Background
Concerns for hyperkalaemia limit the use of mineralocorticoid receptor antagonists (MRAs). The frequency of MRA‐associated hyperkalaemia in real‐world settings and the extent of subsequent ...MRA discontinuation are poorly quantified.
Methods and results
Observational study including all Stockholm citizens initiating MRA therapy during 2007–2010. Hyperkalaemias were identified from all potassium (K+) measurements in healthcare. MRA treatment lengths and dosages were obtained from complete collection of pharmacy dispensations. We assessed the 1‐year incidence and clinical hyperkalaemia predictors, and quantified drug prescription changes after an episode of hyperkalaemia. Overall, 13 726 new users of MRA were included, with median age of 73 years, 53% women and median plasma K+ of 3.9 mmol/L. Within a year, 18.5% experienced at least one detected hyperkalaemia (K+ > 5.0 mmol/L), the majority within the first 3 months of therapy. As a comparison, hyperkalaemia was detected in 6.4% of propensity‐matched new beta‐blocker users. Chronic kidney disease (CKD), older age, male sex, heart failure, peripheral vascular disease, diabetes and concomitant use of angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, beta‐blockers and diuretics were associated with increased hyperkalaemia risk. After hyperkalaemia, 47% discontinued MRA and only 10% reduced the prescribed dose. Discontinuation rates were higher after moderate/severe (K+ > 5.5 mmol/L) and early in therapy (<3 months from initiation) hyperkalaemias. CKD participants carried the highest risk of MRA discontinuation in adjusted analyses. When MRA was discontinued, most patients (76%) were not reintroduced to therapy during the subsequent year.
Conclusion
Among real‐world adults initiating MRA therapy, hyperkalaemia was very common and frequently followed by therapy interruption, especially among participants with CKD.
Systolic pressure is all that matters Williams, Bryan, Prof; Lindholm, Lars H, MD; Sever, Peter, FRCP
The Lancet (British edition),
2008-Jun-28, Letnik:
371, Številka:
9631
Journal Article
Recenzirano
Systolic hypertension is much more common than diastolic hypertension, and systolic blood pressure contributes more of the huge global disease burden attributable to hypertension than does diastolic ...pressure.1-3 However, there has undoubtedly been confusion about the relative merits of targeting systolic versus diastolic blood pressure, which has led to poor recognition in the wider medical community of the importance of systolic pressure.4 We propose a simplified view of hypertension for most affected patients-ie, those aged over 50 years-whereby the thresholds for the diagnosis and treatment of hypertension can be expressed in one dimension: systolic pressure. ... targeting diastolic pressure leaves most patients with uncontrolled systolic pressure.\n On the basis of thresholds for intervention used for trials of blood pressure treatment, most national and international guidelines advocate a target for systolic pressure treatment of below 140 mm Hg, with an even lower therapeutic goal of below 130 mm Hg for patients with diabetes and those at increased cardiovascular risk for other reasons.20-21 These therapeutic targets for systolic pressure are a reasonable consensus based on an assessment of the available evidence.
Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A ...antagonist, darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov , number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0·0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events. Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
Cardiovascular disease (CVD) is the leading cause of the growing global disease burden due to non-communicable diseases. For successful prevention and control of CVD, strategies that focus on ...individuals need to complement population-wide strategies. Strategies that focus on individuals are cost effective only when targeted at high-risk groups. Risk prediction tools that easily and accurately predict an individual's absolute risk of CVD are key to targeting limited resources at high-risk individuals who are likely to benefit the most. Health systems in low-income countries do not have the basic infrastructure facilities to support resource-intensive risk prediction tools, particularly in primary healthcare. The WHO/ISH charts presented here, enable the prediction of future risk of heart attacks and strokes in people living in low and middle income countries, for the first time. Furthermore, since the charts use simple variables they can be applied even in low resource settings. Thus the WHO/ISH risk predication charts and the accompanying guideline will improve the effectiveness of cardiovascular risk management even in settings which do not have sophisticated technology.
Results of randomized controlled trials are consistent in showing reduced rates of stroke, heart failure and cardiovascular events in very old patients treated with antihypertensive drugs. However, ...inconsistencies exist with regard to the effect of these drugs on total mortality.
We performed a meta-analysis of available data on hypertensive patients 80 years and older by selecting total mortality as the main outcome. Secondary outcomes were coronary events, stroke, cardiovascular events, heart failure and cause-specific mortality. The common relative risk (RR) of active treatment versus placebo or no treatment was assessed using a random-effect model. Linear meta-regression was performed to explore the relationship between intensity of antihypertensive therapy and blood pressure (BP) reduction and the log-transformed value of total mortality odds ratios (ORs).
The overall RR for total mortality was 1.06 (95% confidence interval 0.89-1.25), with significant heterogeneity between hypertension in the very elderly trial (HYVET) and the other trials. This heterogeneity was not explained by differences in the follow-up duration between trials. The meta-regression suggested that a reduction in mortality was achieved in trials with the least BP reductions and the lowest intensity of therapy. Antihypertensive therapy significantly reduced (P < 0.001) the risk of stroke (35%), cardiovascular events (27%) and heart failure (50%). Cause-specific mortality was not different between treated and untreated patients.
Treating hypertension in very old patients reduces stroke and heart failure with no effect on total mortality. The most reasonable strategy is the one associated with significant mortality reduction; thiazides as first-line drugs with a maximum of two drugs.
