Would treatment decisions about secondary prevention of CVD based on estimated lifetime benefit rather than 10-year risk reduction be cost-effective?

OBJECTIVE: To test the hypothesis that treatment decisions (treatment with a PCSK9-mAb versus no treatment) are both more effective and more cost-effective when based on estimated lifetime benefit than when based on estimated risk reduction over 10 years. METHODS: A microsimulation model was constructed for 10,000 patients with stable cardiovascular disease (CVD). Costs and quality-adjusted life years (QALYs) due to recurrent cardiovascular events and (non)vascular death were estimated for lifetime benefit-based compared to 10-year risk-based treatment, with PCSK9 inhibition as an illustration example. Lifetime benefit in months gained and 10-year absolute risk reduction were estimated using the SMART-REACH model, including an individualized treatment effect of PCSK9 inhibitors based on baseline low-density lipoprotein cholesterol. For the different numbers of patients treated (i.e. the 5%, 10%, and 20% of patients with the highest estimated benefit of both strategies), cost-effectiveness was assessed using the incremental cost-effectiveness ratio (ICER), indicating additional costs per QALY gain. RESULTS: Lifetime benefit-based treatment of 5%, 10%, and 20% of patients with the highest estimated benefit resulted in an ICER of €36,440/QALY, €39,650/QALY, or €41,426/QALY. Ten-year risk-based treatment decisions of 5%, 10%, and 20% of patients with the highest estimated risk reduction resulted in an ICER of €48,187/QALY, €53,368/QALY, or €52,390/QALY. CONCLUSION: Treatment decisions (treatment with a PCSK9-mAb versus no treatment) are both more effective and more cost-effective when based on estimated lifetime benefit than when based on estimated risk reduction over 10 years.

Radiosurgical, neurosurgical, or no intervention for cerebral cavernous malformations: A decision analysis.

INTRODUCTION: We aimed to evaluate the preferred treatment strategy for patients with symptomatic cerebral cavernous malformations (CCM). METHODS: In a decision model, we compared neurosurgical, radiosurgical, and conservative management. A literature review yielded the risks and outcomes of interventions, intracerebral hemorrhage (ICH), and seizures. Patients with CCM rated their quality of life to determine utilities. We estimated the expected number of quality-adjusted life years (QALYs) and the ICH recurrence risk over five years, according to mode of presentation and CCM location (brainstem vs. other). We performed analyses with a time horizon of five years. RESULTS: Using the best available data, the expected number of QALYs for brainstem CCM presenting with ICH or focal neurological deficit was 2.84 (95% confidence interval [CI]: 2.54-3.08) for conservative, 3.01 (95% CI: 2.86-3.16) for neurosurgical, and 3.03 (95% CI: 2.88-3.18) for radiosurgical intervention; those for non-brainstem CCM presenting with ICH or focal neurological deficit were 3.08 (95% CI: 2.85-3.31) for conservative, 3.21 (95% CI: 3.01-3.36) for neurosurgical, and 3.19 (95% CI: 2.98-3.37) for radiosurgical intervention. For CCM presenting with epilepsy, QALYs were 3.09 (95% CI: 3.03-3.16) for conservative, 3.33 (95% CI: 3.31-3.34) for neurosurgical, and 3.27 (95% CI: 3.24-3.30) for radiosurgical intervention. DISCUSSION AND CONCLUSION: For the initial five years after presentation, our study provides Class III evidence that for CCM presenting with ICH or focal neurological deficit conservative management is the first option, and for CCM presenting with epilepsy CCM intervention should be considered. More comparative studies with long-term follow-up are needed.

Outcome Assessment by Central Adjudicators Versus Site Investigators in Stroke Trials: A Systematic Review and Meta-Analysis.

Background and Purpose- In randomized stroke trials, central adjudication of a trial's primary outcome is regularly implemented. However, recent evidence questions the importance of central adjudication in randomized trials. The aim of this review was to compare outcomes assessed by central adjudicators with outcomes assessed by site investigators. Methods- We included randomized stroke trials where the primary outcome had undergone an assessment by site investigators and central adjudicators. We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, and Google Scholar for eligible studies. We extracted information about the adjudication process as well as the treatment effect for the primary outcome, assessed both by central adjudicators and by site investigators. We calculated the ratio of these treatment effects so that a ratio of these treatment effects >1 indicated that central adjudication resulted in a more beneficial treatment effect than assessment by the site investigator. A random-effects meta-analysis model was fitted to estimate a pooled effect. Results- Fifteen trials, comprising 69 560 participants, were included. The primary outcomes included were stroke (8/15, 53%), a composite event including stroke (6/15, 40%) and functional outcome after stroke measured on the modified Rankin Scale (1/15, 7%). The majority of site investigators were blind to treatment allocation (9/15, 60%). On average, there was no difference in treatment effect estimates based on data from central adjudicators and site investigators (pooled ratio of these treatment effects=1.02; 95% CI, [0.95-1.09]). Conclusions- We found no evidence that central adjudication of the primary outcome in stroke trials had any impact on trial conclusions. This suggests that potential advantages of central adjudication may not outweigh cost and time disadvantages in stroke studies if the primary purpose of adjudication is to ensure validity of trial findings.

