Cost-effectiveness analysis of adding pharmacists to primary care teams to reduce cardiovascular risk in patients with Type 2 diabetes: results from a randomized controlled trial.

BACKGROUND: Adding pharmacists to primary care teams significantly improved blood pressure control and reduced predicted 10-year cardiovascular risk in patients with Type 2 diabetes. This pre-specified sub-study evaluated the economic implications of this cardiovascular risk reduction strategy. METHODS: One-year outcomes and healthcare utilization data from the trial were used to determine cost-effectiveness from the public payer perspective. Costs were expressed in 2014 Canadian dollars and effectiveness was based on annualized risk of cardiovascular events derived from the UKPDS Risk Engine. RESULTS: The 123 evaluable trial patients included in this analysis had a mean age of 62 ( ± 11) years, 38% were men, and mean diabetes duration was 6 ( ± 7) years. Pharmacists provided 3.0 ( ± 1.9) hours of additional service to each intervention patient, which cost $226 ( ± $1143) per patient. The overall one-year per-patient costs for healthcare utilization were $190 lower in the intervention group compared with usual care [95% confidence interval (CI): -$1040, $668). Intervention patients had a significant 0.3% greater reduction in the annualized risk of a cardiovascular event (95% CI: 0.08%, 0.6%) compared with usual care. In the cost-effectiveness analysis, the intervention dominated usual care in 66% of 10,000 bootstrap replications. At a societal willingness-to-pay of $4000 per 1% reduction in annual cardiovascular risk, the probability that the intervention was cost-effective compared with usual care reached 95%. A sensitivity analysis using multiple imputation to replace missing data produced similar results. CONCLUSIONS: Within a randomized trial, adding pharmacists to primary care teams was a cost-effective strategy for reducing cardiovascular risk in patients with Type 2 diabetes. In most circumstances, this intervention may also be cost saving.

Adding pharmacists to primary care teams reduces predicted long-term risk of cardiovascular events in type 2 diabetic patients without established cardiovascular disease: results from a randomized trial.

AIM: To determine the impact of adding pharmacists to primary care teams on predicted 10-year risk of cardiovascular events in patients with Type 2 diabetes without established cardiovascular disease. METHODS: This was a pre-specified secondary analysis of randomized trial data. The main study found that, compared with usual care, addition of a pharmacist resulted in improvements in blood pressure, dyslipidaemia, and hyperglycaemia for primary care patients with Type 2 diabetes. In this sub-study, predicted 10-year risk of cardiovascular events at baseline and 1 year were calculated for patients free of cardiovascular disease at enrolment. The primary outcome was change in UK Prospective Diabetes Study (UKPDS) risk score; change in Framingham risk score was a secondary outcome. RESULTS: Baseline characteristics were similar between the 102 intervention patients and 93 control subjects: 59% women, median (interquartile range) age 57 (50-64) years, diabetes duration 3 (1-6.5) years, systolic blood pressure 128 (120-140) mmHg, total cholesterol 4.34 (3.75-5.04) mmol/l and HbA(1c) 54 mmol/mol (48-64 mmol/mol) [7.1% (6.5-8.0%)]. Median baseline UKPDS risk score was 10.2% (6.0-16.7%) for intervention patients and 9.5% (5.8-15.1%) for control subjects (P = 0.80). One-year post-randomization, the median absolute reduction in UKPDS risk score was 1.0% greater for intervention patients compared with control subjects (P = 0.032). Similar changes were seen with the Framingham risk score (median reduction 1.2% greater for intervention patients compared with control subjects, P = 0.048). The two risk scores were highly correlated (rho = 0.83; P < 0.001). CONCLUSION: Adding pharmacists to primary care teams for 1 year significantly reduced the predicted 10-year risk of cardiovascular events for patients with Type 2 diabetes without established cardiovascular disease.

Canadian Physicians' Use of Antiobesity Drugs and Their Referral Patterns to Weight Management Programs or Providers: The SOCCER Study.

