Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease patients: insights from the Arterial Revascularization Therapy Study (ARTS) trial.

BACKGROUND: Our aims were to compare coronary artery bypass grafting (CABG) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study (ARTS) trial and to determine the costs of these 2 treatment strategies. METHODS AND RESULTS: Patients (n=1205) were randomly assigned to stent implantation (n=600; diabetic, 112) or CABG (n=605; diabetic, 96). Costs per patient were calculated as the product of each patient's use of resources and the corresponding unit costs. Baseline characteristics were similar between the groups. At 1 year, diabetic patients treated with stenting had the lowest event-free survival rate (63.4%) because of a higher incidence of repeat revascularization compared with both diabetic patients treated with CABG (84.4%, P<0.001) and nondiabetic patients treated with stents (76.2%, P=0.04). Conversely, diabetic and nondiabetic patients experienced similar 1-year event-free survival rates when treated with CABG (84.4% and 88.4%). The total 1-year costs for stenting and CABG in diabetic patients were $12 855 and $16 585 (P<0.001) and in the nondiabetic groups, $10 164 for stenting and $13 082 for surgery. CONCLUSIONS: Multivessel diabetic patients treated with stenting had a worse 1-year outcome than patients assigned to CABG or nondiabetics treated with stenting. The strategy of stenting was less costly than CABG, however, regardless of diabetic status.

The ARTS study (Arterial Revascularization Therapies Study).

The rising costs of health care have forced policy makers to make choices, and new treatments are increasingly assessed in terms of the balance between additional costs and additional effects. The recent recognition that stenting has a major and long-lasting effect enhancing balloon PTCA procedure has made it imperative to compare in patients with multivessel disease the standard surgical procedure with multiple stenting in a large scale multinational and multicentre approach (19 countries, 68 sites). Selection and inclusion of patients is based on a consensus of the cardiac surgeon and interventional cardiologist on equal 'treatability' of patients by both techniques with analysis of clinical follow-up (event-free survival) on the short (30 day), medium (1 year), and long-term (3 and 5 year) with analysis of cost-effectiveness and quality of life (EuroQol and SF-36). Of the entire trial, the primary null hypothesis which needs to be rejected is that there will be no difference in event-free survival or effectiveness (E), at 1 year and also that the direct and indirect costs (C) per event-free year are not different between surgery or stenting. For this to become significant with a power of 90% one needs 1200 patients. Between April 97 and June 98, 1205 patients have been randomized with a monthly recruitment of 83 patients. Expected costs, effects and cost-effectiveness ratio (CE ratio) are: Stent high costs 2 VDStent high costs 3 VDStent low costs 2 VDStent low costs 3 VDCABG costs (C)$19.297$24.566$16.638$20.456$21.350 effects (E)81%81%81%81%88% CE ratio$23.876$30.397$20.586$25.322$24.348 Clinically, stenting is not expected to be more effective than CABG, but should be cost effective in both the 2- and 3-VD group when using the lower cost estimate and in the 2 VD group when using the higher cost assumptions.

Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial.

OBJECTIVES: This study was performed to evaluate the effects of L-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. BACKGROUND: Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous carnitine administration during these events has a beneficial effect on function. METHODS: The L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or L-carnitine (233 patients) within 24 h of onset of chest pain. Placebo or L-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. RESULTS: A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with L-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6- and 12-month evaluation was significantly reduced in the L-carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the L-carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients. CONCLUSIONS: L-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event.

How late is too late and how early is early: the clinician's view of the first 100 minutes.

Proper understanding of the pathological process of a ruptured plaque followed by thrombus formation remains the basis for rational therapy of cardiac ischaemia and myocardial infarction. With the advent of better thrombolytic regimens, improved direct reperfusion via angioplasty and streamlined recognition/admission procedures, therapeutic strategies for dealing with acute myocardial infarction have once more turned to the options for early therapy. From recent studies of out-of-hospital thrombolysis or immediate percutaneous transluminal coronary angioplasty, the position is reinforced that 'early' means the first 100 minutes. In the recently completed GUSTO study worldwide involving over 40,000 patients with suspected myocardial infarction, a significant subset received recombinant tissue-type plasminogen activator (rt-PA) (alteplase) in the accelerated Neuhaus formula, within that time frame. Compared to standard streptokinase, this resulted in a very low mortality (3%) and markedly reduced morbidity. The difference between both regimens is highly significant, establishing once and for all the efficacy of rt-Pa in all types of hospitals, provided the patients receive their therapy within 2 hours. Thus, when appropriate therapy, depending in the local availability of facilities, is given promptly, further reductions in myocardial infarction size and ventricular dysfunction can be achieved, resulting in mortality rates of < 5%, at substantial savings in the ever more expensive healthcare resources. So, 'early is < 100 minutes; later may be too late or too costly'.

Expanding indications for thrombolytic therapy in acute myocardial infarction. How late is too late, and how early is early: the clinician's view of the first 100 minutes.

