Karin Schenck-Gustafsson

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease Results of the Study Assessing Goals in the Elderly (SAGE)

Background— Clinical trials have demonstrated that, compared with placebo, intensive statin therapy reduces ischemia in patients with acute coronary syndromes and in patients with stable coronary artery disease. However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable coronary syndromes. Methods and Results— A total of 893 ambulatory coronary artery disease patients (30% women) 65 to 85 years of age with ≥1 episode of myocardial ischemia that lasted ≥3 minutes during 48-hour ambulatory ECG at screening were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d and followed up for 12 months. The primary efficacy parameter (absolute change from baseline in total duration of ischemia at month 12) was significantly reduced in both groups at month 3 and month 12 (both P<0.001 for each treatment group) with no significant difference between the treatment groups. Atorvastatin-treated patients experienced greater low-density lipoprotein cholesterol reductions than did pravastatin-treated patients, a trend toward fewer major acute cardiovascular events (hazard ratio, 0.71; 95% confidence interval, 0.46, 1.09; P=0.114), and a significantly greater reduction in all-cause death (hazard ratio, 0.33; 95% confidence interval, 0.13, 0.83; P=0.014). Conclusions— Compared with moderate pravastatin therapy, intensive atorvastatin therapy was associated with reductions in cholesterol, major acute cardiovascular events, and death in addition to the reductions in ischemia observed with both therapies. The contrast between the therapies’ differing efficacy for major acute cardiovascular events and death and their nonsignificant difference in efficacy for reduction of ischemia suggests that low-density lipoprotein cholesterol–lowering thresholds for ischemia and major acute cardiovascular events may differ. The Study Assessing Goals in the Elderly (SAGE) demonstrates that older men and women with coronary artery disease benefit from intensive statin therapy.

Lipoprotein(a) as a Determinant of Coronary Heart Disease in Young Women

BACKGROUND Lipoprotein(a) [Lp(a)] appears to be a risk factor for coronary heart disease (CHD) in men. The role of Lp(a) in women, however, is less clear. METHODS AND RESULTS We examined the ability of Lp(a) to predict CHD in a population-based case-control study of women 65 years of age or younger who lived in the greater Stockholm area. Subjects were all patients hospitalized for an acute CHD event between February 1991 and February 1994. Control subjects were randomly selected from the city census and were matched to patients by age and catchment area. Lp(a) was measured 3 months after hospitalization by use of an immunoturbidometric method (Incstar) calibrated to the Northwest Lipid Research Laboratories (coefficient of variation was < 9%). Of the 292 consecutive patients, 110 (37%) were hospitalized for an acute myocardial infarction, and 182 were hospitalized (63%) for angina pectoris. The mean age for both patients and control subjects was 56 +/- 7 years. Of participants, 74 patients (25%) and 84 control subjects (29%) were premenopausal. The distributions of Lp(a) were highly skewed in both patients and control subjects, with a range from 0.001 to 1.14 g/L. Age-adjusted odds ratio for CHD in the highest versus the lowest quartile of Lp(a) was 2.3 (95% confidence interval [CI], 1.4 to 3.7). After adjustment for age, smoking, education, body mass index, systolic blood pressure, total cholesterol, triglycerides, and HDL, the odds ratio was 2.9 (95% CI, 1.6 to 5.0). The odds ratios were similar when myocardial infarction and angina patients were compared with their respective control subjects. The odds ratios were 5.1 (95% CI, 1.4 to 18.4) and 2.4 (95% CI, 1.3 to 4.5) in premenopausal and postmenopausal women, respectively. CONCLUSIONS These results suggest that Lp(a) is a determinant of CHD in both premenopausal and postmenopausal women.

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.

Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain

AIMS The main purpose of the present study was to analyse the contemporary use of cardiovascular medications and diagnostic coronary angiography in men and women with suspected coronary artery disease (CAD). Furthermore, we examined the association of outcomes (death, myocardial infarction, repeat coronary angiography, procedural complications) with angiographic findings. METHODS All patients with stable chest pain (n = 12 200) referred for a first-time elective diagnostic coronary angiography during 2006-08 and registered in the Swedish Coronary Angiography and Angioplasty Register (SCAAR) were included. Significant CAD was defined as ≥ 50% luminal narrowing in any epicardial coronary artery. RESULTS In the youngest age group (≤ 59 years), more women than men (78.8 vs. 42.3%, P< 0.001) had normal/non-significant CAD, whereas more men had either left-main or three-vessel disease (18.2 vs. 4.2%, P < 0.001). Event rates were similarly low for men and women with normal/non-significant CAD, except for a higher procedural complication rate in women. Prior to angiography, fewer women than men with high-risk features were prescribed aspirin (83 vs. 86.1%, P = 0.001). CONCLUSION In women, normal/non-significant CAD was highly prevalent, especially among younger women, and associated cardiovascular event rates were low. In men, findings of advanced disease were more common than in women, even younger men. Fewer high-risk women than men were initially prescribed aspirin. The observed sex differences suggest a need for improved identification of women appropriate for investigation with coronary angiography, earlier diagnostics in men, and heightened attention in the evidence-based use of aspirin in risk patients, especially women.

Digoxin-verapamil interaction: Reduction of biliary but not renal digoxin clearance in humans

The interaction between digoxin and verapamil was studied in six patients (mean age ± SD, 61 ± 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady‐state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady‐state plasma concentrations of digoxin, from 0.80 ± 0.24 to 1.15 ± 0.40 nmol/L (p < 0.01). The biliary clearance of digoxin decreased by 43%, from 187 ± 89 to 101 ± 55 ml/min (p < 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 ±31 versus 173 ± 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.