Antiobesity pharmacotherapy and programs/providers that possess weight management expertise are not commonly used by physicians. The underlying reasons for this are not known. We performed a cross-sectional study in 33 Canadian medical practices (36 physicians) examining 1788 overweight/obese adult patients. The frequency of pharmacotherapy use and referral for further diet, exercise, behavioral management and/or bariatric surgery was documented. If drug treatment or referral was not made, reasons were documented by choosing amongst preselected categories. Logistic regression models were used to identify predictors of antiobesity drug use. No single antiobesity management strategy was recommended by physicians in more than 50% of patients. Referral was most common for exercise (49% of cases) followed by dietary advice (46%), and only 5% of eligible patients were referred for bariatric surgery. Significant predictors of initiating/continuing pharmacotherapy were male sex (OR 0.70; 95% CI 0.52-0.94), increasing BMI (1.02; 95% CI 1.01-1.03), and private drug coverage (1.78; 95% CI 1.39-2.29). "Not considered" and "patient refusal" were the main reasons for not initiating further weight management. We conclude that both physician and patient factors act as barriers to the use of weight management strategies and both need to be addressed to increase uptake of these interventions.

Acute effect of metformin on exercise capacity in active males.

AIM: Physical activity and metformin are often used concomitantly in the treatment of diabetes, even though little is known about possible interactions between these treatment modalities. This study was designed to examine the acute effect of metformin on oxygen consumption and lactate concentration during exercise. METHODS: Eleven healthy, active men [mean +/- s.d.: age = 29.9 +/- 3.7 years; body mass index = 25.2 +/- 2.8 kg/m2; maximal oxygen consumption (VO2max) = 53.5 +/- 8.9 ml/kg/min] completed a randomized, double-blind, placebo-controlled, crossover study. The testing protocol consisted of a standardized breakfast with metformin (1000 mg) or placebo. Three hours after breakfast, participants underwent a graded maximal exercise test on a cycle ergometer. Approximately 30 min after this exercise test, participants cycled continuously at an intensity below their ventilatory threshold for 45 min (mean exercise intensity = 69 +/- 5.5% of VO2max). RESULTS: During the graded exercise test, average oxygen consumption was higher for the metformin condition (2.9 vs. 2.8 l/min, p = 0.04); however, there was no treatment effect on VO2max or ventilatory threshold. During continuous exercise, lactate was lower for the metformin condition (4.7 vs. 5.4 mmol/l, p = 0.05). Following a standardized lunch, glucose concentrations were lower in the metformin compared with the placebo condition (5.8 vs. 6.4 mmol/l, p = 0.04). CONCLUSION: A single dose of metformin does not acutely influence maximal oxygen consumption or ventilatory threshold in healthy active males. The lower lactate concentration observed during continuous exercise with metformin was an unexpected finding considering that, in the resting state, metformin has been previously associated with a modest increase in lactate concentrations.

Vascular compliance is reduced in the early stages of type 1 diabetes.

OBJECTIVE: To determine whether arterial compliance of patients with type 1 diabetes is reduced before the development of clinically apparent diabetes complications. RESEARCH DESIGN AND METHODS: Pulse-wave analysis was used to compare vascular compliance between patients with type 1 diabetes and nondiabetic control subjects. Analysis of covariance was used to determine differences between the two groups with adjustment for age if needed. RESULTS: A total of 59 patients with type 1 diabetes were studied; age ranged from 17-61 years. Of the 59 patients, 32 had no evidence of diabetes complications and 27 had microvascular complications. The control group consisted of 57 healthy subjects ranging in age from 23-79 years. In the control group, large artery compliance (C1) and small artery compliance (C2) were inversely proportional to age (r = -0.55 for C1 and -0.50 for C2; P < 0.01). When the control subjects were compared with type 1 diabetic patients without microvascular complications, C1 was 1.51 +/- 0.04 (SEM) for the control group and 1.33 +/- 0.06 (SE) ml/mmHg for the diabetic group, whereas C2 was 0.080 +/- 0.005 (SE) and 0.065 +/- 0.005 (SE) ml/mmHg for the control and diabetic subjects, respectively, when adjusted for age (P = 0.03 for both C1 and C2). CONCLUSIONS: Vascular compliance of both the large and small arteries is reduced in type 1 diabetic patients before any clinical complications from the diabetes are evident. This study serves to emphasize that vascular changes occur at an early point in the disease and may increase risk of cardiovascular events in patients with diabetes. Larger prospective studies are required to confirm this finding and to investigate the efficacy of medical intervention.

