Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

Individual long-term albuminuria exposure during angiotensin receptor blocker therapy is the optimal predictor for renal outcome.

BACKGROUND: Albuminuria reduction due to angiotensin receptor blockers (ARBs) predicts subsequent renoprotection. Relating the initial albuminuria reduction to subsequent renoprotection assumes that the initial ARB-induced albuminuria reduction remains stable during follow-up. The aim of this study was to assess individual albuminuria fluctuations after the initial ARB response and to determine whether taking individual albuminuria fluctuations into account improves renal outcome prediction. METHODS: Patients with diabetes and nephropathy treated with losartan or irbesartan in the RENAAL and IDNT trials were included. Patients with >30% reduction in albuminuria 3 months after ARB initiation were stratified by the subsequent change in albuminuria until Month 12 in enhanced responders (>50% albuminuria reduction), sustained responders (between 20 and 50% reduction), and response escapers (<20% reduction). Predictive performance of the individual albuminuria exposure until Month 3 was compared with the exposure over the first 12 months using receiver operating characteristics (ROC) curves. RESULTS: Following ARB initiation, 388 (36.3%) patients showed an >30% reduction in albuminuria. Among these patients, the albuminuria level further decreased in 174 (44.8%), remained stable in 123 (31.7%), and increased in 91 (23.5%) patients. Similar albuminuria fluctuations were observed in patients with <30% albuminuria reduction. Renal risk prediction improved when using the albuminuria exposure during the first 12 months versus the initial Month 3 change [ROC difference: 0.78 (95% CI 0.75-0.82) versus 0.68 (0.64-0.72); P < 0.0001]. CONCLUSIONS: Following the initial response to ARBs, a large within-patient albuminuria variability is observed. Hence, incorporating multiple albuminuria measurements over time in risk algorithms may be more appropriate to monitor treatment effects and quantify renal risk.

Safety information on QT-interval prolongation: comparison of European Union and United States drug labeling.

Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approved (1st January 2006 to 1st June 2012) in the European Union (EU) and the United States (US), of which 66 mentioned the term 'QT' (two EU only, 28 US only, 36 both). The agreement between authorities about the message on QT prolongation (does not prolong, unclear, possibly prolongs, prolongs) was moderate (kappa 0.434). However, the agreement in expected clinical decisions based on the product labels was much higher (kappa 0.673). The US drug label tends to be more explicit, especially when it considers absence of QT effects.

Quality of drug label information on QT interval prolongation.

BACKGROUND: Information regarding QT-prolongation in the drug label may vary between products. This could lead to suboptimal risk minimization strategies. OBJECTIVE: To systematically assess the variation in the extent and content of information on QT prolongation in the summary of product characteristics (SPC) of recently approved medicinal products. METHODS: Drug labels of products centrally approved in Europe between 2006 and 2012 were screened. Of drugs including the term 'QT' in the SPC, the message on QT-prolongation ('no prolongation'/'unclear drug-QT association'/'possibly QT-prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. RESULTS: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16%, 'QT-prolongation': 18%). 62% contained advices to act with caution in patients with additional risk factors for QT-prolongation. Products that more likely to have QT-prolonging properties according to the SPC provided more information on QT-prolongation in the SPC ('no prolongation': 10% and for the category 'QT-prolongation': 100%). CONCLUSIONS: The extent and content of information on QT-prolongation varies considerably between SPCs, and in almost half of the drugs a clear message on QT-prolongation was lacking in the SPC.

Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.

Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy.

An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function.

Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interindividual difference, however, was noticed in the acute eGFR change. When patients were divided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.

Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials.

AIMS: The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of albuminuria. Since the individual blood pressure and albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes. METHODS AND RESULTS: The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94-0.99) and HR per decrement log albuminuria 0.87 (95% CI 0.76-0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg. CONCLUSION: The SBP and albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin-angiotensin-aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and albuminuria.