Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Cardiovascular outcomes among sildenafil users: results of the International Men's Health Study.

AIM: To assess the incidence of serious cardiovascular disease (CVD) events [i.e. myocardial infarction (MI) and stroke] and all-cause mortality in men with erectile dysfunction (ED) who received prescriptions for sildenafil. METHODS: The International Men's Health Study (IMHS) was a prospective, observational cohort study of patients with ED and a new or existing prescription for sildenafil. Baseline and follow-up questionnaires provided information on demographics, CVD risk factors and ED. Postevent questionnaires were mailed to patients following possible nonfatal CVD events to collect information related to exposure to sildenafil/ED treatments before the event. RESULTS: Thirty-five CVD events were reported in 30 patients in the analysis set (n = 3813). The incidence of all-cause mortality, MI and stroke was 0.4, 0.6 and 0.1 per 100 patient-years of observation respectively. Among the six men who reported using sildenafil in the month before a nonfatal CVD event, two reported use in the 24 h before the event. CONCLUSION: The results of the IMHS support previous reports that ED and CVD are often comorbid and share risk factors.

Statistical linkage of treatment to diagnosis for research and monitoring of practice patterns.

OBJECTIVES: At each patient contact general practitioners enter information about the diagnoses and the interventions in the electronic medical record (EMR) system. If there is only one diagnosis during a single patient-physician contact, then a causal connection between the diagnosis and the intervention is established. Otherwise it is uncertain what may have been the cause of the intervention. METHODS: Ideally the general practitioners would record a match between each intervention and the diagnosis that justifies it. However, most EMR software is not capable of recording explanatory matches. Furthermore, supplying the matches is a resource-demanding task. In this study the general practitioners were supplied with a matching module for the EMR, so data with full matching between intervention and diagnosis was collected (our "gold standard"). The study models how close the full matching can be recreated by model linkage using different kinds of simple assumptions. RESULTS: The modeling demonstrates a raise in the measure of prediction (sensitivity) from 41.9 percent for a completely random linkage to 90.9 percent based on simple assumptions in the model. The small substantial potential further gain makes it less attractive to apply more intricate assumptions or use more complex modeling (including neural networks). CONCLUSIONS: The perspective of the study lies in the support of the general practitioners with software for comparison of their decisions with those of their peers and also with guidelines. Thus a system for simple quality assurance and awareness to untypical decisions could be incorporated into the electronic medical record systems.

Height is not associated with long-term survival after acute myocardial infarction.

BACKGROUND: Studies show an inverse association between height and risk of myocardial infarction. How height affects survival after acute myocardial infarction is uncertain. METHODS: In the Determinants of Myocardial Infarction Onset Study, trained interviewers performed chart reviews and face-to-face interviews with 1935 patients hospitalized with acute myocardial infarction in 45 US medical centers between 1989 and 1993. We excluded 15 patients with missing information on height. After a search of the National Death Index for patients who died before 1996, we analyzed the relationship of height and survival with Cox proportional hazards regression. RESULTS: Of the 1920 eligible patients, 317 (17%) died during a median follow-up of 3.8 years. Height was positively associated with younger age, greater educational attainment, and a lower likelihood of being sedentary among both men and women. Height was not associated with long-term survival among women in unadjusted or adjusted analyses. Among men, height was associated with survival only in unadjusted analyses; adjustment for age eliminated this association. We found no relationship between height and survival in any individual age group among men or women. CONCLUSIONS: Although stature may be associated with the risk of acute myocardial infarction, it is not associated with long-term survival after such an event.

Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data.

Comorbidity is an important confounder in epidemiologic studies. The authors compared the predictive performance of comorbidity scores for use in epidemiologic research with administrative databases. Study participants were British Columbia, Canada, residents aged >or=65 years who received angiotensin-converting enzyme inhibitors or calcium channel blockers at least once during the observation period. Six scores were computed for all 141,161 participants during the baseline year (1995-1996). Endpoints were death and health care utilization during a 12-month follow-up (1996-1997). Performance was measured by using the c statistic ranging from 0.5 for chance prediction of outcome to 1.0 for perfect prediction. In logistic regression models controlling for age and gender, four scores based on the International Classification of Diseases, Ninth Revision (ICD-9) generally performed better at predicting 1-year mortality (c = 0.771, c = 0.768, c = 0.745, c = 0.745) than medication-based Chronic Disease Score (CDS)-1 and CDS-2 (c = 0.738, c = 0.718). Number of distinct medications used was the best predictor of future physician visits (R(2) = 0.121) and expenditures (R(2) = 0.128) and a good predictor of mortality (c = 0.745). Combining ICD-9 and medication-based scores improved the c statistics (1.7% and 6.2%, respectively) for predicting mortality. Generalizability of results may be limited to an elderly, predominantly White population with equal access to state-funded health care.

