Comparative Efficacy of Angiotensin II Antagonists in Essential Hypertension: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Evidence on the long-term clinical benefits of individual members of angiotensin II receptor blockers is limited given the lack of head-to-head studies. We conducted a network meta-analysis to determine the comparative efficacy of different members within this drug class with respect to outcomes of (i) blood pressure reduction (at 24 and 52 weeks) and (ii) prevention of cardiovascular disease (>104 weeks). METHODS: A systematic literature review was conducted - Protocol registration: (PROSPERO - CRD42014007067) - to identify relevant literature from the following databases: Cochrane Library, PubMed, Medline and EMBASE; searched from inception to July 2016. Randomised controlled trials (RCTs) were included if they reported long-term effectiveness relating to blood pressure, mortality, myocardial infarction or stroke. Eligible studies included those with placebo or specific active-treatment comparators (either another angiotensin II receptor blockers or hydrochlorothiazide). A Bayesian random-effects network model was used to combine direct within-trial comparisons between treatment groups with indirect evidence from other trials. RESULTS: Thirty-six studies were identified, representing 28 unique trials. Blood pressure reduction, based on 12 studies (n=807) with fixed dosing regimen, was found to be similar amongst members of the angiotensin receptor blocker drug class at both 24 and 52 weeks. A network meta-analysis of five studies (n=16,716) with a treat-to-target approach found that prevention of all-cause mortality, stroke and myocardial infarction was similar across the angiotensin-receptor blockers therapies initiated. CONCLUSIONS: Current evidence is insufficient to show differences in any members within the angiotensin II receptor blocker drug class with respect to blood pressuring lowering effects or a reduction in cardiovascular diseases.

Cardiovascular and cerebrovascular outcomes of long-term angiotensin receptor blockade: meta-analyses of trials in essential hypertension.

Angiotensin receptor blockers (ARBs) are widely used in managing essential hypertension, with considerable evidence available on their short-term efficacy in lowering blood pressure (BP). However, there currently exists limited "pooled" data examining the long-term efficacy of ARB treatment in controlling BP or mitigating cardiovascular and cerebrovascular events. The purpose of this study was to conduct a systematic review and meta-analysis assessing the long-term effects of ARBs as a class on BP control, myocardial infarction, hospitalization for heart failure, cerebrovascular events (ie, stroke), cardiovascular mortality, and all-cause mortality. MEDLINE, EMBASE, PubMed, and the Cochrane Library databases were searched from inception to March 2015. Two evaluators independently reviewed studies for eligibility. Randomized controlled hypertension trials were included if they reported on ARB efficacy in either BP control (relative to placebo for periods ≥ 6 months) or cardiovascular/cerebrovascular outcomes (relative to non-ARB antihypertensive therapies for periods ≥ 24 months). Studies were pooled with a random-effects model using weighted mean differences (WMDs) and relative risks for continuous and dichotomous outcomes, respectively. A total of 11 articles were included in the narrative synthesis, representing seven unique trials (16,864 participants). Six ARB agents were studied: candesartan, eprosartan, irbesartan, olmesartan, losartan (each represented by one trial arm), and telmisartan (represented by two arms). ARB therapy significantly reduced mean systolic BP (WMD: -4.86; 95% CI: -6.19, -3.53 mm Hg) and diastolic BP (WMD: -2.75; 95% CI: -3.65, -1.86 mm Hg] compared to placebo. The risk of stroke was reduced by 21% in the ARB group compared with alternative antihypertensives (risk ratio: 0.79; 95% CI: 0.66, 0.96). ARBs did not, however, produce statistically significant reductions in the risk of myocardial infarction, heart failure hospitalization, or mortality. Our findings suggest that ARBs, as a class, are more effective than placebo therapy in long-term BP lowering in patients with essential hypertension. Long-term ARB treatment may also confer enhanced protection against stroke but not other cardiovascular outcomes relative to placebo.

Incorporating ulipristal acetate in the care of symptomatic uterine fibroids: a Canadian cost-utility analysis of pharmacotherapy management.

