EVITA: a tool for the early evaluation of pharmaceutical innovations with regard to therapeutic advantage.

BACKGROUND: New drugs are generally claimed to represent a therapeutic innovation. However, scientific evidence of a substantial clinical advantage is often lacking. This may be the result of using inadequate control groups or surrogate outcomes only in the clinical trials. In view of this, EVITA was developed as a user-friendly transparent tool for the early evaluation of the additional therapeutic value of a new drug. METHODS: EVITA does not evaluate a new compound per se but in an approved indication in comparison with existing therapeutic strategies. Placebo as a comparator is accepted only in the absence of an established therapy or if employed in an add-on strategy on top. The evaluation attributes rating points to the drug in question, taking into consideration both therapeutic benefit and risk profile. The compound scores positive points for superiority in efficiency and/or adverse effects as demonstrated in randomized controlled trials (RCTs), whilst negative points are awarded for inferiority and/or an unfavorable risk profile. The evaluation follows an algorithm considering the clinical relevance of the outcomes, the strength of the therapeutic effect and the number of RCTs performed. Categories for therapeutic aim and disease severity, although essential parts of the EVITA assessment, are attributed but do not influence the EVITA score which is presented as a color-coded bar graph. In case the available data were unsuitable for an EVITA calculation, a traffic-type yield sign is assigned instead to criticize such practice. The results are presented online http://www.evita-report.de together with all RCTs considered as well as the reasons for excluding a given RCT from the evaluation. This allows for immediate revision in response to justified criticism and simplifies the inclusion of new data. RESULTS: As examples, four compounds which received approval within the last years were evaluated for one of their clinical indications: lenalidomide, pioglitazone, bupropion and zoledronic acid. Only the first achieved an EVITA score above zero indicating therapeutic advantage. CONCLUSIONS: The strength of EVITA appears to lie in its speedy assessment of the potential therapeutic advantage of a new drug for a given indication. At the same time, this approach draws attention to the typical deficits of data used for drug approval. EVITA is not intended to replace classical health technology assessment reports but rather serves as a screening tool in the sense of horizon scanning.

Verapamil inhibits L-type calcium channel mediated apoptosis in human colon cancer cells.

PURPOSE: Treatment with calcium channel blockers have been associated with increased colon cancer mortality in epidemiologic studies. We examined the potential expression and function of calcium channels in two human colon cancer cell lines. METHODS: Both primary (collected at operation) and commercially-available human colon cancer cell lines were used. The colon cancer cells were incubated with a calcium channel blocker (verapamil) and a calcium channel agonist (BayK 8644) at clinically relevant concentrations. L-type calcium channel mRNA was determined by reverse-transcription polymerase chain reaction. Intracellular calcium ion levels were measured with fluorometry and apoptosis with flow cytometry. RESULTS: Both types of cells expressed L-type calcium channel mRNA, comprising an alpha-1D and a beta-3 subunit, whereas the cells were negative for N-type and P-type channels. The selective calcium channel agonist (BayK 8644), dose-dependently increased intracellular calcium ion levels and the level of apoptosis in primary human colon cancer cells. Pretreatment with verapamil completely abolished both calcium channel agonist-induced influx of calcium and apoptosis in these cells. CONCLUSIONS: These data demonstrate that human colon cancer cells express L-type calcium channels that mediate calcium influx and apoptosis, which warrants further studies to determine whether calcium channel blockers may promote colon cancer growth.

Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care.

