Pieter A. de Graeff

Comparison between New York Heart Association Classification and peak oxygen consumption in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy

To compare the value of the New York Heart Association (NYHA) classification and measurement of peak oxygen consumption (VO2) in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure (CHF), 94 patients with clinically stable NYHA class II and III CHF were prospectively studied. In all patients, left ventricular ejection fraction was less than or equal to 40% (mean 22 +/- 9); 49 patients were in NYHA class II, and 45 were in NYHA class III. Mean peak VO2 was 17 +/- 5 ml/min/kg. During a follow-up period of 23 +/- 11 months, 21 patients died. The 1-, 2- and 3-year cumulative survival rates for the 94 patients were 88, 79 and 69%, respectively. Functional status, as assessed both by peak VO2 and NYHA classification, and left ventricular ejection fraction were significantly worse in the group of nonsurvivors. The most powerful independent predictor of mortality was peak VO2. Although mean peak VO2 was significantly higher in NYHA class II than in NYHA class III (20 +/- 4 vs 13 +/- 3 ml/min/kg, p less than 0.0001), categorization into subgroups on the basis of the attained peak VO2 revealed a marked discrepancy with the NYHA classification. Nevertheless, the survival curves of patients subdivided at a peak VO2 of 16 ml/min/kg showed a strong resemblance with survival curves of both NYHA classes.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy.

To study the prognostic value of heart rate (HR) variability in heart failure, risk assessment of clinical and HR variability parameters was performed in 159 patients with stable chronic heart failure. Besides low left ventricular ejection fraction, HR variability parameters reflecting impaired vagal tone (SDNN, pNN50) were found to predict an increased risk of cardiac death and death due to progressive pump failure.

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.

Long-term effects of amlodipine and lisinopril on left ventricular mass and diastolic function in elderly, previously untreated hypertensive patients : the ELVERA trial

Objective To compare the effects of a calcium antagonist (amlodipine) and an angiotensin converting enzyme inhibitor (lisinopril) on left ventricular mass and diastolic function in elderly, previously untreated hypertensives. Design A double-blind randomized parallel group trial. Effects of amlodipine and lisinopril on left ventricular mass and diastolic function (E/A Ratio) (The ELVERA trial). Setting Rural northern Netherlands: population screening new diagnosed hypertensive subjects. Patients The study population comprised 166 newly diagnosed hypertensive (aged 60–75) with diastolic blood pressure between 95–115 mmHg and/or systolic blood pressure between 160–220 mmHg. Intervention Patients were randomly allocated to receive 5–10 mg amlodipine or 10–20 mg lisinopril for 2 years. Main outcome measures Prior and after 1 and 2 years of treatment left ventricular mass, indexed by body surface (LVMI) was estimated by 2-D mode echocardiography according to Devereux with use of Penn convention. Early to atrial filling ratio (E/A) was assessed by transmitral flow. Change from baseline of LVMI and E/A ratio was evaluated by repeated measurement analysis of the treatment effect in an intention-to-treat analysis. Results Both amlodipine and lisinopril led to equivalent reduction in systolic and diastolic blood pressure. At the end of the study the amlodipine group led to LVMI decrease by 21.8 g/m ⩽ [95% confidence interval (CI), 18.3–25.3] and E/A ratio increased by 0.08 (95% CI, 0.05–0.11). In the lisinopril group LVMI decreased by 22.4 g/m ⩽ (95%, CI, 19.0–25.8) and E/A ratio increased by 0.07 (95% CI, 0.04–0.10). No statistically significant differences were found in changes in LVMI and E/A ratio between amlodipine and lisinopril. Conclusion A long-term study, the ELVERA trial proves that amlodipine and lisinopril reduce left ventricular mass and improve diastolic function to a similar extent in elderly newly diagnosed hypertensive patients.

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.

Myocardial Infarction Enhances Progressive Renal Damage in an Experimental Model for Cardio-Renal Interaction

Studied were the effects of myocardial infarction (MI) on mild renal function loss in unilateral nephrectomized (UnX) rats. UnX was performed, followed after 1 wk by a variable MI (UnX + MI; n = 24). Rats with only UnX (n = 15) or MI (n = 9) and double sham animals (CON, n = 15) served as controls. Renal outcome was measured by proteinuria and plasma creatinine. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function and systolic BP were measured. A division into small and large infarcts after UnX was made a priori, resulting in two groups, one with a mild MI (<20%; n = 15) and one with a moderate MI (>20%; n = 9). Mild proteinuria up to 55.5 mg/d was observed in the UnX + mild MI group, whereas proteinuria rose significantly higher to 124.5 mg/d in the UnX + moderate MI group. Incidence of FGS was significantly increased in both UnX + MI groups compared with all other groups. The average MI size was 18%, 17%, and 25% in the MI, UnX + mild MI, and UnX + moderate MI group, respectively. LVP in both UnX + MI groups was correlated with proteinuria, indicative of a cardio-renal interaction. Clinically, these data imply that more patients are at risk for cardiovascular events and that after such an event, their chance of more renal function loss increases. Finding the underlying mechanism will enable improved protection for both kidneys and heart.

