Educational challenges in implementing genomic medicine.

Clinical medicine is about to embark on an exciting, although harrowing, period of innovation, the result of astonishing advances in genomic science. The current workforce--physicians, nurses, pharmacists, and others--will soon need to adapt to substantial change, driven by genomics, in diagnostic and therapeutic strategies. If errors of omission and commission are to be prevented, sustained efforts in workforce education will be needed on the part of medical schools, training programs, and professional societies.

Coronary artery bypass graft surgery after thrombolytic therapy in the Thrombolysis in Myocardial Infarction Trial, Phase II (TIMI II).

OBJECTIVES: We examined the results of coronary artery bypass graft surgery after thrombolytic therapy in the Thrombolysis in Myocardial Infarction trial, Phase II (TIMI II) with particular emphasis on patient characteristics, the impact of antecedent percutaneous transluminal coronary angioplasty and morbidity and mortality in certain subgroups. BACKGROUND: Coronary bypass surgery is frequently used after thrombolytic therapy, but there is relatively little information with regard to early and late outcomes. METHODS: We analyzed 3,339 patients enrolled in the TIMI II trial. Bypass surgery was performed in 390 patients (11.7%): 54 (14%) within 24 h after entry into the trial or within 24 h of coronary angioplasty and 336 (86%) between 24 h and 42 days after entry. RESULTS: Perioperative mortality rates were, respectively, 16.7% and 3.9% (p < 0.001); perioperative myocardial infarction rates were 5.6% and 6.2%, respectively; and major hemorrhagic events occurred in 74% and 50.9%, respectively (p = 0.002). On multivariate analysis, the only independent predictor of perioperative mortality was bypass surgery within 24 h after entry or after coronary angioplasty. Among patients undergoing bypass surgery within 24 h of entry or after coronary angioplasty, the prevalence of multivessel disease (59.1% vs. 77.8%) and use of the internal thoracic artery (18.5% vs. 62.5%) were lower than in the remaining surgical patients. Among the 322 perioperative survivors, the 1-year mortality rate after discharge was only 2.2% and 1.9%, respectively, in the two groups. Only one patient had a documented recurrent myocardial infarction during the first year. CONCLUSIONS: The increased mortality rate with bypass surgery after thrombolytic therapy, particularly in patients undergoing operation within 24 h of coronary angioplasty or during the involving phase of infarction, must be balanced against the excellent 1-year prognosis and perioperative survivors, who are in general a group at higher risk of death or recurrent infarction. These data provide a basis for comparison for future studies.

Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration.

We carried out a systematic overview using individual patient data from the seven randomised trials that have compared a strategy of initial coronary artery bypass graft (CABG) surgery with one of initial medical therapy to assess the effects on mortality in patients with stable coronary heart disease (stable angina not severe enough to necessitate surgery on grounds of symptoms alone, or myocardial infarction). 1324 patients were assigned CABG surgery and 1325 medical management between 1972 and 1984. The proportion of patients in the medical treatment group who had undergone CABG surgery was 25% at 5 years, 33% at 7 years, and 41% at 10 years: 93.7% of patients assigned to the surgery group underwent CABG surgery. The CABG group had significantly lower mortality than the medical treatment group at 5 years (10.2 vs 15.8%; odds ratio 0.61 [95% CI 0.48-0.77], p = 0.0001), 7 years (15.8 vs 21.7%; 0.68 [0.56-0.83], p < 0.001), and 10 years (26.4 vs 30.5%; 0.83 [0.70-0.98]; p = 0.03). The risk reduction was greater in patients with left main artery disease than in those with disease in three vessels or one or two vessels (odds ratios at 5 years 0.32, 0.58, and 0.77, respectively). Although relative risk reductions in subgroups defined by other baseline characteristics were similar, the absolute benefits of CABG surgery were most pronounced in patients in the highest risk categories. This effect was most evident when several prognostically important clinical and angiographic risk factors were integrated to stratify patients by risk levels and the extension of survival at 10 years was examined (change in survival -1.1 [SE 3.1] months in low-risk group, 5.0 [4.2] months in moderate-risk group, and 8.8 [5.4] months in high-risk group; p for trend < 0.003). A strategy of initial CABG surgery is associated with lower mortality than one of medical management with delayed surgery if necessary, especially in high-risk and medium-risk patients with stable coronary heart disease. In low-risk patients, the limited data show a non-significant trend towards greater mortality with CABG.

Early mortality of acute myocardial infarction in patients with and without prior coronary revascularization surgery. A Coronary Artery Surgery Study Registry Study.

