Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction.

BACKGROUND: Use of proton pump inhibitors (PPIs) has been associated with cardiovascular disease amongst patients not on antiplatelet therapy. The associations of PPI use, duration and dose, with risk of first-time ischemic stroke and myocardial infarction (MI) are poorly understood. METHODS: All Danish individuals with no prior history of MI or stroke, who had an elective upper gastrointestinal endoscopy performed between 1997 and 2012, were identified from nationwide registries. We used multiple Poisson regression to test associations with current PPI use and its dose and used multiple cause-specific Cox regression and g-formula methods to analyze long-term use. RESULTS: Amongst 214 998 individuals, during a median follow-up of 5.8 years, there were 7916 ischemic strokes and 5608 MIs. Current PPI exposure was associated with significantly higher rates of both ischemic stroke (Hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.08-1.19) and MI (HR 1.31, CI 1.23-1.39) after adjusting for age, sex, comorbidities and concomitant medication. High-dose PPI was associated with increased rates of ischemic stroke (HR 1.31, CI 1.21-1.42) and MI (HR 1.43, CI 1.30-1.57). Histamine H2 receptor antagonists (H2RAs) use was not significantly associated with ischemic stroke (HR 1.02, CI 0.84-1.24) or MI (HR 1.15, CI 0.92-1.43). Long-term users of PPIs, compared with nonusers, had a 29% (CI 5%-59%) greater absolute risk of ischemic stroke and a 36% (CI 7%-73%) greater risk of MI within a 6-month period. CONCLUSION: Use of PPIs was associated with increased risks of first-time ischemic stroke and MI, particularly amongst long-term users and at high doses.

Canadian-American differences in the management of acute coronary syndromes in the GUSTO IIb trial: one-year follow-up of patients without ST-segment elevation. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) II Investigators.

BACKGROUND: Little information exists concerning practice patterns between Canada and the United States in the management of myocardial infarction (MI) patients without ST-segment elevation and unstable angina. METHODS AND RESULTS: We examined the practice patterns and 1-year outcomes of 2250 US and 922 Canadian patients without ST-elevation acute coronary syndromes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial. The US hospitals more commonly had on-site facilities for angiography and revascularization. These procedures were performed more often and sooner in the United States than Canada, whereas Canadian patients were more likely to undergo noninvasive stress testing. The length of initial hospital stay was 1 day longer for Canadian than US patients. Recurrent and refractory ischemia was more common in Canada. One-year mortality was comparable between the 2 countries. However, at 6 months, even after baseline differences were accounted for, the (re)MI rate was significantly higher in Canadian than US patients with unstable angina (8.8% versus 5.8%, P:=0.039), as was the composite rate of death or (re)MI (13.1% versus 9.1%, P:=0.016). CONCLUSIONS: One-year mortality was comparable between Canada and the United States in both MI and unstable angina cohorts despite higher intervention rates in the United States. However, outcomes at 6 months among patients with unstable angina differed. Whereas more frequent coronary interventions were not associated with reduced recurrent MI or death among MI patients without ST elevation, they may favorably affect outcomes in patients with unstable angina.

Projects and priorities in cardiovascular modeling.

Studies that either 1) model the likelihood of clinical outcomes as a function of patient characteristics, or 2) examine the factors underlying a specific medical decision are discussed. Although the currently available models represent important contributions, the working group that met during the 1987 Regenstrief Conference identified several important areas for further attention. Described are discussions on ways to improve standardization, accessibility, validation and dissemination of decision models.

Functional capacity after cardiac surgery in elderly patients.

OBJECTIVES: This study was performed to determine whether cardiac surgery improves functional capacity in patients > 70 years of age and to identify factors associated with good and poor functional results in this age group. BACKGROUND: Cardiac surgery has been used increasingly among older patients, but the effectiveness of surgery in this age group remains controversial. METHODS: Self-reported functional capacity was assessed by the Duke Activity Status Index preoperatively and again 1 year after coronary artery bypass or valve replacement surgery in a total of 199 patients with a mean age of 76 years (range 70 to 91). RESULTS: Functional capacity improved significantly after surgery (mean Duke Activity Status Index 27.9 at baseline vs. 36.8 at 12 months, p < 0.001), with improvements in most patients (74%). Six preoperative factors were independent predictors of less improvement in functional capacity between baseline and 1 year: smoking, female gender, higher Charlson comorbidity index, syncope, previous cardiac operation and older age. Postoperative complications were also a highly significant predictor of lower functional capacity at 1 year. CONCLUSIONS: Most older patients have meaningful improvements in functional capacity after cardiac surgery, and clinical factors appear to modify the degree of improvement attainable.