OBJECTIVE: To estimate the incidence and describe characteristics of preventable adverse drug events (pADEs) in ambulatory care. DATA SOURCES: Studies were searched in PubMed (1966-March 2007), International Pharmaceutical Abstracts (1970-December 2006), the Cochrane database of systematic reviews (1993-March 2007), EMBASE (1980-February 2007), and Web of Science (1945-March 2007). Key words included medication error, adverse drug reaction, iatrogenic disease, outpatient, ambulatory care, primary health care, general practice, patient admission, hospitalization, observational study, retrospective studies, health services research, and follow-up studies. Additional articles were found in the reference sections of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: Peer-reviewed articles assessing pADEs in ambulatory care, with detailed descriptions/frequency distributions of (1) ADE/pADE incidence, (2) clinical outcomes, (3) associated drug groups, and/or (4) underlying medication errors were included. Study country, year and design, sample size, follow-up time, ADE/pADE identification method, proportion of ADEs/pADEs and ADEs/pADEs requiring hospital admission, and frequency distribution of adverse outcome, associated drug groups, or medication errors were extracted. DATA SYNTHESIS: Twenty-nine studies met inclusion criteria: 14 were ambulatory-based and 15 were hospital-based. Seven studies enrolled only elderly patients. The median ADE incidence was 14.9 (range 4.0-91.3) per 1000 person-months, and the pADE incidence was 5.6 per 1000 person-months (1.1-10.1). The median ADE preventability rate was 21% (11-38%). The median incidence of ADEs requiring hospital admission was 0.45 (0.10-13.1) per 1000 person-months, and the median incidence of pADEs requiring hospital admission was 4.5 per 1000 person-months. Cardiovascular drugs, analgesics, and hypoglycemic agents together accounted for 86.5% of pADEs, and 77.2% of pADEs resulted in symptoms of the central nervous system, electrolyte/renal system, and gastrointestinal tract. Medication errors resulting in pADEs occurred in the prescribing and monitoring stages. The most frequent drug therapy problem and error of commission reported in ambulatory-based studies on pADEs was the use of inappropriate drugs (42.7%; 40.4-45%). For pADEs requiring hospital admission, the most frequent drug therapy problem and error of omission reported was inadequate monitoring (45.4%; range 22.2-69.8%). Failure to prescribe prophylaxis to patients taking nonsteroidal antiinflammatory drugs or antiplatelet drugs frequently caused gastrointestinal toxicity, whereas lack of monitoring of diuretic, hypoglycemic, and anticoagulant use caused over- or under-diuresis, hyper- or hypoglycemia, and bleeding. CONCLUSIONS: ADEs in ambulatory care are common, with many being preventable and many resulting in hospitalization. Quality improvement programs should target errors in prescribing and monitoring, especially for patients using cardiovascular, analgesic, and hypoglycemic agents.

Refill adherence of antihyperglycaemic drugs related to glucose control (HbA1c) in patients with type 2 diabetes.

The aim of this study was to examine a potential association between: (1) refill adherence to antihyperglycaemic drugs and glucose control, and (2) adherence to antihyperglycaemic and cardiovascular drugs for the same patients. Consecutive patients with type 2 diabetes at six Swedish health centres were included. Refill adherence was determined from repeat prescriptions. Satisfactory refill adherence was defined as the percentage of the patients with refills covering > or =80% of the prescribed treatment time. A total of 994 prescriptions were collected from 422 patients, 346 patients had antihyperglycaemic drugs (mean HbA(1c )6.5%) and 76 were on diet and exercise but not on drugs (mean HbA(1c )6.2%) (P = 0.0098). A total of 257 patients (74%) had satisfactory refill adherence. Mean HbA(1c) for the adherent patients was 6.5% and for the non-adherent patients 6.8% (P = 0.025). For patients on insulin only, 69% had satisfactory refill adherence with mean HbA(1c) 6.6% compared to 7.3% (P = 0.005) for the non-adherent patients. Ninety-two percent of the patients with satisfactory refill adherence to antihyperglycaemic agents were also adherent to cardiovascular drugs compared to 62% among those who were non-adherent to antihyperglycaemic drugs (P < 0.001). Patients with satisfactory refill adherence have lower HbA(1c)-levels and higher adherence to cardiovascular drugs than non-adherent patients.

Can drug treatment prevent disease in common practice?

To assess whether drug treatment in common practice can prevent disease, we analysed four preventive cardiovascular randomised clinical trials (RCTs), expressing efficacy by 1-year Number Needed to Treat (NNT) in RCT and common practice effectiveness by the Disease Impact Number (DIN) in all subjects at risk and by the Population impact Number (PIN) in the entire population, based on a Swedish population survey. Adjustments were made for non-adherence. Calculations were made of alternative 1-year drug costs and number of years an average general practitioner (GP) would need to work in order to prevent one event using the actual treatment. Secondary prevention of MI by simvastatin (NNT, DIN and adjusted PIN = 37, 93 and 2657; GP work time 2.7 years; drug costs Euro 1020 - 13505), and prevention of stroke by antihypertensive treatment in high-risk subjects (elderly with systolic blood pressure > 160 mm Hg; NNT, DIN and adjusted PIN = 167, 239 and 11950; GP work time 6 years; drug costs Euro 6095 - 51567) appeared medically and economically effective. Primary prevention of MI by pravastatin (NNT, DIN and adjusted PIN 208, 2080 and 24470; GP work time 12.2 years; drug costs Euro 5736 - 117676) or by antihypertensive drug treatment in low-risk subjects (diastolic blood pressure 90-99 mm Hg) (NNT, DIN and adjusted PIN 1667, 3334 and 116982; GP work time 58.5 years; drug costs Euro 60895 - 511718) seemed ineffective and expensive.

Anxiolytic-hypnotic drug use associated with trust, social participation, and the miniaturization of community: a multilevel analysis.