BACKGROUND: The Coronary Artery Surgery Study (CASS) Registry is used to evaluate the effect of various baseline clinical and angiographic factors on mortality after acute out-of-hospital myocardial infarction (MI) in patients with and without prior coronary bypass surgery. METHODS AND RESULTS: Among the CASS Registry patients, there were 985 medical and 369 surgical patients who had an MI out of the hospital within 3 years after enrollment. In the medical group, 20% died before hospitalization. Medical patients with baseline three-vessel disease or left ventricular (LV) dysfunction were at high risk of immediate death. For medical patients who were hospitalized with MI, mortality was higher for older patients and those with severe angina as well as for those with extensive disease and LV dysfunction. The total 30-day mortality for medical patients was 36%. In the surgical group, 12% died before hospitalization. Surgical patients with LV dysfunction or prior MI were at highest risk of immediate death. For surgical patients hospitalized with MI, mortality was significantly increased only for patients with baseline LV dysfunction. Mortality was not significantly higher for surgical patients with multivessel disease. The total 30-day mortality for surgical patients was 21%. The prior use of aspirin or beta-blockers was not associated with reduced mortality from subsequent MI for either medical or surgical patients. Although the prevalence of cigarette smoking was high among patients who had an MI, cigarette smoking did not alter the infarct-related mortality rate. CONCLUSIONS: The surgical group had lower mortality rates than the medical group both immediately (p = 0.001), after hospitalization (p less than 0.0001), and at 30 days (p less than 0.0001).

Assessment of global and regional left ventricular performance at rest and during exercise after thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) II Study.

Global and regional left ventricular performances were evaluated with equilibrium radionuclide angiocardiography in patients in the Thrombolysis in Myocardial Infarction (TIMI) II trial at the time of hospital discharge. Studies at rest were available in 1,162 (69%) of the invasive and 1,150 (69%) of the conservative strategy patients, and exercise studies in 1,133 (67%) of the invasive and 1,145 (69%) of the conservative patients. Repeat studies were performed at the time of 6-week follow-up. Global and regional ejection fraction at rest were both comparable in patients assigned to each of the treatment strategies. However, at the time of hospital discharge patients in the invasive strategy had normal exercise responses more frequently (29.7 vs 25.8% p = 0.01), greater peak exercise LV ejection fraction (54.8 +/- 13.8% vs 53.1 +/- 14.1%, p = 0.004), greater exercise--rest change in LV ejection fraction (3.7 +/- 6.7% vs 2.7 +/- 7.2%, p less than 0.001) and greater peak exercise infarct zone regional ejection fraction (53.2 +/- 31.1% vs 50.3 +/- 33.0%, p less than 0.001) than patients assigned to the conservative strategy. At 6-week follow-up these differences between treatment strategies were no longer evident. When data were restricted to those collected at comparable work loads, similar differences in hospital discharge exercise performance between invasive vs conservative strategy patients were observed. Thus, there is a small transient difference in exercise global and regional LV performance associated with an invasive as opposed to conservative strategy after thrombolytic therapy. These differences are noted at the time of hospital discharge but not at 6 weeks, and are unlikely to confer clinical benefit.

Selective versus routine predischarge coronary arteriography after therapy with recombinant tissue-type plasminogen activator, heparin and aspirin for acute myocardial infarction. TIMI II Investigators.

To ascertain whether predischarge arteriography is beneficial in patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator (rt-PA), heparin and aspirin, the outcome of 197 patients in the Thrombolysis in Myocardial Infarction (TIMI) IIA study assigned to conservative management and routine predischarge coronary arteriography (routine catheterization group) was compared with the outcome of 1,461 patients from the TIMI IIB study assigned to conservative management without routine coronary arteriography unless ischemia recurred spontaneously or on predischarge exercise testing (selective catheterization group). The two groups were similar with regard to important baseline variables. During the initial hospital stay, coronary arteriography was performed in 93.9% of the routine catheterization group and 34.7% of the selective catheterization group (p less than 0.001), but the frequency of coronary revascularization (angioplasty or coronary artery bypass surgery) was similar in the two groups (24.4% versus 20.7%, p = NS). Coronary arteriograms showed a predominance of zero or one vessel disease (stenosis greater than or equal to 60%) in both groups (routine catheterization group 73.1%, selective catheterization group 61.3%). During the 1st year after infarction, rehospitalization for cardiac reasons and the interim performance of coronary arteriography were more common in the selective catheterization group (37.9% versus 27.6%, p = 0.007 and 28.6% versus 11.6%, p less than 0.001, respectively); however, the interim rates of death, nonfatal reinfarction and performance of coronary revascularization procedures were similar. At the end of 1 year, coronary arteriography had been performed one or more times in 98.9% of the routine catheterization group and 59.4% of the selective catheterization group (p less than 0.001), whereas death and nonfatal reinfarction had occurred in 10.2% versus 7.0% (p = 0.10) and 8.6% versus 9.0% (p = 0.87), respectively. Because the selective coronary arteriography policy exposes about 40% fewer patients to the small but finite risks and inconvenience of the procedure without compromising the 1 year survival or reinfarction rates, it seems to be an appropriate management strategy.

Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study.

In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial, patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study, the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy, a group of 1,434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group, within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point, resting global ejection fraction at hospital discharge, averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall, there was no difference in mortality between the immediate intravenous and deferred groups, but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent chest pain (18.8% versus 24.1%, p less than 0.02) at 6 days in the immediate intravenous group. Thus, in appropriate postinfarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality.

Considerations for a national heart attack alert program.

Coronary heart disease (CHD) remains the leading cause of death in the United States--in women as well as men. In 1987, CHD was responsible for 512,138 deaths, of which 253,542 deaths were attributed to acute myocardial infarction (AMI) and accounted for over $43 billion in direct and indirect costs. The disease spares no one. Primary prevention is clearly important, but for those in whom primary prevention has not been applied or has failed, acting to minimize the effect of a heart attack is of paramount importance. Many of its victims do not obtain appropriate medical care, or obtain it too late for the latest lifesaving technologies to be effective. The goal of treatment is to prevent death and to salvage as much heart tissue as possible. To achieve this goal, it is essential to minimize the time from the first symptoms and signs to treatment. Opportunities exist at each phase of an evolving AMI to intervene promptly and appropriately to prevent sudden death and to preserve cardiac muscle and thereby reduce CHD morbidity and mortality. Yet, formidable problems also exist. These and other issues are presently being studied by the National Heart, Lung, and Blood Institute staff and advisors in consideration of whether to establish a national educational program aimed at reducing CHD morbidity and mortality through the rapid identification and treatment of those with AMI.

The Thrombolysis in Myocardial Infarction (TIMI) Trial phase II: additional information and perspectives.

Given the many thrombolytic agents and the number of ways in which they can be combined with mechanical revascularization, the treatment of acute myocardial infarction has been the subject of active study and lively debate, which are likely to continue for some time. Several studies, including TIMI IIA (2,3,10,22), have suggested that immediate catheterization and angioplasty offer no clinical benefit and have a greater complication rate than a more delayed invasive strategy, but TIMI II (1) and SWIFT (16) trials have suggested that an even more conservative strategy of reserving catheterization and coronary angioplasty after thrombolytic therapy for patients with recurrent spontaneous or exercise-induced ischemia may be the most desirable approach for the majority of patients similar to those entered into these trials.

Long-term follow-up of coronary angioplasty: the 1977-1981 National Heart, Lung, and Blood Institute registry.

Between September 1977 and September 1981, 1587 consecutive patients underwent a first coronary angioplasty (PTCA) at 16 clinical centres. After excluding patients with prior coronary bypass surgery (CABG) and left main or minimal vessel disease, 1390 were available for in-hospital and long-term follow-up. Mean duration of follow-up was 5.9 years (range 0-9.0 years). PTCA was successful (all attempted lesions reduced greater than or equal to 20%) in 882 patients (63.4%) and, overall, 624 patients (44.9%) had complete (COREV) and 766 (55.1%) incomplete (INCOREV) revascularization or a failed PtCA. In-hospital events included death in 0.7%, myocardial infarction (MI) in 5.0% and CABG in 24.0% of patients. Patients with COREV had significantly lower rates of these events than the INCOREV group. At 6 years, mortality in all registry patients was 6.5% and MI rate 15.0%; CABG was performed after the initial hospitalization in 15.5% of patients and repeat PTCA in 19.1%. All events, except repeated PTCA, were less frequent in the COREV than the INCOREV group. Among patients with a successful first PTCA, cumulative 6-year mortality was 5.8% and incidence of MI 10.8%; 16.9% underwent CABG and 24.7% repeat PTCA during follow-up. CABG was slightly more frequent in INCOREV than COREV patients with successful PTCA, but all other events were similar in the two groups, suggesting that INCOREV 'by intent' has a good prognosis. In patients with INCOREV, mortality and incidence of MI were higher during follow-up for patients with multivessel rather than single vessel disease. However, the incidence of CABG and repeat PTCA was similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)