Length of hospital stay after acute myocardial infarction in the Myocardial Infarction Triage and Intervention (MITI) Project registry.

OBJECTIVES: This study sought to identify current trends in length of stay in patients with an acute myocardial infarction and to evaluate which demographic, clinical, procedural and hospital-related factors explain the variation and reduction in length of stay observed during the study period. BACKGROUND: Hospital length of stay is an important contribution to cost of care. Previous studies of length of stay after acute myocardial infarction have been performed largely on administrative data bases and do not reflect current practice patterns. METHODS: We used univariate and multivariate models to evaluate which demographic, clinical and administrative factors influenced length of stay in 11,932 patients with acute myocardial infarction admitted to 19 Seattle-area hospitals between 1988 and 1994. RESULTS: Length of hospital stay decreased from (mean +/- SD) 8.5 +/- 8.2 to 6.0 +/- 5.8 days during the study period. Demographic and clinical characteristics known at the time of admission explained only 6% of variation in length of stay, whereas hospital complications, procedure use and type of admitting hospital explained an additional 27% of variation. The use of primary angioplasty and early diagnostic coronary angiography predicted a shorter length of stay; however, none of the measured variables explained the 29% reduction in length of stay that occurred between 1988 and 1994. CONCLUSIONS: Although hospital complications, procedure use and hospital characteristics are important predictors of length of hospital stay, none of these factors explains the 29% reduction in length of stay observed in postmyocardial infarction patients between 1988 and 1994. It is likely that unmeasured economic and administrative factors play important roles in influencing hospital length of stay.

The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis.

OBJECTIVES: This study was designed to compare the prognostic value of an abnormal troponin level derived from studies of patients with non-ST elevation acute coronary syndromes (ACS). BACKGROUND: Risk stratification for patients with suspected ACS is important for determining need for hospitalization and intensity of treatment. METHODS: We identified clinical trials and cohort studies of consecutive patients with suspected ACS without ST-elevation from 1966 through 1999. We excluded studies limited to patients with acute myocardial infarction and studies not reporting mortality or troponin results. RESULTS: Seven clinical trials and 19 cohort studies reported data for 5,360 patients with a troponin T test and 6,603 with a troponin I test. Patients with positive troponin (I or T) had significantly higher mortality than those with a negative test (5.2% vs. 1.6%, odds ratio [OR] 3.1). Cohort studies demonstrated a greater difference in mortality between patients with a positive versus negative troponin I (8.4% vs. 0.7%, OR 8.5) than clinical trials (4.8% if positive, 2.1% if negative, OR 2.6, p = 0.01). Prognostic value of a positive troponin T was also slightly greater for cohort studies (11.6% mortality if positive, 1.7% if negative, OR 5.1) than for clinical trials (3.8% if positive, 1.3% if negative, OR 3.0, p = 0.2) CONCLUSIONS: In patients with non-ST elevation ACS, the short-term odds of death are increased three- to eightfold for patients with an abnormal troponin test. Data from clinical trials suggest a lower prognostic value for troponin than do data from cohort studies.

Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

Comparison of predictions based on observational data with the results of randomized controlled clinical trials of coronary artery bypass surgery.

Clinical decisions are most secure when based on findings from several large randomized clinical trials, but relevant randomized trial data are often unavailable. Analyses using clinical data bases might provide useful information if statistical methods can adequately correct for the lack of randomization. To test this approach, the findings of the three major randomized trials of coronary bypass surgery were compared with predictions of multivariable statistical models derived from observations in the Duke Cardiovascular Disease Databank. Clinical characteristics of patients at Duke University Medical Center who met eligibility requirements for each major randomized trial were used in the models to predict 5 year survival rates expected for medical and surgical therapy in each randomized trial. Model predictions agreed well with randomized trial results and were within the 95% confidence limits of the observed survival rates in 24 (92%) of 26 clinical subgroups. The overall correlation between predicted and observed survival rates was good (Spearman coefficient 0.73, p less than 0.0001). These results suggest that carefully performed analyses of observational data can complement the results of randomized trials.