Effect of conjugated estrogen on peripheral flow-mediated vasodilation in postmenopausal women

Estrogen replacement protects against cardiovascular morbidity and mortality in postmenopausal women. Conjugated estrogen is the main hormone used in these studies. However, the vascular effects of this type of estrogen are, to a large extent, unexplored. The objective of this study was to evaluate short-term endothelium-dependent vascular effects of intravenously conjugated estrogen at 2 dose levels. Eleven postmenopausal women were included. Each study subject was given 2.5 and 5 mg of conjugated estrogen or placebo in random order with at least 1 week between each investigation in a double-blind study design. The vascular reactivity of the brachial artery was studied using the duplex technique before and 30 minutes after the intravenous administration of study drug. Reactive hyperemia was used to study the flow-mediated vasodilation. Serum estradiol increased significantly and dose dependently 5 minutes after conjugated estrogen infusion. The flow-mediated vasodilation at baseline before drug administration was 1.8 +/- 2.0% (mean +/- SD) after an average 400% increase in local blood flow. Conjugated estrogen at a dose of 2.5 mg caused an increase in flow-mediated vasodilation from 1.8 +/- 2.1% at baseline to 5.4 +/- 2.8% after infusion (p <0.05 vs placebo), whereas 5 mg caused an increase from 1.9 +/- 1.5% at baseline to 7.0 +/- 3.3% after infusion (p <0.05 vs placebo). Intravenous injection of conjugated estrogen significantly improves the peripheral vascular reactivity in postmenopausal women.

Quinidine reduces biliary clearance of digoxin in man.

Abstract. Quinidine is known to reduce the renal clearance of digoxin, but this effect does not completely explain the influence of quinidine on the total clearance of digoxin. We therefore studied the effect of quinidine administration on biliary clearance of digoxin in five patients with atrial fibrillation. Biliary clearance of digoxin under steady state conditions before and during treatment with quinidine was investigated using a duodenal‐marker‐perfusion technique. Quinidine caused an average 42% (range 21–65%, P < 0·02) reduction of the measured biliary clearance of digoxin. We conclude that the biliary effect adds to the previously demonstrated inhibitory effect of quinidine on the renal clearance of digoxin and helps to explain the decrease in total clearance of the drug. This is the first demonstration in man of a pharmacokinetic drug interaction at the level of biliary excretion.

Effect of quinidine on digoxin concentration in skeletal muscle and serum in patients with atrial fibrillation. Evidence for reduced binding of digoxin in muscle.

QUINIDINE causes a rise in serum steady-state concentrations of digoxin1 2 3 4 5 and reduces both renal and nonrenal clearances of digoxin.6 7 8 A redistribution of digoxin from tissue stores was s...

Differences in drug utilisation between men and women: a cross-sectional analysis of all dispensed drugs in Sweden

Objectives Ascertain the extent of differences between men and women in dispensed drugs since there is a lack of comprehensive overviews on sex differences in the use of prescription drugs. Design Cross-sectional population database analysis. Methods Data on all dispensed drugs in 2010 to the entire Swedish population (9.3 million inhabitants) were obtained from the Swedish Prescribed Drug Register. All pharmacological groups with ambulatory care prescribing accounting for >75% of the total volume in Defined Daily Doses and a prevalence of >1% were included in the analysis. Crude and age-adjusted differences in prevalence and incidence were calculated as risk ratios (RRs) of women/men. Results In all, 2.8 million men (59%) and 3.6 million women (76%) were dispensed at least one prescribed drug during 2010. Women were dispensed more drugs in all age groups except among children under the age of 10. The largest sex difference in prevalence in absolute numbers was found for antibiotics that were more common in women, 265.5 patients (PAT)/1000 women and 191.3 PAT/1000 men, respectively. This was followed by thyroid therapy (65.7 PAT/1000 women and 13.1 PAT/1000 men) and antidepressants (106.6 PAT/1000 women and 55.4 PAT/1000 men). Age-adjusted relative sex differences in prevalence were found in 48 of the 50 identified pharmacological groups. The pharmacological groups with the largest relative differences of dispensed drugs were systemic antimycotics (RR 6.6 CI 6.4 to 6.7), drugs for osteoporosis (RR 4.9 CI 4.9 to 5.0) and thyroid therapy (RR 4.5 CI 4.4 to 4.5), which were dispensed to women to a higher degree. Antigout agents (RR 0.4 CI 0.4 to 0.4), psychostimulants (RR 0.6 CI 0.6 to 0.6) and ACE inhibitors (RR 0.7 CI 0.7 to 0.7) were dispensed to men to a larger proportion. Conclusions Substantial differences in the prevalence and incidence of dispensed drugs were found between men and women. Some differences may be rational and desirable and related to differences between the sexes in the incidence or prevalence of disease or by biological differences. Other differences are more difficult to explain on medical grounds and may indicate unequal treatment.

Hemodynamic and antiarrhythmic effects of tocainide in patients with acute myocardial infarction

In order to evaluate the hemodynamic and antiarrhythmic efficacy of tocainide, studies were performed in patients suffering acute myocardial infarction. Intravenous tocainide was administered over a 15-minute period in order to determine its acute effects and subsequently, in a randomized double-blind study with placebo control, to determine its effects over a 24-hour period in acute myocardial infarction. Tocainide resulted in a significant decrease of frequent and complex ventricular arrhythmias acutely and had only minimal effects of hemodynamics in most patients. In the long-term studies, tocainide produced no adverse hemodynamic effects when compared with placebos.