assessment of mechanical hemolysis was available in 60% of the patients. The degree of mechanical hemolysis was low and did not change with time. Although the follow-up is still short, the Björk-Shiley Monostrut prosthesis appears to represent an improvement over previous Björk-Shiley models, particularly with regard to durability.

Cause of Late Death after Cardiac Surgery in the Very Elderly: a Single Institution Experience

Objectives : The referrals of elderly for cardiac surgery are increasing. The aim of this retrospective study is to review the long-term survival and to identify causes of late death in elderly after cardiac surgery. Design : Between 1990 and 1993, 130 octogenarians underwent cardiac surgery in our department. A majority (88%) had elective surgery. One hundred and nine patients (84%) were in New York Heart Association functional class III or IV, preoperatively. Mean follow-up time was 5.4 - 2.5 years (range 0-10 years). Follow-up was 100% complete. Results : Hospital mortality was 3.8% (5/130). Actuarial survival at 1 and 5 years were 90.0 - 2.6% ( n = 117) and 62.3 - 4.3% ( n = 81), respectively. Forty-six operative survivors died from cardiac-related death during follow-up. Multivariate predictors of postoperative death were higher age, poor left ventricular ejection fraction, preoperative renal insufficiency and combined surgical procedures. Conclusion : Our results in this paper indicate that cardiac-related mortality represents the majority of late deaths after cardiac surgery in octogenarians.

OPEN-HEART SURGERY IN A GROWING GERIATRIC POPULATION : PATIENT SELECTION AND RISK FACTORS TO BE CONSIDERED

AimsThis report describes our experience with cardiac surgery in elderly patients and aims to ascertain predictors of poor outcome. PatientsFive hundred and ninety-eight (598) consecutive patients aged 75 years and older underwent cardiac surgery at the Department of Cardiothoracic Surgery, University Hospital of Lund, Sweden, between January 1980 and December 1993. There were 324 men (54%) and 274 women (46%); their age varied between 75 and 91 years (mean age ± SD, 77.8 ± 2.6 years). One hundred and twenty-nine patients underwent aortic, mitral or combined valve replacement, 273 patients underwent exclusive coronary revascularization (CABG) alone and 109 underwent a surgical procedure which included valve replacement and concomitant CABG. The remainder (87 patients) underwent other, more complex surgical procedures. ResultsThe 30-day or in-hospital mortality rate was 5.5% (0.8% for valve replacement, 5.1% for CABG, 5.5% for valve replacement with concomitant CABG, and 12.6% for other procedures). Concomitant severe diseases occurred in 34.9% of the patients. All surviving patients were evaluated during June 1994. None of the patients was lost to follow-up. The 566 long-term survivors have been followed for an average of 23.0 months (median 21; range 1–53 months). Late mortality was 12.0% in the 566 hospital survivors. Only 1 7 patients experienced late complications (after hospital discharge), as an adverse effect linked to heart surgery.

Mechanical versus biological aortic valve implants in the elderly. A comparison of early and mid-term results

OBJECTIVE Our aim was to compare, in a non randomized study, the surgical outcome in elderly patients with mechanical (Group 1; n=83) and bioprosthetic valve implants (Group 2; n=136). METHODS During a three year period, 219 patients >75 years underwent Aortic Valve Replacement. The groups matched according to age, sex, comorbidity, valve pathology and concomitant Coronary Artery Bypass Surgery. Follow-up was a total of 469 patient-years (mean follow-up 2.1 years, maximum 4,4 years). RESULTS Operative mortality was zero and the overall early mortality was 2.3 % (within 30 days). Actuarial survival was 87.5 +/- 4.0% and 66.1 +/- 7.7% (NS) at 4 years in Group 1 and Group 2, respectively. Freedom from valve-related death was 88.9 +/- 3.8% in Group 1 and 69.9+/-7.9% (NS) in Group 2 at 4 years. CONCLUSION Aortic Valve Replacement in the elderly (>75 years) is a safe procedure even in cases where concomitant coronary artery revascularization is performed. Only a few anticoagulant-related complications were reported and this may indicate that selected groups of elderly patients with significant life expectancy may benefit from mechanical implants.

Cineradiographic functional evaluation of the Björk-Shiley monostrut prosthesis. A follow-up study of 46 consecutive patients.

In 46 patients, 51 Björk-Shiley monostrut valves were studied with high-speed cineradiography 9 months after implantation. Each valve was viewed in lateral, frontal and oblique projections for 10-12 heart beats. In the aortic valves the opening time was 0.04-0.067 (mean 0.052) and closing time 0.04-0.067 (mean 0.046) sec. In all these valves the maximum opening angle was 70 degrees. Disc rotation could be monitored in 29/31 valves, and during 10 heart beats averaged 20 degrees. Disc slide of 2.0-2.5 mm was seen in 27/31 valves. It occurred during the last 40-50 degrees of opening and the first 20-40 degrees of closing. In mitral valves with sinus rhythm (12/20), the opening time was 0.053-0.106 (mean 0.073) and closing time 0.040-0.106 (mean 0.061) sec. Mean disc rotation (recorded in 17/20 valves) during 10 heart beats was 25 degrees, and disc slide of 2.0-2.5 mm was found in all but one case, mainly during the last 50 degrees of opening and the first 30 degrees of closing. The valve opened to 70 degrees in all but one patient, in whom the disc clearly impinged against the left ventricular wall and opened only to 35-50 degrees at rest. At reexamination a year later the patient was asymptomatic, in sinus rhythm, and the disc had regained full movement with 70 degrees opening.