OBJECTIVE: To present a Canadian economic evaluation on the cost-utility of ulipristal acetate (5 mg orally daily) compared to leuprolide acetate (3.75 mg intramuscular monthly) in the treatment of moderate-to-severe symptoms of uterine fibroids in women eligible for surgery. METHODS: A probabilistic decision tree was constructed to model the pre-operative pharmacological management of uterine fibroids under the primary perspective of the Ontario public payer. The model parameterized data from clinical trials, observational studies, and public costing databases. The outcome measure was the incremental cost-utility ratio. Uncertainty in the model was explored through sensitivity and scenario analyses. RESULTS: Ulipristal was associated with faster control of excessive menstrual bleeding, fewer symptoms of hot flashes and lower health care resource consumption. The ulipristal strategy dominated leuprolide as it provided patients with more quality-adjusted life years (0.177 versus 0.165) at a lower cost ($1,273 versus $1,366). Across a range of sensitivity analyses, the results remained robust except to the dose of the comparator drug. If leuprolide was administered at 11.25 mg, once every 3 months, the expected cost for the leuprolide strategy would decline and the associated incremental cost-utility ratio for ulipristal would be $168/quality-adjusted life year. CONCLUSION: Ulipristal offers a unique opportunity to effectively and rapidly control menstrual bleeding in patients with uterine fibroids; thereby improving their quality of life while minimizing the probability of moderate-to-severe hot flashes that are common with leuprolide. The current economic analysis suggests that ulipristal remains the dominant strategy across extensive sensitivity analyses.

Do different decision-analytic modeling approaches produce different results? A systematic review of cross-validation studies.

When choosing a modeling approach for health economic evaluation, certain criteria are often considered (e.g., population resolution, interactivity, time advancement mechanism, resource constraints). However, whether these criteria and their associated modeling approach impacts results remain poorly understood. A systematic review was conducted to identify cross-validation studies (i.e., modeling a problem using different approaches with the same body of evidence) to offer insight on this topic. With respect to population resolution, reviewed studies suggested that both aggregate- and individual-level models will generate comparable results, although a practical trade-off exists between validity and feasibility. In terms of interactivity, infectious-disease models consistently showed that, depending on the assumptions regarding probability of disease exposure, dynamic and static models may produce dissimilar results with opposing policy recommendations. Empirical evidence on the remaining criteria is limited. Greater discussion will therefore be necessary to promote a deeper understanding of the benefits and limits to each modeling approach.

Harmonization of HTA--based reimbursement and regulatory approval activities: a qualitative study.

BACKGROUND: Regulatory approval and reimbursement are necessary to bring health technologies to market. As both are distinct processes, the lack of interaction between regulators and payers has been criticized for resulting in health system inefficiencies. OBJECTIVES: This study describes the experiences of health system stakeholders on the development and implementation of initiatives to better harmonize HTA-reimbursement and regulatory activities, as well as Canadian perceptions on such initiatives. METHODS: Thematic analysis of semi-structured interviews was conducted. Participants represented those whom have published or worked actively in this area or who held positions in HTA and/or reimbursement agencies that gave them insight into the Canadian healthcare system. Interviews were recorded, transcribed and analyzed to identify emerging themes and relationships. RESULTS: Fourteen individuals from twelve organizations participated, including representatives from Canada, US, UK and Netherlands. Harmonization was identified as either a means to: (i) develop economies of scale in the generation of clinical data; and/or (ii) align the lifecycle of a health technology. For such initiatives to be successfully implemented, the following key issues emerged: (i) fostering healthy relationships; (ii) promoting well-intentions; (iii) defining governance and leadership clearly; and (iv) securing organizational infrastructure. CONCLUSIONS: Attempts to harmonize reimbursement and regulatory activities is in its infancy; although, much can be learned from current Canadian and international experiences. Within Canada there is much interest, although concerns have been raised on the extent to which harmonization is possible. Successful policy implementation would require inter-agency collaborations, with particular attention towards capacity building and strong leadership.

Cost-effectiveness analysis parallel to a randomized controlled trial comparing vertical scar reduction and inverted T-shaped reduction mammaplasty.

BACKGROUND: A previous randomized controlled trial showed no clear superiority of vertical scar over inverted T-shaped reduction mammaplasty in terms of health-related quality of life. No economic evaluation has been undertaken comparing vertical scar reduction and inverted T -shaped reduction. METHODS: A total of 255 patients were randomized to either vertical scar or inverted T -shaped reduction. The effectiveness was measured with the Health Utilities Index Mark 3. Direct and productivity costs were captured parallel to the randomized controlled trial. Perspectives of the Ministry of Health, patient, and society were considered. RESULTS: Inverted T -shaped reduction dominated vertical scar reduction from the Ministry of Health perspective by being slightly less costly ($3090.06 versus $3106.58) and slightly more effective (0.87 quality-adjusted life-years versus 0.86 quality-adjusted life-years). From the societal and patient perspectives, vertical scar reduction was both less costly and less effective. At the commonly quoted Canadian threshold of $50,000 per quality-adjusted life-year gained, the probability that vertical scar reduction was cost-effective was 29.3, 68.2, and 66.9 percent from the Ministry of Health, patient, and societal perspectives. Subgroup analysis of reductions less than 500 g found that vertical scar reduction was more likely cost-effective. CONCLUSIONS: Vertical scar reduction is more likely than not cost-effective from patient and societal perspectives but not from the Ministry of Health perspective at a willingness-to-pay threshold of $50,000 per quality-adjusted life-year. If we limit vertical scar reduction for resections less than 500 g per breast, this technique is more likely cost-effective from all perspectives.