Aim
Half of heart failure (HF) patients have chronic kidney disease (CKD) complicating their pharmacological management. We evaluated physicians' and patients' patterns of use of evidence‐based ...medical therapies in HF across CKD stages.
Methods and results
We studied HF patients with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction enrolled in the Swedish Heart Failure Registry in 2009–2018. We investigated the likelihood of physicians to prescribe guideline‐recommended therapies to patients with CKD, and of patients to fill the prescriptions within 90 days of incident HF (initiating therapy), to adhere (proportion of days covered ≥80%) and persist (continued use) on these treatments during the first year of therapy. We identified 31 668 patients with HFrEF (median age 74 years, 46% CKD). The proportions receiving a prescription for angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor–neprilysin inhibitors (ACEi/ARB/ARNi) were 96%, 92%, 86%, and 68%, for estimated glomerular filtration rate (eGFR) ≥60, 45–59, 30–44, and <30 ml/min/1.73 m2, respectively; for beta‐blockers 94%, 93%, 92%, and 92%, for mineralocorticoid receptor antagonists (MRAs) 45%, 44%, 37%, 24%; and for triple therapy (combination of ACEi/ARB/ARNi + beta‐blockers + MRA) 38%, 35%, 28%, and 15%. Patients with CKD were less likely to initiate these medications, and less likely to adhere to and persist on ACEi/ARB/ARNi, MRA, and triple therapy. Among stoppers, CKD patients were less likely to restart these medications. Results were consistent after multivariable adjustment and in patients with HFmrEF (n = 15 114).
Conclusions
Patients with HF and CKD are less likely to be prescribed and to fill prescriptions for evidence‐based therapies, showing lower adherence and persistence, even at eGFR categories where these therapies are recommended and have shown efficacy in clinical trials.
Patients with heart failure and chronic kidney disease are less likely to receive and persist on guideline‐recommended medical therapies.
This study was designed to evaluate whether different antihypertensive treatment regimens with similar blood pressure reduction have different effects on new-onset atrial fibrillation (AF).
It is ...unknown whether angiotensin II receptor blockade is better than beta-blockade in preventing new-onset AF.
In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study 9,193 hypertensive patients and patients with electrocardiogram-documented left ventricular hypertrophy were randomized to once-daily losartan- or atenolol-based antihypertensive therapy. Electrocardiograms were Minnesota coded centrally, and 8,851 patients without AF by electrocardiogram or history, who were thus at risk of developing AF, were followed for 4.8 +/- 1.0 years.
New-onset AF occurred in 150 patients randomized to losartan versus 221 to atenolol (6.8 vs. 10.1 per 1,000 person-years; relative risk 0.67, 95% confidence interval CI 0.55 to 0.83, p < 0.001) despite similar blood pressure reduction. Patients receiving losartan tended to stay in sinus rhythm longer (1,809 +/- 225 vs. 1,709 +/- 254 days from baseline, p = 0.057) than those receiving atenolol. Moreover, patients with new-onset AF had two-, three- and fivefold increased rates, respectively, of cardiovascular events, stroke, and hospitalization for heart failure. There were fewer composite end points (n = 31 vs. 51, hazard ratio = 0.60, 95% CI 0.38 to 0.94, p = 0.03) and strokes (n = 19 vs. 38, hazard ratio = 0.49, 95% CI 0.29 to 0.86, p = 0.01) in patients who developed new-onset AF in the losartan compared to the atenolol treatment arm of the study. Furthermore, Cox regression analysis showed that losartan (21% risk reduction) and new-onset AF both independently predicted stroke even when adjusting for traditional risk factors.
Our novel finding is that new-onset AF and associated stroke were significantly reduced by losartan- compared to atenolol-based antihypertensive treatment with similar blood pressure reduction.
Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more ...resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist darusentan, placebo, or the central α-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for darusentan (-15±14 mm Hg) were greater than for guanfacine (-12±13 mm Hg; P<0.05) but not greater than placebo (-14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (-9±12 mm Hg) more than placebo (-2±12 mm Hg) or guanfacine (-4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo or guanfacine. We conclude that darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.
Epilepsy is one of the most common chronic neurological conditions. Today, close to 30 different medications to prevent epileptic seizures are in use; yet, far from all patients become seizure free ...upon medical treatment. Thus, there is a need for new pharmacological approaches including novel drug targets for the management of epilepsy. Despite the fact that a role for cAMP signaling in epileptogenesis and seizures was first suggested some four decades ago, none of the current medications target the cAMP signaling system. The reasons for this are probably many including limited knowledge of the underlying biology and pathology as well as difficulties in designing selective drugs for the different components of the cAMP signaling system. This review explores selected aspects of cAMP signaling in the context of epileptogenesis and seizures including cAMP response element binding (CREB)-mediated transcriptional regulation. We discuss the therapeutic potential of targeting cAMP signaling in epilepsy and point to an increased knowledge of the A-kinase anchoring protein-based signaling hubs as being of seminal importance for future drug discovery within the field. Further, in terms of targeting CREB, we argue that targeting upstream cAMP signals might be more fruitful than targeting CREB itself. Finally, we point to astrocytes as cellular targets in epilepsy since cAMP signals may regulate astrocytic K
+
clearance affecting neuronal excitability.
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