Importance of clinical measures of ischemia in the prognosis of patients with documented coronary artery disease.

To examine the value of clinical measures of ischemia for stratifying prognosis, 5,886 consecutive patients who had symptomatic significant (greater than or equal to 75% stenosis) coronary artery disease were studied. Using the Cox regression model in a randomly selected half of the patients, the prognostically independent clinical variables were weighted and arranged into a simple angina score: angina score = angina course X (1 + daily angina frequency) + ST-T changes, where angina course was equal to 3 if unstable or variant angina was present, 2 if the patient's angina was progressive with nocturnal episodes, 1 if it was progressive without nocturnal symptoms and 0 if it was stable; 6 points were added for the presence of "ischemic" ST-T changes. This angina score was then validated in an independent patient sample. The score was a more powerful predictor of prognosis than was any individual anginal descriptor. Furthermore, the angina score added significant independent prognostic information to the patient's age, sex, coronary anatomy and left ventricular function. Patients with three vessel disease and a normal ventricle (n = 1,233) had a 2 year infarction-free survival rate of 90% with an angina score of 0 and a 68% survival rate with an angina score greater than or equal to 9. With an ejection fraction less than 50% and three vessel disease (n = 1,116), the corresponding infarction-free survival figures were 76 and 56%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of thrombolytic therapy in the community hospital: established principles and unresolved issues.

In patients with acute myocardial infarction presenting to community hospitals, thrombolytic therapy should be initiated as rapidly as possible under the supervision of a physician. Paramedic or nurse-initiated pre-hospital therapy is currently investigational. Each hospital must have a detailed evaluation and treatment protocol for acute myocardial infarction that specifies the timetable for patient evaluation, who should or should not receive thrombolytic therapy and the proper dose and mode of administration of the agent or agents to be used. Monitoring after the administration of thrombolytic therapy should focus on arrhythmias, hemodynamic problems, recurrent ischemia and bleeding. The role of early cardiac catheterization to detect patients who have unsuccessful thrombolysis or who require mechanical revascularization procedures is under active investigation. The design of the Thrombolysis and Angioplasty in Acute Myocardial Infarction (TAMI) 5 study, which addresses the role of acute interventional catheterization in the treatment of patients with acute myocardial infarction, is described.

Feasibility and cost-saving potential of outpatient cardiac catheterization.

To determine the feasibility and cost-saving potential of substituting outpatient for inpatient cardiac catheterization, 986 consecutive procedures were studied at a large referral hospital. Patients were classified prospectively as to their eligibility for outpatient cardiac catheterization according to published guidelines. Resource consumption was recorded, and cost savings were then calculated by analyzing the specific supply and personnel costs that could change as a result of inpatient versus outpatient status. Of the total of 986 patients who underwent diagnostic catheterization, 240 (24%) were outpatients, 279 (28%) were inpatients but had no exclusion criteria for outpatient catheterization and 467 (47%) were inpatients who had one or more exclusions for outpatient catheterization. The most common reasons for exclusion from outpatient catheterization were congestive heart failure (22%), unstable angina (15%), noncoronary heart disease (14%), recent myocardial infarction (11%) and severe noncardiac disease (9%). Inpatients with no exclusions for the outpatient procedure tended to be sicker than outpatients because they were older (p = 0.002), had a lower ejection fraction (p = 0.009) and had more triple vessel coronary artery disease (p less than 0.0001). The cost of the catheterization procedure itself was not different between inpatients and outpatients. Laboratory testing was more frequent among inpatients, however, and "room and board" costs were significantly higher. Although the difference in hospital charges for inpatients and outpatients was $580, a rigorous analysis indicated that the potential cost savings was only 38% of this amount, or $218 per eligible patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical judgment and therapeutic decision making.