Cost-effectiveness of PCSK9 inhibition in addition to standard lipid-lowering therapy in patients at high risk for vascular disease.

BACKGROUND: As proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibodies are entering the market, we assessed the cost-effectiveness of PCSK9 inhibition added to standard lipid-lowering therapy in patient groups at high risk for major adverse cardiovascular events (MACE). METHODS: A lifetime Markov Model was designed to estimate healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) for PCSK9 inhibition added to standard therapy in patients with Familial Hypercholesterolemia (FH), patients with vascular disease at high MACE recurrence risk, and patients with vascular disease with diabetes mellitus. The balance between costs and health outcomes was established for a broad range of potential relative risk reductions and drug costs. RESULTS: The expected QALY gain per patient and ICER in the main scenario were 1.4 QALYs for €78,485/QALY gained in patients with FH, 0.22 QALYs for €176,735/QALY gained in those with vascular disease and a predicted risk of MACE ≥30% in 10years, and 0.22 QALYs for €295,543/QALY gained in those with vascular disease and diabetes. Results were sensitive to assumptions on PCSK9 inhibitor treatment efficacy, and vascular event risks. CONCLUSION: The costs and effects of PCSK9 inhibition added to standard lipid-lowering treatment in patient groups at high risk for MACE can be estimated and adapted to a specific clinical setting. PCSK9 inhibition could be cost-effective in patients with FH. In patients with vascular disease PCSK9 inhibition is less cost-effective, however, a price development may change clinical practice. This model may aid treatment and reimbursement decisions regarding PCSK9 inhibitors.

Cost-Effectiveness of Intensifying Lipid-Lowering Therapy With Statins Based on Individual Absolute Benefit in Coronary Artery Disease Patients.

BACKGROUND: A validated prediction model estimates the absolute benefit of intensive versus standard lipid-lowering therapy (LLT) with statins on next major cardiovascular events for individual patients with coronary artery disease. We aimed to assess whether targeting intensive LLT therapy to coronary artery disease patients with the highest predicted absolute benefit is cost-effective compared to treating all with standard or all with intensive LLT. METHODS AND RESULTS: A lifetime Markov model was constructed for coronary artery disease patients (n=10 000) with mean age 61 years. Number of major cardiovascular events, (non) vascular death, costs, and quality-adjusted life years (QALYs) were estimated for the following strategies: (1) standard LLT for all (reference strategy); (2) intensive LLT for those with 5-year absolute major cardiovascular events risk reduction (ARR) ≥3%, ≥2.3%, or ≥1.5% (corresponding to ≥20%, ≥15%, or ≥10% 5-year major cardiovascular events risk); and (3) intensive LLT for all. With intensive LLT for those with ≥3% 5-year ARR (13% of patients), 380 QALYs were gained for €2423/QALY. Using a threshold of ≥2.3% ARR (26% of patients), 630 QALYs were gained for €5653/QALY. Using a threshold of ≥1.5% ARR (56% of patients), 1020 QALYs were gained for €10 960/QALY. By treating all intensively, 1410 QALYs were gained (0.14 QALY per patient) for €17 223/QALY. With benefit-based treatment, 0.16 to 0.17 QALY was gained per treated patient. CONCLUSIONS: Intensive LLT with statins for all coronary artery disease patients results in the highest overall QALY gain against acceptable costs. However, the number of QALYs gained with intensive LLT by statins in individual patients can be increased with selective benefit-based treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00327691 and NCT00159835.

Cost-effectiveness of surgical decompression for space-occupying hemispheric infarction.