CAPTOPRIL REDUCES PURINE LOSS AND REPERFUSION ARRHYTHMIAS IN THE RAT-HEART AFTER CORONARY-ARTERY OCCLUSION

Captopril was perfused through isolated rat hearts; its effects after local ischemia and reperfusion were assessed. Upon reperfusion all untreated (10 out of 10) but only 4 (out of 10) captopril-treated (80 micrograms/ml) hearts fibrillated (P less than 0.02). Purine overflow increased upon reperfusion but was reduced by captopril (597 +/- 62 and 333 +/- 41 nmol/min gdwt respectively; P less than 0.05). The pressure-rate index and the apex displacement were severely impaired after 30 min of reperfusion (32 +/- 16 and 10 +/- 5% respectively of initial values) but captopril reduced the injury of mechanical function (60 +/- 8; P less than 0.05 and 61 +/- 11; P less than 0.05 respectively). These results show that captopril reduces ventricular fibrillation and the loss of high energy phosphate nucleotides and thereby partly maintains mechanical function impaired by ischemia and reperfusion.

A Decade of Safety-Related Regulatory Action in the Netherlands A Retrospective Analysis of Direct Healthcare Professional Communications from 1999 to 2009

Background: As pre-approval trials are inherently limited in assessing the complete benefit-risk profile of a new drug, serious safety issues may emerge once a drug gains widespread use after approval. Regulators face the dilemma of balancing timely market access with the need for complete data on risks. This challenge has led to a life-cycle approach but, so far, few data are available on post-approval safety issues requiring regulatory action.Objective: The aim of this study is to determine the frequency, timing and nature of safety issues that necessitated safety-related regulatory action in the form of a Direct Healthcare Professional Communication (DHPC) issued by pharmaceutical companies in collaboration with the Dutch Medicines Evaluation Board during the past decade.Methods: All DHPCs issued in the Netherlands from 1 January 1999 to 1 January 2009 were retrospectively collected from the national regulatory authorities. Elapsed time between the approval date and the issue of the DHPC was determined. Characteristics of the action including the nature of the safety issue (according to Medical Dictionary for Regulatory Activities [MedDRA®] terminology), type of drug and procedural aspects of the regulatory action taken were reviewed. DHPC characteristics were tabulated and explorative non-parametric tests were performed to study the effect of safety issue, drug class, drug type, orphan drug and first-in-class status on elapsed time from approval to the DHPC.Results: 157 DHPCs were issued concerning 112 different active substances, approximately 9% (112/1200) of active substances available in the Netherlands in 2007. The number of DHPCs issued increased by 2.1 (95% CI 1.2, 3.1; p< 0.001) DHPCs per year over the past decade, reaching a total of 25 in 2008. The median time between approval and DHPC was 5.3 years (range 0.13-48 years). No significant trend in elapsed time to DHPC was observed in relation to the studied years (p = 0.06). One-third of all DHPCs were issued in the first 3 years after approval, but 27% (n=43/157) of the DHPCs were issued 10 or more years after approval. Timing of DHPCs differed depending on safety issue, drug class, drug type and orphan drug status. DHPCs mostly concerned adverse events in the system organ class of ‘cardiac disorders’ (15%), ‘injury, poisoning and procedural complications’ (13%) and ‘general disorders and administration site conditions’ (10%). In ten cases the drug was eventually withdrawn. Withdrawal occurred a median duration of 2.4 years after registration (range of 1.5–48 years) and was most frequently due to cardiac disorders (including QT interval prolongation; four occasions) and hepatobiliary disorders (two occasions).Conclusions: In the past decade, the number of DHPCs has increased over time. This is likely caused by a multitude of factors: increased risk awareness by the public, media, regulators and other stakeholders; the type of drugs approved, such as orphan drugs and biologicals; and the regulatory process, including conditional approvals. The number of DHPCs may in the future increase further with the possibility of screening large epidemiological databases proactively for adverse drug events. Nine percent of all marketed drugs required a safety-related action. Regulatory action is taken shortly (<3 years) after market approval nearly as often as after intermediate (3–10 years) and long-term (>10 years) market exposure. These findings underline the need for risk management during the whole life cycle of a drug.

Value of digoxin in heart failure and sinus rhythm: New features of an old drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.