The concept of social capital has gained wide interest in public health research in recent years. However, we suggest a concept that was introduced and developed by Fukuyama, named "miniaturization of community", as an alternative to that of social capital. The concept of miniaturization of community emphasizes that a high level of social participation can be accompanied by a low level of trust, both at the individual and at the community level, which may in turn result in social disorder and lack of social cohesion. When society becomes more disordered, people may tend to feel more insecure and anxious. Use of anxiolytic-hypnotic drugs (AHDs) could under such circumstances be a coping strategy. In this study, we first wanted to investigate whether the contextual component of the miniaturization of community concept (i.e. area high social participation and low trust) is associated with individual AHD use, over and above individual characteristics. Secondly, we aimed to study whether people living in the same municipality share a similar probability of AHD use, after adjusting for individual characteristics, and if so, how large this contextual phenomenon is. We used data on 20,319 women and 17,850 men aged 18-79 years from 58 municipalities in six regions in central Sweden, who participated in the Life & Health year 2000 postal survey. We applied multilevel logistic regression analysis with individuals at the first level and areas at the second level. Our results suggest that living in an area with a high level of miniaturization of community seems to be associated with individual AHD use, beyond people's individual characteristics including their own level of social participation and trust. The concept of miniaturization of community may be an extension of the classic concept of social capital and may increase our understanding of contextual effects on health.

Increased introduction, advertising, and sales of preventive drugs during 1986-2002 in Sweden.

The objective of this study was to survey how introduction of new drugs and promotional activities influence drug sales in Sweden. All drugs on the Swedish market were categorized as curative, symptom-alleviating, substitutive, or preventive. The number of new drugs introduced, drug sales in volume and value, and the number of drug advertisements appearing in the major Swedish medical journal during 1986-2002 were determined for each of the 4 drug categories. Between 1986 and 1998, the relative shares of the 4 drug categories were relatively constant. From 1998 to 2002, the share of new preventive drugs increased from 24% to 30%, their share of advertisements increased from 20% to 35%, and their sales value increased from 25% to 30%. During the same period, the shares of other drugs decreased correspondingly. Pharmaceutical companies have shifted their attention to the introduction, advertising, and sales of preventive drugs in an attempt to exploit preventive medicine. This might lead to waste of resources when expensive preventive drugs are used by numerous patients over many years, as the benefit of preventive drugs for the individual patient cannot be judged easily.

Kinetics-effect relations of insulin-releasing drugs in patients with type 2 diabetes: brief overview.

Sulfonylureas and glinides have similar mechanisms of action but differ in receptor affinity and binding sites and in absorption and elimination rates. This promotes differences in potency, rate of onset, and duration of action. While prominent in single-dose studies, these differences have less importance during long-term sulfonylurea treatment: at ordinary dosages, rapid- and short-acting (glipizide) and slow- and long-acting (glyburide) sulfonylureas maintained continuously effective plasma levels and similar 24-h glucose control. Moreover, there was no difference in patient outcome between the first-generation sulfonylurea chlorpropamide and the second-generation glyburide in the U.K. Prospective Diabetes Study. However, the risk of long-lasting and hence dangerous hypoglycemia is higher with these two long-acting sulfonylureas. Conversely, this risk should be low with the short-acting glinides, but seemingly at the expense of less effective glucose control. The most important kinetics-effect relations are that hyperglycemia delays sulfonylurea absorption and that the sulfonylurea dose-response curve is bell shaped; continuous sulfonylurea exposure over a certain level (e.g., 10 mg glipizide) impairs rather than improves insulin and glucose responses to sulfonylurea (downregulation). Accordingly, a vicious circle may be established: unrelenting hyperglycemia may promote sulfonylurea dose increase, which increases hyperglycemia, promoting further dose increase and eventually therapeutic failure.

Survival in patients with type 2 diabetes in a Swedish community: skaraborg hypertension and diabetes project.

OBJECTIVE: To explore risk factors for all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS: A prospective population-based study of 400 patients with type 2 diabetes who consecutively completed an annual checkup in primary care in Skara, Sweden, during 1992-1993. Vital status was ascertained to year 2000. Baseline characteristics as predictors for mortality were analyzed by Cox regression and expressed as relative risks (RRs), with 95% CIs. RESULTS: During a mean follow-up time of 5.9 years, 131 patients died (56 deaths per 1,000 patients per year). In both sexes, all-cause mortality was predicted by HbA(1c) (by 1%; RR 1.14, 95% CI 1.01-1.27), and by LDL-to-HDL cholesterol ratios (1.15, 1.00-1.32). Increased mortality was also seen with prevalent hypertension (1.72, 1.21-2.44), microalbuminuria (1.87, 1.27-2.76), and previous cardiovascular disease (1.70, 1.15-2.50). Subanalyses revealed that increased mortality related to HbA(1c) was restricted to hypertensive patients with type 2 diabetes (1.23, 1.04-1.47). Serum triglycerides (by 1 mmol/l) predicted all-cause mortality in women (1.25, 1.06-1.47). CONCLUSIONS: Poor glucose and lipid control and hypertension predicted all-cause mortality. Survival was also predicted by prevalent microalbuminuria and by previous cardiovascular disease. Confirming results from clinical trials, this population-based study has implications for primary and secondary prevention.