Hyperplacentosis: a novel cause of hyperthyroidism.

Human chorionic gonadotropin (hCG), which is capable of thyrotropic activity, is believed responsible for the hyperthyroidism of gestational trophoblastic disease and hyperemesis gravidarum. Hyperplacentosis is a condition of heightened trophoblastic activity characterized by increased placental weight and circulating hCG levels higher than those associated with normal pregnancy. We report the first case of hyperthyroidism associated with hyperplacentosis. Correction of the hyperthyroidism occurred after hysterotomy and correlated with declining hCG levels. Hyperplacentosis should be included among the causes of hCG-mediated hyperthyroidism.

Quantitative determination of parathyroid hypertensive factor by enzyme-linked immunosorbent assay.

A new competitive enzyme immunoassay for the detection parathyroid hypertensive factor (PHF) in human plasma using a PHF-horseradish peroxidase conjugate and IgM antibody adsorbed on the microtiter plate was established. The antibodies raised against rat PHF could recognize human PHF. Cross-reactivity of anti-PHF antibodies with other serum haptens and proteins was negligible. Conjugation of PHF with horseradish peroxidase did not neutralize the antigen activity. The limit of detection of PHF was 0.02 U/mL in reference units and PHF levels between 0.02 and 1 U/mL could be detected. Within-run coefficient of variation (CV) was less than 10%, and between-run CV was less than 15% for over the dynamic range of the assay. Preliminary clinical studies were performed with plasma samples from hypertensive patients with confirmed diagnosis. Parathyroid hypertensive factor levels, as detected with this immunoassay, were positively correlated with PHF levels detected with the semiquantitative blood pressure (BP) bioassay previously used. Parathyroid hypertensive factor levels detected with the enzyme-linked immunosorbent assay (ELISA) were also correlated with BP in patients. The PHF ELISA provides a selective, simple, and rapid method that can be used for routine determination of PHF in human plasma, and provides useful clinical information.

Parathyroid hypertensive factor secretion from subcultured spontaneously hypertensive rat parathyroid cells.

Cells dissociated from spontaneously hypertensive rat (SHR) parathyroid glands were grown in culture. Media harvested from the cell cultures were analyzed for parathyroid hypertensive factor (PHF) using the blood pressure bioassay. Cells raised in DMEM containing normal (1.8 mmol/L) CaCl2 secreted a negligible amount of PHF, while cells cultured in Ham's F-12 medium containing low (0.3 mmol/L) CaCl2 secreted higher amounts of PHF. The PHF secretion in Ham's F-12 medium was highest in early passage cells, and was maintained for approximately 12 to 15 passages. PHF purified from the cell culture medium exhibited chromatographic properties identical to those previously described for PHF isolated from SHR plasma or SHR parathyroid gland organ culture medium. These results support the parathyroid gland as the organ of origin of PHF.

The effect of valsartan and captopril on lipid parameters in patients with type II diabetes mellitus and nephropathy.

The study compared valsartan 80 mg or 160 mg o.d. with captopril 25 mg t.i.d. or placebo on plasma lipids in normotensive and treated hypertensive patients with type II diabetes and microalbuminuria. One hundred and twenty-two adult outpatients were randomised to receive either valsartan 80 mg or 160 mg, captopril 25 mg or placebo for 360 days. Changes from baseline to endpoint in plasma lipid parameters were measured. The primary criterion for tolerability was the incidence of adverse events. All treatment groups showed minor changes in lipid parameters. Triglyceride increased by 2.7% (valsartan 160 mg) to 9.1% (placebo). Total cholesterol decreased under valsartan 80 mg, while other groups showed increases of up to 0.031 mmol/l. Decreases in total cholesterol (p = 0.018), apolipoprotein B (p = 0.042) and apolipoprotein A1 (p = 0.025), were significant for the comparison of 80 mg valsartan and captopril. Valsartan 80 mg or 160 mg o.d. does not cause deleterious changes in the diabetic lipid profile and, unlike captopril, is not associated with dry cough.