Impact of diabetes on long-term survival after acute myocardial infarction: comparability of risk with prior myocardial infarction.

OBJECTIVE: To determine the effect of diabetes on long-term survival after acute myocardial infarction and to compare its effect with that of a previous myocardial infarction. RESEARCH DESIGN AND METHODS: In a prospective cohort study, we followed 1,935 patients hospitalized with a confirmed acute myocardial infarction at 45 U.S. medical centers between 1989 and 1993, as part of the Determinants of Myocardial Infarction Onset Study. Trained interviewers performed chart reviews and face-to-face interviews with all patients. We analyzed survival using Cox proportional hazards regression to control for potentially confounding factors. RESULTS: Of the 1,935 patients, 320 (17%) died during a mean follow-up of 3.7 years. A total of 399 patients (21%) had previously diagnosed diabetes. Diabetes was associated with markedly higher total mortality in unadjusted (hazard ratio [HR] 2.4; 95% CI 1.9-3.0) and adjusted (1.7; 1.3-2.1) analyses. The magnitude of the effect of diabetes was identical to that of a previous myocardial infarction. The effect of diabetes was not significantly modified by age, smoking, household income, use of thrombolytic therapy, type of hypoglycemic treatment, or duration of diabetes, but the risk associated with diabetes was higher among women than men (adjusted HRs 2.7 vs. 1.3, P = 0.01). CONCLUSIONS: Diabetes is associated with markedly increased mortality after acute myocardial infarction, particularly in women. The increase in risk is of the same magnitude as a previous myocardial infarction and provides further support for aggressive treatment of coronary risk factors among diabetic patients.

Triggering myocardial infarction by marijuana.

BACKGROUND: Marijuana use in the age group prone to coronary artery disease is higher than it was in the past. Smoking marijuana is known to have hemodynamic consequences, including a dose-dependent increase in heart rate, supine hypertension, and postural hypotension; however, whether it can trigger the onset of myocardial infarction is unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed 3882 patients (1258 women) with acute myocardial infarction an average of 4 days after infarction onset. We used the case-crossover study design to compare the reported use of marijuana in the hour preceding symptoms of myocardial infarction onset to its expected frequency using self-matched control data. Of the 3882 patients, 124 (3.2%) reported smoking marijuana in the prior year, 37 within 24 hours and 9 within 1 hour of myocardial infarction symptoms. Compared with nonusers, marijuana users were more likely to be men (94% versus 67%, P<0.001), current cigarette smokers (68% versus 32%, P<0.001), and obese (43% versus 32%, P=0.008). They were less likely to have a history of angina (12% versus 25%, P<0.001) or hypertension (30% versus 44%, P=0.002). The risk of myocardial infarction onset was elevated 4.8 times over baseline (95% confidence interval, 2.4 to 9.5) in the 60 minutes after marijuana use. The elevated risk rapidly decreased thereafter. CONCLUSIONS: Smoking marijuana is a rare trigger of acute myocardial infarction. Understanding the mechanism through which marijuana causes infarction may provide insight into the triggering of myocardial infarction by this and other, more common stressors.

Prior alcohol consumption and mortality following acute myocardial infarction.