BACKGROUND AND PURPOSE: Surgical decompression reduces mortality and increases the probability of a favorable functional outcome after space-occupying hemispheric infarction. Its cost-effectiveness is uncertain. METHODS: We assessed clinical outcomes, costs, and cost-effectiveness for the first 3 years in patients who were randomized to surgical decompression or best medical treatment within 48 hours after symptom onset in the Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial (HAMLET). Data on medical consumption were derived from case record files, hospital charts, and general practitioners. We calculated costs per quality-adjusted life year (QALY). Uncertainty was assessed with bootstrapping. A Markov model was constructed to estimate costs and health outcomes after 3 years. RESULTS: Of 39 patients enrolled within 48 hours, 21 were randomized to surgical decompression. After 3 years, 5 surgical (24%) and 14 medical patients (78%) had died. In the first 3 years after enrollment, operated patients had more QALYs than medically treated patients (mean difference, 1.0 QALY [95% confidence interval, 0.6-1.4]), but at higher costs (mean difference, €127,000 [95% confidence interval, 73,100-181,000]), indicating incremental costs of €127,000 per QALY gained. Ninety-eight percent of incremental cost-effectiveness ratios replicated by bootstrapping were >€80,000 per QALY gained. Markov modeling suggested costs of ≈€60,000 per QALY gained for a patient's lifetime. CONCLUSIONS: Surgical decompression for space-occupying infarction results in an increase in QALYs, but at very high costs. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN94237756.

Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis.

BACKGROUND AND PURPOSE: In the discussion on the cost-effectiveness of screening, precise estimates of severe asymptomatic carotid stenosis are vital. Accordingly, we assessed the prevalence of moderate and severe asymptomatic carotid stenosis by age and sex using pooled cohort data. METHODS: We performed an individual participant data meta-analysis (23 706 participants) of 4 population-based studies (Malmö Diet and Cancer Study, Tromsø, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study). Outcomes of interest were asymptomatic moderate (> or =50%) and severe carotid stenosis (> or =70%). RESULTS: Prevalence of moderate asymptomatic carotid stenosis ranged from 0.2% (95% CI, 0.0% to 0.4%) in men aged <50 years to 7.5% (5.2% to 10.5%) in men aged > or =80 years. For women, this prevalence increased from 0% (0% to 0.2%) to 5.0% (3.1% to 7.5%). Prevalence of severe asymptomatic carotid stenosis ranged from 0.1% (0.0% to 0.3%) in men aged <50 years to 3.1% (1.7% to 5.3%) in men aged > or =80. For women, this prevalence increased from 0% (0.0% to 0.2%) to 0.9% (0.3% to 2.4%). CONCLUSIONS: The prevalence of severe asymptomatic carotid stenosis in the general population ranges from 0% to 3.1%, which is useful information in the discussion on the cost-effectiveness of screening.

Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties.

BACKGROUND: Previous modeling studies on treatment of unruptured intracranial aneurysms largely disregarded detailed data on treatment risks and omitted several factors that could influence cost-effectiveness. We performed a cost-effectiveness analysis of surgical and endovascular treatment of unruptured aneurysms for different rupture rates and life expectancies, and assessed the influence of excess mortality risks in these persons, de novo development of aneurysms, and utility of awareness of having an untreated aneurysm, and also identified important factors for which data are lacking. METHODS: We used a Markov model to compare surgical, endovascular, and no treatment of unruptured intracranial aneurysms. Inputs for the model were taken mainly from meta-analyses. Direct medical costs were derived from Dutch cost studies and expressed in 2005 Euros. We performed sensitivity analyses to evaluate model robustness. RESULTS: For 50-year-old patients, treatment of unruptured aneurysms is cost-effective for all rupture rate scenarios between 0.3% and 3.5%/year. In 70-year-old patients, treatment is not cost-effective in men with rupture rates < or =1%/year and women with rupture rates < or =0.5%/year. With lower utility of awareness of an untreated aneurysm, the cost-effectiveness of treatment strongly increased. The effect of excess mortality risks on the incremental cost-effectiveness ratios was modest. The risk of formation of new aneurysms had no relevant impact. CONCLUSIONS: Patients' life expectancy, risk of rupture, and utility of awareness of an untreated aneurysm mainly define cost-effectiveness. However, important uncertainties remain on the rupture risk according to size and location of the aneurysm and on the utility of awareness of untreated aneurysm. More data on these factors are needed to define and individualize cost-effectiveness analyses.