Safety of tissue expander/implant versus autologous abdominal tissue breast reconstruction in postmastectomy breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Breast reconstruction after mastectomy for breast cancer should be informed by evidence-based knowledge, such as complication rates. The authors compared the safety of tissue expander/implant reconstruction with that of autologous abdominal tissue reconstruction. METHODS: A systematic literature review identified peer-reviewed studies published from January of 2000 to October of 2012 that compared tissue expander/implant against autologous abdominal tissue reconstruction in the MEDLINE, EMBASE, Cochrane Library, PubMed, and ProQuest Dissertations and Theses databases. Two reviewers independently screened all reports and selected the relevant articles using specific inclusion criteria. Data were extracted from the relevant articles using a standardized abstraction form. RESULTS: Fourteen observational studies were identified that included more than 3000 reconstructed breasts. Significant differences were found between these two approaches. The relative risk associated with reconstructive failure favored autologous abdominal tissue (relative risk, 0.14; 95 percent CI, 0.06 to 0.32; I = 0 percent). Surgical-site infection was significantly lower in autologous abdominal tissue reconstruction compared with tissue expander/implant (relative risk, 0.37; 95 percent CI, 0.25 to 0.55; I = 0 percent), although skin or flap necrosis was higher in autologous abdominal tissue reconstruction compared with tissue expander/implant (relative risk, 2.79; 95 percent CI, 1.87 to 4.17). Studies were of low to moderate quality according to the Newcastle-Ottawa scale. CONCLUSIONS: This study suggests that tissue expander/implant reconstruction has a higher risk of reconstructive failure and surgical-site infection compared with autologous abdominal tissue reconstruction. With the lack of long-term safety studies on different approaches to breast reconstruction, additional long-term comparative studies are needed to support evidence-based decision-making. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Harmonization of reimbursement and regulatory approval processes: a systematic review of international experiences.

A considerable degree of overlap exists between reimbursement and regulatory approval of health technologies, and harmonization of certain aspects is both possible and feasible. Various models to harmonization have been suggested in which a number of practical attempts have been drawn from. Based on a review of the literature, approaches can be categorized into those focused on reducing uncertainty and developing economies of scale in the evidentiary requirements; and/or aligning timeframes and logistical aspects of the review process. These strategies can further be classified based on the expected level of structural and organizational change required to implement them into the existing processes. Passive processes require less modification, whereas active processes are associated with greater restructuring. Attempts so far at harmonization have raised numerous legal and practical issues and these must be considered when introducing a more harmonized framework into the existing regulatory and reimbursement arrangements.

Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials.

BACKGROUND: The extent to which individual statins vary in terms of clinical outcomes across all populations, in addition to secondary and primary prevention has not been studied extensively in meta-analyses. METHODS: We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials. Systematic review registration: PROSPERO 2011:CRD42011001470. RESULTS: There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. No trial directly compared all six statins to each other. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.82-0.92) and major coronary events (OR 0.69, 95% CI 0.64-0.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.48-0.94) and fluvastatin (OR 0.59, 95% CI 0.36-0.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75-0.90) and major coronary events (OR 0.69, 95% CI 0.62-0.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.43-0.99) and simvastatin (OR 0.68, 95% CI 0.38-0.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.83-0.99) and major coronary events (OR 0.69, 95% CI 0.61-0.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected. CONCLUSIONS: Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol-reducing effects. The observed differences between statins should be investigated in future prospective studies.

Discovery of a novel class of aldol-derived 1,2,3-triazoles: potent and selective inhibitors of human cytochrome P450 19A1 (aromatase).

The discovery of a novel five-component 1,2,3-triazole-containing pharmacophore that exhibits potent and selective inhibition of aromatase (CYP 450 19A1) is described. All compounds are derived from an initial aldol reaction of a phenylacetate derivative with an aromatic aldehyde. Structure-activity data generated from both syn- and anti-aldol adducts provides initial insights into the requirements for both potency and selectivity.

Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole.

Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.