Clinical decision making is under increased scrutiny due to concerns about the cost and quality of medical care. Variability in physician decision making is common, in part because of deficiencies in the knowledge base, but also due to the difference in physicians' approaches to clinical problem solving. Evaluation of patient prognosis is a critical factor in the selection of therapy, and careful attention to methodology is essential to provide reliable information. Randomized controlled clinical trials provide the most solid basis for the establishment of broad therapeutic principles. Because randomized studies cannot be performed to address every question, observational studies will continue to play a complementary role in the evaluation of therapy. Randomized studies in progress, meta analyses of existing data, and increased use of administrative and collaborative clinical data bases will improve the knowledge base for decision making in the future.

Cardiac rupture, mortality and the timing of thrombolytic therapy: a meta-analysis.

This study examined the relation between the risk of cardiac rupture and the timing of thrombolytic therapy for acute myocardial infarction. To test the hypothesis that cardiac rupture is prevented by early thrombolytic therapy but is promoted by late treatment, randomized controlled trials of thrombolytic agents for myocardial infarction were pooled. A logistic regression model including 58 cases of cardiac rupture among 1,638 patients from four trials showed that the odds ratio (treated/control) of cardiac rupture was directly correlated with time to treatment (p = 0.01); at 7 h, the odds ratio was 0.4 (95% confidence limits 0.17 to 0.93); at 11 h, it was 0.93 (0.53 to 1.60) and at 17 h, it was 3.21 (1.10 to 10.1). Analysis of data from the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) trial independently confirmed the relation between time to thrombolytic therapy and risk of cardiac rupture (p = 0.03). Analysis of 4,692 deaths in 44,346 patients demonstrated that the odds ratio of death was also directly correlated with time to treatment (p = 0.006); at 3 h, the odds ratio for death was 0.72 (0.67 to 0.77); at 14 h, it was 0.88 (0.77 to 1.00) and at 21 h, it was 1 (0.82 to 1.37). Thrombolytic therapy early after acute myocardial infarction improves survival and decreases the risk of cardiac rupture. Late administration of thrombolytic therapy also appears to improve survival but may increase the risk of cardiac rupture.

Randomized comparison of the cost and effectiveness of iopamidol and diatrizoate as contrast agents for cardiac angiography.

To evaluate the effectiveness and cost of low osmolarity, nonionic contrast agents for cardiac angiography, 443 patients were randomized to receive either iopamidol or diatrizoate. All adverse events that occurred within 24 h of the procedure were recorded prospectively by study personnel and classified according to previously determined criteria. Major events were defined as life threatening or requiring a procedure to treat, or both. Costs of the catheterization procedure, pharmacy, hospital laboratory and treatment of adverse events were determined on the basis of actual resource use. A total of 20 patients (8.5%) had major and 143 (61%) had minor adverse events with diatrizoate use; 10 patients (4.8%) had major and 53 (25%) had minor adverse events with iopamidol (p = 0.12 for major events; p less than 0.001 for total events). Most adverse events were treated fairly easily and inexpensively. The median overall cost was $186 higher for patients after iopamidol use compared with diatrizoate (p less than 0.0001), but all costs except the cost of the contrast agent were not significantly different between the two groups. Thus, patients who received iopamidol for cardiac angiography had a significantly lower rate of adverse events than those who received diatrizoate, but this difference was achieved at a considerably high overall cost.

Painless exercise ST deviation on the treadmill: long-term prognosis.

To evaluate the clinical correlates and long-term prognostic significance of silent ischemia during exercise, 1,698 consecutive symptomatic patients with coronary artery disease who had both treadmill testing and cardiac catheterization were studied. These patients were classified into three groups: Group 1 = patients with no exercise ST deviation (n = 856), Group 2 = patients with painless exercise ST deviation (n = 242) and Group 3 = patients with both angina and ST segment deviation during exercise (n = 600). Patients with exercise angina had a history of a longer and more aggressive anginal course (with a greater frequency of angina, with nocturnal episodes and/or progressive symptom pattern) and more severe coronary artery disease (almost two-thirds had three vessel disease). The 5 year survival rate among the patients with painless ST deviation was similar to that of patients without ST deviation (86% and 88%, respectively) and was significantly better than that of patients with both symptoms and ST deviation (5 year survival rate 73% in patients with exercise-limiting angina). Similar trends were obtained in subgroups defined by the amount of coronary artery disease present. In the total study group of 1,698 patients, silent ischemia on the treadmill was not a benign finding (average annual mortality rate 2.8%) but, compared with symptomatic ischemia, did indicate a subgroup of patients with coronary artery disease who had a less aggressive anginal course, less coronary artery disease and a better prognosis. Thus, silent ischemia during exercise testing in patients with symptomatic coronary artery disease represents an intermediate risk response in the spectrum of exercise-induced ischemia.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Differences in the treatment of myocardial infarction in the United States and Canada. A comparison of two university hospitals.

