Thao Huynh

Smoked cannabis for chronic neuropathic pain: a randomized controlled trial

Background: Chronic neuropathic pain affects 1%–2% of the adult population and is often refractory to standard pharmacologic treatment. Patients with chronic pain have reported using smoked cannabis to relieve pain, improve sleep and improve mood. Methods: Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events. Results: We recruited 23 participants (mean age 45.4 [standard deviation 12.3] years, 12 women [52%]), of whom 21 completed the trial. The average daily pain intensity, measured on the 11-point numeric rating scale, was lower on the prespecified primary contrast of 9.4% v. 0% tetrahydrocannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% confidence interval [CI] 0.02–1.4). Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief. Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p = 0.001; faster, p < 0.001; more drowsy, p = 0.003) and improved quality of sleep (less wakefulness, p = 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough. Conclusion: A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated. Further long-term safety and efficacy studies are indicated. (International Standard Randomised Controlled Trial Register no. ISRCTN68314063)

Bridging the gender gap: Insights from a contemporary analysis of sex-related differences in the treatment and outcomes of patients with acute coronary syndromes

BACKGROUND The question of whether gender-related disparities still exist in the treatment and outcomes of patients presenting with acute coronary syndromes (ACS) remains controversial. Using data from 4 registries spanning a decade, we sought to determine whether sex-related differences have persisted over time and to examine the treating physicians rationale for adopting a conservative management strategy in women compared with men. METHODS From 1999 to 2008, 14,196 Canadian patients with non-ST-segment elevation ACS were recruited into the Acute Coronary Syndrome I (ACSI), ACSII, Global Registry of Acute Coronary Events (GRACE/GRACE(2)), and Canadian Registry of Acute Coronary Events (CANRACE) prospective multicenter registries. RESULTS Women in the study population were found to be significantly older than men and were more likely to have a history of heart failure, diabetes, or hypertension. Fewer women were treated with thienopyridines, heparin, and glycoprotein IIb/IIIa inhibitors compared with men in GRACE and CANRACE. Female gender was independently associated with a lower in-hospital use of coronary angiography (adjusted odds ratio 0.76, 95% CI 0.69-0.84, P < .001) and higher in-hospital mortality (adjusted odds ratio 1.26, 95% CI 1.02-1.56, P = .036), irrespective of age (P for interaction =.76). Underestimation of patient risk was the most common reason for not pursuing an invasive strategy in both men and women. CONCLUSIONS Despite temporal increases in the use of invasive cardiac procedures, women with ACS are still more likely to be treated conservatively, which may be due to underestimation of patient risk. Furthermore, they have worse in-hospital outcomes. Greater awareness of this paradox may assist in bridging the gap between current guidelines and management practices.

Understanding Physicians' Risk Stratification of Acute Coronary Syndromes: Insights From the Canadian ACS 2 Registry

BACKGROUND An important treatment-risk paradox exists in the management of acute coronary syndromes (ACSs). However, the process of risk stratification by physicians and its relationship to the management of ACS have not been well studied. Our objective was to examine patient risk assessment by physicians in relation to treatment and objective risk score evaluation and the underlying patient characteristics that physicians consider to indicate high risk. METHODS The prospective Canadian ACS 2 Registry recruited 1956 patients admitted for non-ST-segment elevation ACS in 36 hospitals in October 2002 to December 2003. We recorded patient risk assessment by the treating physician and case management on standardized case report forms and calculated the Thrombolysis in Myocardial Infarction (TIMI), Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Global Registry of Acute Cardiac Events (GRACE) risk scores. RESULTS Of the 1956 patients with ACS, 347 (17.8%) were classified as low risk, 822 (42.0%) as intermediate risk, and 787 (40.2%) as high risk by their treating physicians. Patients considered as high risk were more likely to receive aggressive medical therapies and to undergo coronary angiography and revascularization. However, there were only weak correlations between risk assessment by physicians and all 3 validated risk scores. In multivariable analysis, history of stroke, worse Killip class, presence of ST-segment deviation, T-wave inversion, and positive cardiac biomarker status were all independently associated with high-risk categorization by the treating physician, while advanced age and previous coronary bypass surgery were independent negative predictors. There was no significant association between the high-risk category and several established prognosticators, such as history of heart failure, hemodynamic variables, and creatinine level. CONCLUSIONS Contemporary risk stratification of ACS appears suboptimal and may perpetuate the treatment-risk paradox. Physicians may not recognize and incorporate the most powerful adverse prognosticators into overall patient risk assessment. Routine use of validated risk score may enhance risk stratification and facilitate more appropriate tailoring of intensive therapies toward high-risk patients.