Primary hyperaldosteronism and adrenal incidentaloma: an argument for physiologic testing before adrenalectomy.

OBJECTIVE: To determine the frequency of nonfunctioning adrenal masses in patients with primary hyperaldosteronism. DESIGN: A case series. SETTING: A tertiary care hypertension clinic. PATIENTS: Twenty-seven consecutive patients with primary hyperaldosteronism. MEASUREMENTS: Blood pressure, serum electrolytes, supine and upright plasma renin, cortisol and aldosterone levels, selective adrenal vein aldosterone and cortisol levels, adrenal computed tomography (CT) scans and pathology reports. RESULTS: There was considerable overlap in the clinical features and laboratory investigations for patients with unilateral aldosteronoma and those with bilateral adrenal hyperplasia. Of the 27 patients who had confirmed primary hyperaldosteronism investigated at this centre, 25 had a definitive diagnosis assigned on the basis of postural stimulation tests, adrenal CT scans, and bilateral adrenal vein sampling, surgery or a combination of test results. Of this group, 18 had adrenal masses visualized on CT. However, only 13 of these 18 patients had an adrenal aldosteronoma subsequently proven by selective adrenal vein sampling or surgery, or both; the other 5 patients were found to have bilateral adrenal hyperplasia with nonfunctioning adrenal masses. CT had a sensitivity of 100% for the diagnosis of aldosteronoma, but the specificity was only 58% and the positive predictive value was only 72%. The likelihood ratio for the diagnosis of aldosteronoma in patients with primary hyperaldosteronism and an adrenal mass on CT was only 2.4. CONCLUSION: Given the poor specificity of CT in patients with primary aldosteronism, full biochemical and physiologic testing should be done before adrenalectomy in patients with suspected adrenal aldosteronoma.

Contemporary practice patterns in the management of newly diagnosed hypertension.

OBJECTIVE: To determine what proportion of patients with hypertension are managed in accordance with guidelines established by the Canadian Hypertension Society. DESIGN: Retrospective medical record review. SETTING: Outpatients seen in primary care offices and internal medicine referral clinics in Edmonton. PATIENTS: All 969 adults who presented with a new diagnosis of essential hypertension from Sept. 1, 1993, to Dec. 31, 1995. OUTCOME MEASURES: Initial laboratory tests performed, advice concerning nonpharmacologic treatment given, antihypertensive drugs prescribed and any contraindications to thiazide diuretics or beta-adrenergic blocking agents documented. RESULTS: The mean age of the 969 patients in the sample was 52.5 years; 129 (13%) of the patients were older than 70 years of age; and 500 (52%) were women. Most of the patients (704, 73%) had mild or moderate diastolic hypertension. In the 617 patients who underwent laboratory tests related to hypertension, the creatinine level was determined in 466 (76%), the cholesterol level in 372 (60%), a urinalysis was conducted in 378 (61%), the serum potassium level was checked in 343 (56%), the sodium level in 323 (52%) and an electrocardiogram was performed in 303 (49%). Liver function tests, which are not recommended in the guidelines, were performed in 338 patients (55%). Although there were differences in prescribing among physicians in the 711 patients given first-line therapy, most (238, 34%) were prescribed angiotensin-converting-enzyme (ACE) inhibitors. Lifestyle modification, without drug therapy, was suggested for 180 (25%) of the patients. Although the guidelines recommend their use for first-line drug therapy, only 82 patients (12%) were given beta-adrenergic blocking agents and only 75 (11%) were given thiazide diuretics. Of the patients who were prescribed an antihypertensive other than a thiazide or beta-adrenergic blocking agent as first-line drug therapy, only 161 (43%) had a documented contraindication to thiazides or beta-adrenergic blocking agents. CONCLUSIONS: There is variation in the contemporary care of patients with hypertension. Further studies are required to determine the reasons underlying physicians' noncompliance with the evidence-based guidelines established by the Canadian Hypertension Society.