CONTEXT: Studies have found that individuals who consume 1 alcoholic drink every 1 to 2 days have a lower risk of a first acute myocardial infarction (AMI) than abstainers or heavy drinkers, but the effect of prior drinking on mortality after AMI is uncertain. OBJECTIVE: To determine the effect of prior alcohol consumption on long-term mortality among early survivors of AMI. DESIGN AND SETTING: Prospective inception cohort study conducted at 45 US community and tertiary care hospitals between August 1989 and September 1994, with a median follow-up of 3.8 years. PATIENTS: A total of 1913 adults hospitalized with AMI between 1989 and 1994. MAIN OUTCOME MEASURE: All-cause mortality, compared by self-reported average weekly consumption of beer, wine, and liquor during the year prior to AMI. RESULTS: Of the 1913 patients, 896 (47%) abstained from alcohol, 696 (36%) consumed less than 7 alcoholic drinks/wk, and 321 (17%) consumed 7 or more alcoholic drinks/wk. Compared with abstainers, patients who consumed less than 7 drinks/wk had a lower all-cause mortality rate (3.4 vs 6.3 deaths per 100 person-years; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.43-0.71) as did those who consumed 7 or more drinks/wk (2.4 vs 6.3 deaths per 100 person-years; HR, 0.38; 95% CI, 0.25-0.55; P<.001 for trend). After adjusting for propensity to drink and other potential confounders, increasing alcohol consumption remained predictive of lower mortality for less than 7 drinks/wk, with an adjusted HR of 0.79 (95% CI, 0.60-1.03), and for 7 or more drinks/wk, with an adjusted HR of 0.68 (95% CI, 0.45-1.05; P =.01 for trend). The association was similar for total and cardiovascular mortality, among both men and women, and among different types of alcoholic beverages. CONCLUSION: Self-reported moderate alcohol consumption in the year prior to AMI is associated with reduced mortality following infarction.

On the evaluation of drug benefits policy changes with longitudinal claims data: the policy maker's versus the clinician's perspective.

Cost containment in pharmaceutical-benefit plans are often controversially debated for their potential of unintended consequences on health and overall expenditures. Thorough evaluations are needed but hypotheses and design considerations are complex. Our objective is to provide a structured framework for the evaluation of drug-benefit changes using longitudinal claims data. Differential cost sharing (DCS) will serve as a recent example. Benefit-plan managers are mainly interested in the overall performance of their plan. In a policy model, any observed policy-related effects may be compared with what would have happened had the intervention not been implemented by extrapolating the pre-policy trend from the same patients. These estimates will reflect the global consequences of the policy maker's decision. However, such estimates represent summary effects of benefits and harms, separately identifiable in those complying with the intended policy and those not complying. Results from a policy model apply only to a specific policy implementation and tend to underestimate effects when non-compliance is high. Clinical-decision makers and patients, by contrast, are interested in the consequences of patients' actual compliance to the policy. A clinical model assesses the effects of DCS depending on the actual treatment in contrast to the treatment intended by the policy. However, this model must sometimes make, unprovable assumptions about the appropriate control of selection factors. In conclusion, both policy and clinical models should be tested with a clear understanding of their perspectives, hypotheses, and interpretations, using quasi-experimental time-series designs to evaluate the effects of drug cost-containment policies.

Causation of bias: the episcope.

A risk ratio or difference from a meta-analysis is as many as ten steps away from the unobservable causal risk ratios and differences in target populations. The steps are like lenses, filters, or other fallible components of the epidemiologist's "telescope" for observing populations. Each step is another domain where different biases can be caused. How biases combine across domains in the production of epidemiologic evidence can be quickly explained to nonepidemiologists by using a sequence of causal arrow diagrams with easy notation: (a) agent of interest, (b) background risk factors, (c) correlated causes, (d) diagnosis, (e) exposure measurement, (f) filing of data, (g) grouping of cohorts, (h) harvesting of cases and controls, (i) interpretations of investigators, (j) judgments of journals, and (k) knowledge of meta-analysts. For epidemiologists, this article serves as a review of ideas about confounding, information bias, and selection bias and underscores the need for routinely analyzing the sensitivity of study findings to multiple hypothesized biases.

Use of comorbidity scores for control of confounding in studies using administrative databases.

BACKGROUND: Comorbidity scores are increasingly used to reduce potential confounding in epidemiological research. Our objective was to compare metrical and practical properties of published comorbidity scores for use in epidemiological research with administrative databases. METHODS: The literature was searched for studies of the validity of comorbidity scores as predictors of mortality and health service use, as measured by change in the area under the receiver operating characteristic (ROC) curve for dichotomous outcomes, and change in R(2) for continuous outcomes. RESULTS: Six scores were identified, including four versions of the Charlson Index (CI) which use either the three-digit International Classification of Diseases, Ninth Revision (ICD-9) or the full ICD-9-CM (clinical modification) code, and two versions of the Chronic Disease Score (CDS) which used outpatient pharmacy records. Depending on the population and exposure under study, predictive validities varied between c = 0.64 and c = 0.77 for in-hospital or 30-day mortality. This is only a slight improvement over age adjustment. In one study the simple measure 'number of diagnoses' outperformed the CI (c = 0.73 versus c = 0.65). Proprietary scores like Ambulatory Diagnosis Groups and Patient Management Categories do not necessarily perform better in predicting mortality. Comorbidity indices are susceptible to a variety of coding errors. CONCLUSIONS: Comorbidity scores, particularly the CDS or D'Hoore's CI based on three-digit ICD-9 codes, may be useful in exploratory data analysis. However, residual confounding by comorbidity is inevitable, given how these scores are derived. How much residual confounding usually remains is something that future studies of comorbidity scores should examine. In any given study, better control for confounding can be achieved by deriving study-specific weights, to aggregate comorbidities into groups with similar relative risks of the outcomes of interest.