Comparison of Primary Percutaneous Coronary Intervention and Fibrinolytic Therapy in ST-Segment-Elevation Myocardial Infarction Bayesian Hierarchical Meta-Analyses of Randomized Controlled Trials and Observational Studies

Background— Published meta-analyses comparing primary percutaneous coronary intervention with fibrinolytic therapy in patients with ST-segment–elevation myocardial infarction include only randomized controlled trials (RCTs). We aim to obviate the limited applicability of RCTs to real-world settings by undertaking meta-analyses of both RCTs and observational studies. Methods and Results— We included all RCTs and observational studies, without language restriction, published up to May 1, 2008. We completed separate bayesian hierarchical random-effect meta-analyses for 23 RCTs (8140 patients) and 32 observational studies (185 900 patients). Primary percutaneous coronary intervention was associated with reductions in short-term (≤6-week) mortality of 34% (odds ratio, 0.66; 95% credible interval, 0.51 to 0.82) in randomized trials, and 23% lower mortality (odds ratio, 0.77; 95% credible interval, 0.62 to 0.95) in observational studies. Primary percutaneous coronary intervention was associated with reductions in stroke of 63% in RCTs and 61% in observational studies. At long-term follow-up (≥1 year), primary percutaneous coronary intervention was associated with a 24% reduction in mortality (odds ratio, 0.76; 95% credible interval, 0.58 to 0.95) and a 51% reduction in reinfarction (odds ratio, 0.49; 95% credible interval, 0.32 to 0.66) in RCTs. However, there was no conclusive benefit of primary percutaneous coronary intervention in the long term in the observational studies. Conclusions— Compared with fibrinolytic therapy, primary percutaneous coronary intervention was associated with short-term reductions in mortality, reinfarction, and stroke in ST-segment–elevation myocardial infarction. Primary percutaneous coronary intervention was associated with long-term reductions in mortality and reinfarction in RCTs, but there was no conclusive evidence for a long-term benefit in mortality and reinfarction in observational studies.

Combination therapy with tirofiban and enoxaparin in acute coronary syndromes

BACKGROUND Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and enoxaparin, a low molecular weight heparin, have each been shown to be effective at reducing cardiac ischemic events compared to unfractionated heparin alone in separate trials of patients with unstable angina and non-Q-wave myocardial infarction. The combination of these agents may offer further therapeutic benefit. MATERIALS AND METHODS Fifty-five patients with non-Q-wave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 microgram/kg/min i.v.) for 48-108 h coadministered with either enoxaparin (1 mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. adjusted to activated partial-thromboplastin time) (n=27) to evaluate pharmacokinetics, pharmacodynamics, and safety. The primary objective of the study was to investigate the effect of unfractionated heparin versus enoxaparin on the plasma clearance of tirofiban. RESULTS Coadministration of tirofiban and enoxaparin was generally well tolerated. Plasma clearance of tirofiban was 176.7+/-59.8 and 187.5+/-81.8 ml/min, respectively, for enoxaparin and unfractionated heparin-treated patients (P=NS). The mean difference was well within the prespecified criterion for comparability. Administration of tirofiban with enoxaparin vs. unfractionated heparin resulted in lesser variability and a trend towards greater inhibition of platelet aggregation using 5 microM adenosine phosphate agonist. More patients achieved target inhibition of platelet aggregation >70% in the tirofiban and enoxaparin group (84% vs. 65%, P=0.19). Median bleeding time was 21 min for tirofiban and enoxaparin vs. > or =30 min for tirofiban and unfractionated heparin (P=NS). For a given level of inhibition of platelet aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9 min, P=0.02). Tirofiban plasma concentration and clearance were comparable whether coadministered with enoxaparin or unfractionated heparin. There were no major or minor bleeding events in either group by the TIMI criteria. INTERPRETATION The more consistent inhibition of platelet aggregation and lower adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and unfractionated heparin support the therapeutic potential of combining these two agents. These data from the first clinical report of coadministration of a glycoprotein IIb/IIIa receptor antagonist and a low molecular weight heparin are consistent with prior data which show differential pharmacodynamic effects of enoxaparin and unfractionated heparin on platelet aggregation.