Resistant hypertension: an overview.

OBJECTIVE: To review the factors contributing to treatment resistance in hypertensive patients and assess the evidence from therapeutic trials in these patients. DESIGN: A MEDLINE search using the words 'resistant hypertension', 'refractory hypertension' and 'treatment resistance, hypertension' was carried out to identify relevant articles. The bibliographies of articles were used to screen for other relevant articles. All available English-language articles on the epidemiology, prognosis and management of hypertension resistant to standard treatment were reviewed. RESULTS: Resistant hypertension is an important public health problem and a common reason for referral of patients to specialized hypertension clinics. Patients with uncontrolled hypertension are at increased risk of stroke, myocardial infarction, congestive heart failure and renal failure. Many factors may play a role in the development of resistant hypertension, including misdiagnosis (pseudoresistance), noncompliance, occult secondary causes for hypertension, volume overload, obesity, cigarette smoking, excess alcohol intake, sleep apnea, interfering medications and suboptimal combinations of antihypertensives. Only beta-blockers and thiazide diuretics have been demonstrated to reduce cardiovascular morbidity and mortality in hypertension. The trials evaluating third-line agents in patients with resistant hypertension have demonstrated additional blood pressure lowering with all classes of agents, and the randomized controlled trials have not demonstrated any statistically significant differences between the agents in either efficacy or tolerability. CONCLUSIONS: Evaluation of the patient with resistant hypertension should include 24 h ambulatory blood pressure monitoring and an extensive search for hypertensive end organ damage. Contributing factors should be sought and stepped care should still form the basis for treatment decisions. The choice of third-line agent should be dictated by the patient's renin profile, current medication and any concomitant diseases.

Parathyroid hypertensive factor predicts efficacy in the treatment of essential hypertension with verapamil.

Parathyroid hypertensive factor (PHF) is a circulating hypertensive factor, levels of which are inversely related to renin profile. Given this relationship, it was hypothesized that a PHF level might serve as an alternate predictor of antihypertensive efficacy in hypertensive patients, avoiding the difficulties associated with renin profiling. To test this hypothesis, thirty patients with essential hypertension were placed on 240 mg once daily of a slow release verapamil preparation for a period of one month following a one month run-in period. Results showed an average reduction in mean arterial pressure (MAP)of -7 mmHg (range -5 to - 18) and an average reduction in PHF of -4 mmHg (range 7 to -28). Pre-treatment PHF level correlated with the blood pressure response to verapamil (r = -0.61, p = 0.0004). There was no correlation between any index of renin status and blood pressure. The only other correlation of note was between normalized, ionized calcium and change in blood pressure (r = -0.46, p =0.02). In a forward stepwise multivariate model with MAP as the dependent variable, PHF and normalized, ionized calcium levels were the only biochemical or demographic predictors of response to verapamil. These results suggest that PHF level may be useful in determining the initial choice of antihypertensive agent in hypertensive patients.

Protein binding of sotalol enantiomers in young and elderly human and rat serum using ultrafiltration.

The protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32 +/- 2 years, n = 5) and elderly (73 +/- 6 years, n = 5) male and female humans, and young (8 weeks, n = 4) and elderly (60 weeks, n = 3) male Sprague-Dawley rats. Serum samples were collected and immediately frozen at -20 degrees C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05 M phosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL-1 and 500 ng mL-1 of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut-off), capped, equilibrated to 37 degrees C, and centrifuged at 1850g for 1.5 h at 37 degrees C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non-stereoselective.

Pharmacokinetics of verapamil and norverapamil enantiomers after administration of immediate and controlled-release formulations to humans:evidence suggesting input-rate determined stereoselectivity.