Is centralization of ovarian cancer care warranted? A cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of tertiary referral care for ovarian cancer patients in the Netherlands. METHODS: We collected clinical and registry data on 1077 newly diagnosed ovarian cancer patients treated from 1996-2003 in a random sample of Dutch hospitals. Decision modelling was used to compare the cost-effectiveness of treatment in general hospitals, semi-specialized hospitals, and tertiary care centers. The actual direct medical costs of ovarian cancer treatment were evaluated. Long-term outcomes in terms of costs, quality-adjusted life-years (QALYs), and incremental costs per QALY gained were estimated. To assess uncertainty, multivariable sensitivity analyses and scenario analyses were performed. RESULTS: Treatment of ovarian cancer patients in semi-specialized hospitals costs on average euro882 more than in general hospitals (95% confidence interval -720 to 2462) and yields 0.12 additional QALYs (95% CI 0.02 to 0.22), resulting in an incremental cost-effectiveness ratio (ICER) of euro7135. Patients treated in tertiary care centers incurred again higher costs (euro10,591, 95% CI 8757 to 12,480) and also higher QALYs (0.10, 95% CI 0 to 0.21), resulting in an ICER of euro102,642 compared to semi-specialized hospitals. If the optimal debulking rate in tertiary care centers would increase to 70%, costs could drop below euro30,000 per QALY. CONCLUSION: Current treatment of ovarian cancer patients in semi-specialized hospital settings is a cost-effective strategy, while treatment in tertiary care centers becomes only cost-effective when better surgical results would be achieved.

Cost-effectiveness of aspirin treatment in the primary prevention of cardiovascular disease events in subgroups based on age, gender, and varying cardiovascular risk.

BACKGROUND: Aspirin is effective for the primary prevention of cardiovascular events, but it remains unclear for which subgroups of individuals aspirin is beneficial. We assessed the cost-effectiveness of aspirin separately for men and women of different ages with various levels of cardiovascular disease risk. METHODS AND RESULTS: A Markov model was developed to predict the number of cardiovascular events prevented, quality-adjusted life-years, and costs over a 10-year period. Event rates were taken from Dutch population data, and the relative effectiveness of aspirin was taken from a gender-specific meta-analysis. Sensitivity analyses and Monte Carlo simulations were conducted to evaluate the robustness of the results. In 55-year-old persons, aspirin prevented myocardial infarctions in men (127 events per 100,000 person-years) and ischemic strokes in women (17 events per 100,000 person-years). Aspirin implies a net investment and a quality-adjusted life-year gain in men 55 years of age; the incremental cost-effectiveness ratio was 111,949 euros per quality-adjusted life-year (1 euro=$1.27 as of June 2007). Aspirin was cost-effective for 55- and 65-year-old men with moderate cardiovascular risk and men 75 years of age (10-year cardiovascular disease risk >10%). Conversely, aspirin was beneficial for women 65 years of age with high cardiovascular risk and women 75 years of age with moderate cardiovascular risk (10-year cardiovascular disease risk >15%). Results were sensitive to drug treatment costs, effectiveness of aspirin treatment, and utility of taking aspirin. CONCLUSIONS: Aspirin treatment for primary prevention is cost-effective for men with a 10-year cardiovascular disease risk of >10% and for women with a risk of >15%. This occurs much later in life for women than men. Therefore, opportunities for the primary prevention of aspirin seem limited in women, and a differentiated preventive strategy seems warranted.

Claims in advertisements for antihypertensive drugs in a Dutch medical journal.

BACKGROUND: Advertising claims must not conflict with the official summary of product characteristics. After a drug has been approved, new clinical evidence may become available. AIMS: To determine how the pharmaceutical industry deals with evolving clinical evidence in advertising claims for antihypertensive drugs, and whether such pharmaceutical promotion is up to standard. METHODS: We examined all advertisements from the Dutch Journal of Medicine published between 1996 and 2004. We judged whether claims were in agreement with the information available from the summary of product characteristics or evidence from cited clinical trials. Subsequently, we reviewed whether these claims had been assessed by the Code of Practice authority. RESULTS: We identified 50 unique advertisements with, in total, 492 appearances for 16 antihypertensive drugs. Claims of blood pressure lowering and convenient use were all judged to be sufficiently substantiated. For calcium-channel blockers, insufficiently supported safety claims had been made in three cases (41 appearances). Claims suggesting effects on long-term outcomes started in 1999 for angiotensin II receptor blockers, and were made during the whole period for several other antihypertensive drugs. In 16 cases (135 appearances), such claims were not supported by the available information. Some claims were premature, others transferred results from a specific patient group to the general population of hypertensive patients. Only two cases were reviewed by the Code of Practice authority. CONCLUSIONS: Overall, 35% of the advertisements for antihypertensive drugs contained suggestive claims not supported by the offered evidence. The current system of self-regulation cannot ensure that pharmaceutical promotion is always accurate, balanced and evidence-based.