Clinical Utility of C-Reactive Protein Measured at Admission, Hospital Discharge, and 1 Month Later to Predict Outcome in Patients With Acute Coronary Disease: The RISCA (Recurrence and Inflammation in the Acute Coronary Syndromes) Study

OBJECTIVES This study was designed to prospectively determine, in patients with an acute coronary syndrome, whether the inflammatory marker, C-reactive protein (CRP), measured at hospital admission, discharge, and 1 month later has incremental value to predict outcomes at 1 year. BACKGROUND The clinical utility of CRP measurements in patients with acute coronary syndromes remains uncertain. Limitations of previous studies have been retrospective design and incomplete adjustment for readily available clinical prognosticators. METHODS The CRP marker was measured at admission, hospital discharge, and 1 month later in consecutive patients hospitalized for acute coronary syndromes in 8 tertiary and secondary hospitals. The primary outcome was a composite of death, nonfatal myocardial infarction (MI), and unstable angina (UA) with electrocardiogram (ECG) changes at 1 year. RESULTS A total of 1,210 patients, age 62 +/- 12 years, 64% with acute myocardial infarction (MI) and 36% with unstable angina (UA), were recruited. At 1 year, the primary outcome occurred in 142 patients (11.7%) and included 58 deaths (4.8%), 79 nonfatal MIs (6.5%), and 26 UA episodes with ECG changes (2.1%). The unadjusted odds ratios (ORs) (95% confidence intervals) of CRP values at admission, hospital discharge, and 1 month later for the occurrence of the primary outcome were 1.20 (1.06 to 1.36), 0.98 (0.85 to 1.14), and 1.23 (1.00 to 1.50), respectively. After multivariate adjustment, ORs were 1.04 (0.91 to 1.20), 0.90 (0.77 to 1.06), and 1.12 (0.93 to 1.34), respectively. The individual components of the primary outcome were also not independently associated with any of the 3 CRP measurements. CONCLUSIONS The modest predictive ability of CRP following admission for an acute coronary syndrome disappeared after adjusting for common clinical variables. This large prospective study does not support the incremental value of measuring CRP in this clinical setting.

Influence of Age on Use of Cardiac Catheterization and Associated Outcomes in Patients With Non-ST-Elevation Acute Coronary Syndromes

Randomized controlled trials support the use of an early invasive strategy in high-risk patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Although risk increases with age, limited data are available to support this strategy in older patients. The aims of this study were to examine temporal trends in the management and outcomes of NSTE ACS in elderly patients and to explore reasons for the lower use of early angiography in the aged population. Data from 11,732 patients with NSTE ACS were collected from 3 consecutive Canadian registries (ACS I, ACS II, and Global Registry of Acute Coronary Events [GRACE]/GRACE2) from 1999 to 2007. Rates of in-hospital cardiac catheterization, revascularization, infarction or reinfarction, and death were stratified by age (<65, 65 to 74, and > or = 75 years). Although overall, rates of in-hospital catheterization and revascularization increased over time (p <0.001), the largest increase occurred in patients aged <65 years. The strongest independent negative predictor of the use of cardiac catheterization was age > or = 75 years (adjusted odds ratio 0.45, 95% confidence interval 0.37 to 0.56, p <0.001). Use of an early invasive approach was associated with a reduction in 1-year mortality across all age groups, but the absolute difference was greatest in patients aged > or = 75 years. The underestimation of risk by physicians (ascertained in ACS II) was the most common reason for choosing a conservative strategy. In conclusion, despite an overall increased use of an early invasive strategy, elderly patients with NSTE ACS remain significantly less likely to undergo cardiac catheterization and revascularization and are often erroneously perceived to be at low risk by their physicians. Future studies should determine whether more aggressive treatment of these high-risk elderly patients improves outcomes.