Verapamil is a racemic calcium channel-blocking drug that undergoes extensive hepatic first-pass metabolism to an active metabolite, norverapamil. The enantiomers of verapamil and norverapamil have differing negative inotropic, chronotropic, and dromotropic activities and differing effects on vascular smooth muscles; the S-enantiomers having greater activity. It is hypothesized that the R/S concentration ratio of verapamil enantiomers may be input-rate dependent. The pharmacokinetics of verapamil and norverapamil enantiomers were studied in 11 young, healthy male and female volunteers after oral administration of 80 mg immediate-release (IR) verapamil every 8 hours, and a 240 mg dose once daily of controlled-release (CR) formulation on two separate occasions. Both dosage regimens were continued for 1 week with a minimum 1-week period between the two drug treatments. After the last dose of each regimen, plasma samples were collected over the period corresponding to the dosing interval. Enantiomer concentrations were determined using a microwave-facilitated precolumn derivatization with high performance liquid chromatographic quantification. Stereospecific assay revealed that: (1) stereoselective R- and S-enantiomer disposition occurred regardless of formulation administered; (2) a trend of R:S concentration ratios of verapamil differed between the two formulations; and (3) fluctuations between Cmax and Cmin values of the two formulations were statistically different over respective dosing intervals (greater fluctuation after CR administration). Using nonstereospecific data analyses, however, the pharmacokinetic parameters for verapamil and norverapamil were similar for both formulations over a 24-hour period. We suggest that kinetic differences can be attributed to differences in release rates of drug from the tablet matrices. The relative bioavailabilities of verapamil and norverapamil from the two products may, therefore, be subject to input rate-dependent processes.

PHF: the new parathyroid hypertensive factor.

Parathyroid Hypertensive Factor (PHF) was discovered in SHR rats as a circulating substance with a unique delayed (60-90 min) hypertensive effect when injected into a normotensive assay rat. Subsequently, this correlation with hypertension was established in humans, especially in low-renin, salt-sensitive patients. Animal model studies also confirmed this correlation. Endocrinectomy and glandular replacement studies suggested that the parathyroid gland was the source of PHF. Subsequently, glands and cells in culture were also shown to secrete the substance. Other studies verified the parathyroid origin of PHF. The mechanism of action of PHF was shown to rely mainly on the opening of L-type calcium channels in vascular smooth muscle cells with an increase in [Ca2++]i. It is known that diseases other than hypertension often show increased [Ca2++]i and clinical features similar to hypertension, among them Type II diabetes. A recent study shows a correlation between circulating PHF level and Type II diabetes irrespective of the blood pressure status of the patient. It is suggested that PHF may be a [Ca++]i modulator, an excessive amount of which in the circulation may act on various target tissues, resulting in various disease symptoms with hypertension as an example. There may be many other such PHF-related diseases yet to be identified.

Mechanism of the vascular action of parathyroid hypertensive factor.

The present studies investigated the effect of parathyroid hypertensive factor (PHF) on intracellular calcium regulation in VSMC. Nifedipine inhibited the hypertensive effect of PHF in Sprague-Dawley (SD) rats in vivo. PHF amplified the L-type calcium current in vascular smooth-muscle cells (VSMCs) isolated from SD rat tail artery. PHF potentiated the tension induced by norepinephrine (NE) in the presence of normal added CaCl2 and inhibited the tension dependent on Ca2+ release from intracellular calcium store(s) induced by NE in SD rat tail artery helical strips. PHF potentiated the intracellular free calcium concentration ([Ca2+]i) increment induced by KCl in cultured VSMCs from SD rat tail artery. All of the in vitro cellular calcium effects of PHF temporally correlated with its delayed hypertensive effect in vivo. PHF did not affect the accumulation of inositol phosphates in SD rat tail artery. Infusion of theophylline blunted the hypertensive effect of PHF in SD rats, suggesting that PHF may stimulate phosphodiesterase (PDE) activity. We suggest that PHF may potentiate the effects of other vasoconstrictors on calcium channels and increase [Ca2+]i, which would then lead to an increase in the responsiveness of the VSMC to other vasoconstrictors, and therefore an increase in blood pressure. The action of PHF may involve stimulation of PDE activity.