Dynamic training and circulating levels of corticotropin-releasing factor, beta-lipotropin and beta-endorphin in rheumatoid arthritis.

The study aimed at evaluating the effects of a dynamic training program on circulating levels of corticotropin-releasing factor (CRF), beta-lipotropin (beta-LPH), and beta-endorphin (beta-EP) in 8 patients (5 females and 3 males, aged 39-65 years) with classical/definite rheumatoid arthritis (RA). Blood samples were collected immediately before, in the middle of, and after a 6-week high-intensity training period as well as after a subsequent 1-year period of low-intensity training. In addition, baseline data were obtained 3 weeks before the start of the training program. Use of multivariate analyses of variance, and of analyses of variance of contrast variables, indicated a short-term effect of the high-intensity training program for beta-EP with increased levels (P less than 0.05) between the 3rd and the 6th weeks, no significant differences being obtained for CRF or beta-LPH here. Corresponding analyses with regard to the combined high and low-intensity training program revealed CRF (P less than 0.01), and beta-LPH (P less than 0.01) levels to increase over time, no long-term effect being found for beta-EP. Despite the intensity of the dynamic training program, no change was found in pain experience as measured on a visual analogue scale.

Peroxisome proliferator-activated receptor-gammaPro12Ala polymorphism and the association with blood pressure in type 2 diabetes: skaraborg hypertension and diabetes project.

OBJECTIVE: This study explored whether the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with blood pressure in subjects with type 2 diabetes. DESIGN: A community-based, cross-sectional observation study. SETTING: Primary care. PATIENTS: One hundred and ninety-two men and 192 women with type 2 diabetes who consecutively underwent annual follow-up. MAIN OUTCOME MEASURE: The PPARgammaPro12Ala genotype was determined by polymerase chain reaction-based techniques. Associations between genotype and blood pressure were analysed by linear regression and expressed as differences in blood pressure (delta) with 95% confidence interval (CI). RESULTS: The mean systolic blood pressure and the diastolic blood pressure were 160 mmHg (standard deviation = 22.8) and 84 mmHg (standard deviation = 9.6), respectively. Subjects with Pro/Ala (24%) or Ala/Ala (2%) had lower diastolic blood pressure (delta = 2.8; 95% CI, 0.6-5.0) when adjusted for age and gender compared with Pro/Pro subjects (74%). This association was restricted to men (delta = 4.4; 95% CI, 1.3-7.4), who also had a borderline significant difference in systolic blood pressure (delta = 6.9; 95% CI, -0.8 to 13.8). In men the difference in diastolic blood pressure remained after adjustment for age, body mass index, serum triglycerides, serum insulin and haemoglobin A(1c) (delta = 4.6; 95% CI, 1.1-8.1). A subanalysis of normotensive men (n = 100) confirmed the difference associated with the Pro12Ala polymorphism in diastolic blood pressure (delta = 5.2; 95% CI, 0.6-10.0). CONCLUSIONS: The common Pro12Ala polymorphism in PPARgamma is associated with lower diastolic blood pressure in male subjects with type 2 diabetes.

Pricing and costs of drugs in the United States and Sweden: a comparison based on drug acquisition costs at the patient outcome level.

Cost consequences of antihypertensive drug pricing were compared in the United States and Sweden. Because of price differences, US drug acquisition costs to prevent one cardiovascular event were 339%, 127%, and 22% higher using the most prescribed calcium channel blocker, angiotensin-converting enzyme inhibitor, and beta blocker, but 65% lower with hydrochlorothiazide. As thiazides are as effective as, but cheaper than, the alternatives, the costs of effective antihypertensive drug treatment may be pronouncedly reduced in both countries. This emphasizes not only the importance of drug pricing but also the cost-increasing influence of commercial marketing. More producer-independent and evidence-based drug information to prescribers is necessary.

[Result of a CPP-project at a primary health care center. Diabetes care in primary health care is resource-demanding]. / Resultat av KPP-projekt på en vårdcentral. Diabetessjukvård resurskrävande i primärvården.

Cost Per Patient (CPP) is a method to calculate health care costs for every individual health care contact. The method, which supplies information about diagnosis-related health care consumption, and was employed at the Primary Health Care Centre of Odeshög, Sweden. The study was conducted during 2001 and showed that 2% of the patients who had at least one contact with the health care centre were consuming 20% of the center's total resources. Furthermore, the single highest healthcare consumption was noted among the group of diabetic patients, mainly due to associated illness and the need for home care among those who were unable to manage their insulin injections themselves.