Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride:the PATHWAY-2 mechanisms substudies

Background: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. Methods: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25–50 mg, bisoprolol 5–10 mg, and doxazosin 4–8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10–20 mg once daily on clinic systolic blood pressure during an optional 6–12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008–007149–30, and ClinicalTrials.gov, number NCT02369081. Findings: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17–33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3–22·5), compared with a reduction of 18·3 mm Hg (16·2–20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95–4·08) on placebo to 4·50 (4·44–4·57) on amiloride (p<0·0001). Interpretation: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension

Cholesterol- and blood pressure-lowering drug use for secondary cardiovascular prevention in 2004 - 2013 Europe

Background: Suboptimal use of cardiovascular prevention medications has been reported. We report recent trends in secondary cardiovascular disease (CVD) prevention drug use in Europe. Design: Study of Health and Retirement in Europe (SHARE), a large longitudinal 2004-2013 cohort study in middle-aged and elderly Europeans. Methods: Cross-sectional and panel logistic regression models were used to study trends in cholesterol- and blood pressure (BP)-lowering drug use and effects of individual characteristics among participants with CVD in SHARE. Results: 21,371 SHARE participants reported cardiovascular disease and, at initial report, 40% and 60% of them used cholesterol- or BP-lowering drugs, respectively. Increasing cross-sectional time trends were observed for both medication classes (odds ratios [OR] of use in 2013 vs 2004, 1.6 [95%CI 1.4-1.7] and 1.5 [1.4-1.6], respectively). However, among individuals with multiple observations, the use of both classes declined over time (2013 vs 2004 OR 0.63 [0.51-0.77] and 0.68 [0.55-0.84]; both trend p<0.001), and with increasing duration since last cardiovascular event (OR 0.74 [0.60-0.91], trend p=0.01 and OR 0.82 [0.66-1.03], trend p=0.06, respectively for durations of 9 years or more versus less than one year). Among people with CVD, those obese, retired or with hypercholesterolemia, hypertension, worse self-perceived health, and, in the case of lipid-lowering medication, with diabetes, were more likely to use these medications. Conclusions: Despite moderately increasing cross-sectional time trends, the use of secondary CVD prevention drugs remains low in Europe with substantial discontinuation over time and with increasing duration from an acute cardiovascular event

Cholesterol-and blood-pressure-lowering drug use for secondary cardiovascular prevention in 2004-2013 Europe

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: DA received funding by a university research grant, awarded by the Hamburg Center for Health Economics, University of Hamburg, Germany. This paper uses data from SHARE Wave 1-5, as of 31 March 2015. The SHARE data collection has been primarily funded by the European Commission through the 5th Framework Programme (project QLK6-CT-2001-00360 in the thematic programme Quality of Life), through the 6th Framework Programme (projects SHARE-I3, RII-CT-2006-062193, COMPARE, CIT5- CT-2005-028857, and SHARELIFE, CIT4-CT-2006-028812) and through the 7th Framework Programme (SHARE-PREP, N° 211909, SHARE-LEAP, N° 227822 and SHARE M4, N° 261982). Additional funding from the US National Institute on Aging (U01 AG09740-13S2, P01 AG005842, P01 AG08291, P30 AG12815, R21 AG025169, Y1-AG-4553-01, IAG BSR06-11 and OGHA 04-064) and the German Ministry of Education and Research as well as from various national sources is gratefully acknowledged (www.share-project.org)

The economic impact of Marfan syndrome: a non-experimental, retrospective, population-based matched cohort study

BACKGROUND: Marfan syndrome is a rare disease of the connective tissues, affecting multiple organ systems. Elevated morbidity and mortality in these patients raises the issue of costs for sickness funds and society. To date, there has been no study analysing the costs of Marfan syndrome from a sickness fund and societal perspective. OBJECTIVE: To estimate excess health resource utilisation, direct (non-)medical and indirect costs attributable to Marfan syndrome from a healthcare payer and a societal perspective in Germany in 2008. METHODS: A retrospective matched cohort study design is applied, using claims data. For isolating the causal effect of Marfan syndrome on excess costs, a genetic matching algorithm was used to reduce differences in observable characteristics between Marfan syndrome patients and the control group. 892 patients diagnosed with Marfan syndrome (ICD-10 Q87.4) were matched from a pool of 26,645 control individuals. After matching, we compared health resource utilisation and costs. RESULTS: From the sickness fund perspective, an average Marfan syndrome patient generates excess annual costs of €2496 compared with a control individual. From the societal perspective, excess annual costs amount to €15,728. For the sickness fund, the strongest cost drivers are inpatient treatment and care by non-physicians. From the sickness fund perspective, the third (25–41 years) and first (0–16 years) age quartiles reveal the greatest surplus in total costs. Marfan syndrome patients have 39% more physician contacts, a 153% longer average length of hospital stay, 119% more inpatient stays, 33% more prescriptions, 236% more medical imaging and 20% higher average prescription costs than control individuals. Depending on the prevalence, the economic impact from the sickness fund perspective ranges between €24.0 million and €61.4 million, whereas the societal economic impact extends from €151.3 million to €386.9 million. CONCLUSIONS: Relative to its low frequency, Marfan syndrome requires high healthcare expenditure. Not only the high costs of Marfan syndrome but also its burden on patients’ lives call for more awareness from policy-makers, physicians and clinical researchers. Consequently, the diagnosis and treatment of Marfan syndrome should begin as soon as possible in order to prevent disease complications, early mortality and substantial healthcare expenditure