Increased risk of congestive heart failure among infarctions with nighttime onset.

BACKGROUND: The onset of acute myocardial infarction varies by time of day, with a peak in the morning and a trough at night. Whether infarct-related complications differ by the timing of the infarction is unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we performed chart reviews and face-to-face interviews with 3625 patients with acute myocardial infarction. We assessed the time of onset of symptoms, the presence of ventricular tachycardia or congestive heart failure, and peak creatine kinase levels (in 1043 patients). We found significant circadian variation in the risk of congestive heart failure (P =.001). The risk dropped from 17% for infarctions that began between 6 PM and midnight to 10% for infarctions that began between 6 AM and noon. Adjustment for differences in the time from symptom onset to presentation for care and use of thrombolytic agents did not change the results. We found no circadian variation in the risk of ventricular tachycardia or in peak creatine kinase levels. CONCLUSIONS: The risk of congestive heart failure is highest among infarctions that begin at night. Further research may clarify whether this reflects differences in the pathophysiologic characteristics of infarction or the quality of medical care provided for daytime and nighttime infarctions.

Should we use a case-crossover design?

The first decade of experience with case-crossover studies has shown that the design applies best if the exposure is intermittent, the effect on risk is immediate and transient, and the outcome is abrupt. However, this design has been used to study single changes in exposure level, gradual effects on risk, and outcomes with insidious onsets. To estimate relative risk, the exposure frequency during a window just before outcome onset is compared with exposure frequencies during control times rather than in control persons. One or more control times are supplied by each of the cases themselves, to control for confounding by constant characteristics and self-confounding between the trigger's acute and chronic effects. This review of published case-crossover studies is designed to help the reader prepare a better research proposal by understanding triggers and deterrents, target person times, alternative study bases, crossover cohorts, induction times, effect and hazard periods, exposure windows, the exposure opportunity fallacy, a general likelihood formula, and control crossover analysis.

Lack of effect of recent alcohol consumption on the course of acute myocardial infarction.

BACKGROUND AND OBJECTIVE: Alcohol has marked effects on hemodynamic and hemostatic variables that might alter the presentation of acute myocardial infarction that follows its use. We sought to determine whether recent alcohol consumption alters the course or complications of acute myocardial infarction. METHODS: In the Determinants of Myocardial Infarction Onset Study, we performed chart reviews and face-to-face interviews with 2161 patients who did not receive thrombolytic therapy. We assessed alcohol use before infarction, peak creatine kinase levels (1043 patients), electrocardiographic interpretations (1408 patients), and the presence of ventricular arrhythmias or congestive heart failure (all patients). RESULTS: Among the 2161 patients, 399 (18.5%) drank alcohol within 24 hours before myocardial infarction. We found no significant difference in mean peak creatine kinase level between those who had recently used alcohol and those who had not in an adjusted comparison (-6.1% difference; 95% confidence interval [CI] -20.3%-10.7%; P =.46). We also found no differences in adjusted risk for Q-wave infarction, congestive heart failure, or ventricular arrhythmias (odds ratios 1.03 [95% CI, 0.73-1.45; P =.88], 1.01 [95% CI, 0.67-1.54; P =.95], and 1.04 [95% CI, 0.66-1.65; P =.86]). Categorization of the duration since last alcohol use into 6-hour intervals revealed no trends between time since last use of alcohol and any of these outcomes. CONCLUSIONS: Recent alcohol use is not associated with changes in infarct size or risk for Q-wave infarction, congestive heart failure, or ventricular arrhythmia among this population.

Triggering of myocardial infarction by cocaine.