OBJECTIVE: To compare practice patterns and clinical outcomes for a costly yet common condition, acute myocardial infarction. DESIGN: Retrospective cohort study in two university hospitals (Stanford [Calif] University and McGill University, Montreal, Quebec) and a patient survey. PATIENTS: All consecutive patients (n = 518) treated for acute myocardial infarction in the coronary care unit of those two hospitals over 2 years. MEASURES: Rates of diagnostic and therapeutic procedures, mortality, reinfarction, and level of functional status (by chart review and patient survey). RESULTS: Demographic and clinical characteristics were similar for the two groups. Noninvasive tests were more common at McGill (exercise tests, 56% vs 20%; tests of left ventricular function, 86% vs 59%; P < .0001 for both). In contrast, invasive procedures were more common at Stanford (angiography, 55% vs 34%; angioplasty, 30% vs 13%; and bypass surgery, 10% vs 4%; P < .0001). At a median follow-up of 20 months, reinfarction and mortality rates were similar at Stanford and McGill (13% vs 8% and 28% vs 27%, respectively; P > .05 for both). In contrast, the angina rate was slightly lower at Stanford (33% vs 40%; P = .15), and the functional status of Stanford patients was better than that of McGill patients (mean Duke Activity Status Index score, 28.8 and 22.9, respectively; P = .006). This functional status difference persisted after adjustment for differences in clinical factors, including coronary revascularization. CONCLUSION: The aggressive treatment of the American patients with myocardial infarction did not improve reinfarction and mortality rates compared with the conservative treatment of the Canadian patients. The superior functional status of the American patients merits further investigation.

Diagnostic test use in different practice settings. A controlled comparison.

Health maintenance organizations (HMOs) have lower than average medical care costs, but the reasons remain controversial. The diagnostic practices of cardiologists from an HMO, a university, and a community were therefore surveyed. First, cardiologists defined indications for coronary bypass surgery and then evaluated randomly selected case summaries of patients with chest pain. After review, the cardiologist rated the need for an exercise thallium scintiscan and for a coronary angiogram in each case. Community cardiologists had the broadest indications for bypass surgery. The HMO cardiologists chose thallium scintigraphy significantly less often than the other two types of cardiologists did. The HMO and university cardiologists both rated the need for coronary angiography significantly lower than did community cardiologists. Physicians in different practice settings therefore recommend costly diagnostic and therapeutic methods differently, even for identical patients.

Clinical experience and predicting survival in coronary disease.

To study the accuracy with which long-term prognosis can be predicted in patients with coronary artery disease, prognostic predictions obtained from a large, diverse sample of practicing cardiologists were compared with predictions from a multivariable statistical model. Test samples of 10 patients each were selected from a large series of medically treated patients with significant coronary disease. Using detailed clinical summaries, 49 cardiologists each predicted the probability of 3-year survival and infarction-free survival for 10 patients. Cox regression models, developed using patients who were not in the test samples, were also used to predict corresponding outcome probabilities for each test patient. Overall, the model estimates of prognosis were significantly better than the doctors' predictions. The rank correlation of model predictions with 3-year survival was 0.60, compared with 0.52 for the physicians. Model predictions added significant prognostic information to the doctors' predictions, whereas the converse was not true. Where predictions were made by multiple doctors, the inter-physician variability was substantial. Neither practice characteristics nor extent of clinical experience significantly affected the physicians' predictive accuracy. In coronary artery disease, statistical models developed from carefully collected data can provide prognostic predictions that are more accurate than predictions of experienced clinicians made from detailed case summaries.