Aspirin, Warfarin, or the Combination for Secondary Prevention of Coronary Events in Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Surgery

Background—Patients with a non–ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy. This trial investigated the potential benefit of secondary prevention with warfarin. Methods and Results—In a double-blind randomized trial, 135 patients with unstable angina or non–ST-segment elevation myocardial infarction, with prior CABG, and who were poor candidates for a revascularization procedure received therapy with aspirin and placebo+warfarin, warfarin and placebo+aspirin, or aspirin and warfarin for 12 months. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5. The primary end point (death or myocardial infarction or unstable angina requiring hospitalization 1 year after randomization) occurred in 14.6% of the patients in the warfarin-alone group, in 11.5% of patients in the aspirin-alone group, and in 11.3% of patients randomized to the combination therapy (P =0.76). Subgroup analyses by risk features provided no indications that warfarin alone or in combination with aspirin could be of benefit over aspirin alone. Bleeding was more frequent in the 2 groups of patients administered warfarin. Conclusions—Moderate-intensity oral anticoagulation alone or combined with low-dose aspirin does not appear to be superior to low-dose aspirin in the prevention of recurrent ischemic events in patients with non–ST-elevation acute coronary syndromes and previous CABG.

Prolonged corrected QT interval in anti-Ro/SSA–positive adults with systemic lupus erythematosus

To examine whether anti‐Ro/SSA antibodies are associated with an increased risk of corrected QT (QTc) prolongation, and to study the stability of this relationship over time.

Effect of marriage on duration of chest pain associated with acute myocardial infarction before seeking care

Background: Coronary artery disease is the most common cause of death in the Western world, and being married decreases the risk of death from cardiovascular causes. We aimed to determine whether marital status was a predictor of the duration of chest pain endured by patients with acute myocardial infarction before they sought care and whether the patient’s sex modified the effect. Methods: We conducted a retrospective, population-based cohort analysis of patients with acute myocardial infarction admitted to 96 acute care hospitals in Ontario, Canada, from April 2004 to March 2005. We excluded patients who did not experience chest pain. Using multivariable regression analyses, we assessed marital status in relation to delayed presentation to hospital (more than six hours from onset of pain), both overall and stratified by sex. In patients who reported the exact duration of chest pain, we assessed the effect of marital status on the delay in seeking care. Results: Among 4403 eligible patients with acute myocardial infarction, the mean age was 67.3 (standard deviation 13.6) years, and 1486 (33.7%) were women. Almost half (2037 or 46.3%) presented to a hospital within two hours, and 3240 (73.6%) presented within six hours. Overall, 75.3% (2317/3079) of married patients, 67.9% (188/277) of single patients, 68.5% (189/276) of divorced patients and 70.8% (546/771) of widowed patients presented within six hours of the onset of chest pain. Being married was associated with lower odds of delayed presentation (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.30–0.71, p < 0.001) relative to being single. Among men, the OR was 0.35 (95% CI 0.21–0.59, p < 0.001), whereas among women the effect of marital status was not significant (OR 1.36, 95% CI 0.49–3.73, p = 0.55). Interpretation: Among men experiencing acute myocardial infarction with chest pain, being married was associated with significantly earlier presentation for care, a benefit that was not observed for married women. Earlier presentation for medical care appears to be one reason for the observed lower risk of cardiovascular death among married men, relative to their single counterparts.