Proper understanding of the pathologic process of a ruptured plaque followed by thrombus formation, with acute assessment of the deranged pathophysiology of the coronary circulation as a sequel, remains the basis for rational therapy of cardiac ischemia. With the advent of better thrombolytic regimens, improved direct reperfusion via angioplasty, and streamlined recognition/admission procedures, therapeutic strategies for dealing with acute myocardial infarction have once more turned to the options for early therapy. From recent studies of out-of-hospital thrombolysis or immediate percutaneous transluminal coronary angioplasty, the position is reinforced that "early" means the first 100 minutes. It is hoped that the large Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO) study, which specifically analyses the effect of early reperfusion by optimal alteplase and actilyse (recombinant tissue-type plasminogen activator [rt-PA]) versus streptokinase regimens will confirm this essential concept once and for all. Thus, when appropriate therapy--depending in the local availability of facilities--is promptly given, further reductions in myocardial infarction size and ventricular dysfunction can be achieved, resulting in mortality rates < 5%, at substantial savings in ever more expensive healthcare resources. "Early is < 100 minutes; later may be too late or too costly."

On the options for the European cardiologist in the enlarging European Community.

In conclusion, European integration in 1992 will mean several things for the European cardiologist, the most important of which are the following: 1. The E.S.C. will and must be able to exert more influence than ever before on the legislative and executive processes in Brussels, now and in 1993, and therefore collectively in the partner countries. 2. Only then, like its American counterparts the A.C.C. and A.H.A., will the E.S.C. be able to join with the politicians to guide the all-important question of allotment of funds. Funds for patient care, teaching, research, advanced planning, for investments in hospitals and laboratories, are all part of our fight against heart disease. These can much better be applied for and allocated on a European scale than on a national basis. The mere avoidance of duplication and repetition may be the greatest benefit of integration. 3. Only by strengthening the E.S.C. with a "cadre" of experienced cardiologists we can deliver the expert manpower which this integrative process will require: "Let not our Society miss the opportunities which 1992 offers!" 4. As a final point, only when we, as a professional unit show that we can make choices, and desist from asking everything possible for every patient we see, will we be able to regain and retain the trust of the patient as well as the political representatives of our member nations. Let us capture this genie before it, too, escapes from the bottle (Braunwald, 1988). These points are symbolized in Figure 1.

Efficacy of nicorandil versus propranolol in mild stable angina pectoris of effort: a long-term, double-blind, randomized study.

Nicorandil is a potent coronary vasodilator. To assess its long-term antianginal effect, we designed a randomized, parallel double-blind trial of 6 weeks' duration comparing nicorandil (10 or 20 mg b.i.d.) with propranolol (40 or 80 mg t.i.d.). The study comprised 77 men with stable angina, no maintenance medication at entry, and an exercise test positive for angina and ST-segment depression. The therapy was started with 10 mg nicorandil b.i.d. or 40 mg propranolol t.i.d. After 3 weeks, the dosage could be doubled according to clinical criteria. Four men receiving nicorandil and one receiving propranolol were withdrawn with side effects; in three cases, the data were not complete. Thus, comparative data were obtained in 69 patients; in 51 of these (26 receiving nicorandil and 25 receiving propranolol), the dosage was increased to the higher level. Blood pressure and heart rate were unaltered by nicorandil and lowered by propranolol. The number of anginal attacks decreased relative to baseline on nicorandil and propranolol (p < 0.002), but total exercise duration was not influenced by either drug. The exercise test performed 2 h after either pill ingestion showed a decrease and a delay in occurrence of myocardial ischemia. The test performed 12 h after medication exhibited reduced ischemia, whereas only propranolol resulted in delayed ST-segment depression. The double product of heart rate and systolic blood pressure was affected only slightly by nicorandil and reduced significantly by propranolol (p < 0.001). Thus, nicorandil medication affords similar improvement as propranolol in patients with angina pectoris, but the mode of action appears to be different.

On jumbo and junkie trials: a fumbled affair, a jungle, or the ultimate solution?

Important Clinical trials conducted between 1980 and 1990 provided early leads to the community of practicing cardiologists and general physicians on the fundamentals of the therapy of acute myocardial infarction. On the other hand trials like ISIS-III or GUSTO, the current giant among jumbo trials, could not solve the real problems arising in clinical practice. The large-scale clinical trials should be reserved for interventions that have been shown convincingly in smaller trials. The problem of restenosis after PTCA is discussed and the place of animal research is emphasized as the basis of the design of future clinical trials. These exciting data require a human study but with a scale that proves the efficacy of the intervention and substantiates the underlying hypothesis even in a small population.

Percutaneous transluminal coronary angioplasty for unstable angina.

Coronary angioplasty is an effective treatment for patients with angina at rest, either refractory or initially stabilized but returning despite pharmacologic treatment, and with early postinfarction angina. The procedure has a high initial success rate, but there is an increased risk of major complications resulting from a higher incidence of acute closure, which may be related to preexisting thrombus. Resolution of this problem may be achieved by the use of more potent antiplatelet treatment, pretreatment with thrombolytic agents, or treatment that can be applied locally (e.g., laser energy, atherectomy) at the site of the unstable plaque. Results in this study have been obtained from selected groups of patients: those with predominantly single-vessel disease and well-preserved left ventricular function. It remains to be determined whether the same benefits can be achieved in patients with multivessel disease or in those who have severely reduced left ventricular function.