BACKGROUND: Cocaine has been implicated as a trigger of acute myocardial infarction in patients with and those without underlying coronary atherosclerosis. However, the magnitude of the increase in risk of acute myocardial infarction immediately after cocaine use remains unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed 3946 patients (1282 women) with acute myocardial infarction an average of 4 days after infarction onset. Data were collected on the use of cocaine and other potential triggers of myocardial infarction. We compared the reported use of cocaine in the hour preceding the onset of myocardial infarction symptoms with its expected frequency by using self-matched control data based on the case-crossover study design. Of the 3946 patients interviewed, 38 (1%) reported cocaine use in the prior year and 9 reported use within the 60 minutes preceding the onset of infarction symptoms. Compared with nonusers, cocaine users were more likely to be male (87% vs 67%, P=0.01), current cigarette smokers (84% vs 32%, P<0.001), younger (44+/-8 vs 61+/-13 years, P<0.001), and minority group members (63% vs 11%, P<0.001). The risk of myocardial infarction onset was elevated 23.7 times over baseline (95% CI 8.5 to 66.3) in the 60 minutes after cocaine use. The elevated risk rapidly decreased thereafter. CONCLUSIONS: Cocaine use is associated with a large abrupt and transient increase in the risk of acute myocardial infarction in patients who are otherwise at relatively low risk. This finding suggests that studying the pathophysiological changes produced by cocaine may provide insights into the mechanisms by which myocardial infarction is triggered by other stressors.

Recent aspirin use is associated with smaller myocardial infarct size and lower likelihood of Q-wave infarction.

BACKGROUND: Controversy exists about the effect of recent aspirin use on infarct size and the likelihood of Q-wave infarction in patients who sustain myocardial infarction. METHODS: We performed face-to-face interviews and chart reviews on 3665 patients with acute myocardial infarction for the Determinants of Myocardial Infarction Onset Study. For the 2206 patients who did not receive thrombolytic therapy, we assessed aspirin use, peak creatine kinase levels (in 1043 patients), and electrocardiographic interpretations (in 1447 patients). RESULTS: Of the initial 1043 patients, 317 (30. 3%) subjects reported aspirin use in the 4 days before their infarction. The mean +/- SD peak creatine kinase level for aspirin users was 701 +/- 570 IU/mL versus 851 +/- 727 IU/mL for nonusers, an 18% difference (95% confidence interval [CI], 8% to 26%; P <.001). After adjustment for confounding factors, the difference was 12% (95% CI, 2% to 21%; P =.03). Similarly, 38.9% of the aspirin users and 48.7% of the nonusers sustained a Q-wave infarction, an odds ratio of 0.67 (95% CI, 0.54 to 0.83, P <.001). The adjusted odds ratio was 0.77 (95% CI, 0.61 to 0.97, P =.03). CONCLUSIONS: Recent aspirin use was associated with smaller infarct size and fewer Q-wave infarctions among this population of early survivors of acute myocardial infarction who did not receive thrombolytic therapy.

Influences of educational interventions and adverse news about calcium-channel blockers on first-line prescribing of antihypertensive drugs to elderly people in British Columbia.

BACKGROUND: The way in which dissemination of evidence changes medical practice needs to be better understood. Controversy about calcium-channel blockers (CCB) in the past 3 years has provided a natural experiment, enabling assessment of the impact of media stories, a national warning letter, a teleconference, small group workshops, and newsletters on first-line prescribing of antihypertensive drugs. METHODS: We included all physicians (4403) in British Columbia who prescribed a thiazide diuretic, beta-blocker, inhibitor of angiotensin-converting enzyme (ACE), or CCB as the first antihypertensive agent for 36,507 residents aged 66 years and over, with no previous or concurrent sign of underlying cardiovascular disease. We used a database covering all prescriptions to elderly people to measure the change in proportion of newly treated patients who received each class of drug as first-line therapy. We used a matched cohort design for assessment of the teleconference and workshops, a randomised community design for the newsletters, and time-series analysis for the media impacts. FINDINGS: The proportion of patients who received a CCB as first-line therapy declined gradually from 22% in early 1994 to 15% in late 1996. This proportion was not affected by two waves of adverse news about CCBs in 1995, but fell by 5% for 5 months and by 3% for 1 month after two waves in 1996. The proportion of patients who received either a CCB or an ACE inhibitor as first-line therapy, contrary to guidelines, was still 42% overall in 1996. The workshops and newsletters were followed by shifts from first-line CCB to first-line thiazide prescribing. INTERPRETATION: Changes in prescribing practices occur gradually with the accumulation of small impacts from educational interventions and lay media attention.