Robert J. Padley

Levosimendan vs. dobutamine: outcomes for acute heart failure patients on β‐blockers in SURVIVE†

Many chronic heart failure (CHF) patients take β‐blockers. When such patients are hospitalized for decompensation, it remains unclear how ongoing β‐blocker treatment will affect outcomes of acute inotrope therapy. We aimed to assess outcomes of SURVIVE patients who were on β‐blocker therapy before receiving a single intravenous infusion of levosimendan or dobutamine.

Beneficial association of β-blocker therapy on recovery from severe acute heart failure treatment: Data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial

Objectives:Beta-blocker therapy is recommended for most patients with chronic heart failure, although such therapy may be discontinued or reduced during hospitalizations. The aim is to determine whether &bgr;-blocker use at study entry and/or at discharge has an impact on 31- and 180-day survival. Design:Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support study was designed as a randomized, double-blind, active-controlled, multi-center study. Setting:Multinational. Patients:A total of 1,327 critically ill patients hospitalized with low-output heart failure in need of inotropic therapy. Intervention:Levosimendan versus dobutamine. Measurements:All-cause mortality at 31 and 180 days in patients who survived initial hospitalization with/without &bgr;-blocker use at entry and/or at discharge. Results:Patients on &bgr;-blockers at entry and at discharge had significantly lower 31-day (p < .0001) and 180-day (p < .0001) mortality compared to patients without &bgr;-blockers use at both time points. The association was robust when adjusted for age and co-morbidities (p = .006 at 31 days; p = .003 at 180 days). Conclusions:Those results strongly suggest, in severe acutely decompensated heart failure patients, admitted on &bgr;-blockers, to continue on them at discharge.

Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: The SUPREME Study

BACKGROUND Aggressive treatment of low-density lipoprotein cholesterol (LDL-C) fails to prevent most cardiovascular (CV) events. Concurrent treatment of LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) should be considered in patients with dyslipidemia. OBJECTIVE The efficacy and safety of a proprietary niacin extended-release and simvastatin (NER/S) combination were compared to atorvastatin monotherapy in a multicenter, Prospective, Randomized (3:2), Open-label, Blinded Endpoint (PROBE) study. METHODS Following ≥4 weeks without lipid-modifying therapies, 193 patients with dyslipidemia were treated with NER/S (n = 114; 1000/40 mg/day, weeks 1 to 4; 2000/40 mg/day weeks 5 to 12) or atorvastatin (n = 79; 40 mg/day, weeks 1 to 12). RESULTS Compared to atorvastatin, NER/S had a larger beneficial effect on HDL-C (primary end point: 30.1 ± 2.3% and 9.4 ± 2.6%, respectively; P <.001), TG (P = .02), and lipoprotein(a) (Lp[a]; P <.001), and similar effects on LDL-C and non-HDL-C. Two-thirds of patients treated with NER/S concurrently attained LDL-C (CV risk-adjusted goals), HDL-C (≥40 mg/dL), and TG (<150 mg/dL) targets, compared to one-third of patients treated with atorvastatin (P <.001). Flushing was the most common treatment-emergent adverse event (TEAE) (67.5% NER/S and 10.1% atorvastatin; P <.001). Seventy-five percent of flushing episodes were mild to moderate. More patients treated with NER/S discontinued due to TEAEs (21.1% and 3.8%; P <.001); the most common TEAE was flushing. CONCLUSION Compared to atorvastatin, NER/S provided superior improvements in HDL-C, TG, and Lp(a) and comparable improvements in non-HDL-C and LDL-C. Treatment with NER/S should be considered for patients with dyslipidemia requiring comprehensive lipid control.

Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy.

Background The purpose of this research was to compare the effects of niacin extended-release in combination with simvastatin (NER/S) versus atorvastatin monotherapy on high-density lipoprotein (HDL) particle number and size in patients with hyperlipidemia or dyslipidemia from the SUPREME study. Methods This was a post hoc analysis of patients (n = 137) who completed the SUPREME study and who had lipid particle number and size measurements at both baseline and at week 12 by nuclear magnetic resonance spectroscopy. Following ≥4 weeks without lipid-modifying therapy (washout period), the patients received NER/S 1000/40 mg/day for 4 weeks followed by NER/S 2000/40 mg/day for 8 weeks, or atorvastatin 40 mg/day for 12 weeks. Median percent changes in HDL particle number and size from baseline to week 12 were compared between the NER/S and atorvastatin treatment groups using the Wilcoxon rank-sum test. Distribution of HDL particle subclasses at week 12 was compared between the treatment groups using the Cochran–Mantel–Haenszel test. Results Treatment with NER/S resulted in a significantly greater percent reduction in small HDL particle number at week 12 compared with atorvastatin monotherapy (−1.8% versus 4.2%, P = 0.014), and a numerically greater percent increase in large HDL particle number (102.4% versus 39.2%, P = 0.078) compared with atorvastatin monotherapy. A significantly greater percent increase in HDL particle size from baseline at week 12 was observed with NER/S compared with atorvastatin (6.0% versus 1.3%, P < 0.001). NER/S treatment also resulted in a significant shift in HDL particle size from small and medium at baseline to large at week 12 (P < 0.0001). Conclusion Treatment with NER/S resulted in larger favorable changes in number and size of HDL particle subclasses compared with atorvastatin monotherapy, including a numerically greater increase in number of large HDL particles, and a significantly greater decrease in number of small HDL particles compared with atorvastatin monotherapy. In addition, NER/S treatment resulted in a significant change in HDL particle size distribution from small and medium to large.

Acetylsalicylic Acid Reduces Niacin Extended-Release-Induced Flushing in Patients with Dyslipidemia

BackgroundNiacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy.ObjectiveTo evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia.MethodsA randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (Clinical-Trials.gov identifier: NCT00626392). Patients (n=277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1.ResultsIn week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups.ConclusionThese data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use.

Flushing ASsessment Tool (FAST©) : Psychometric Properties of a New Measure Assessing Flushing Symptoms and Clinical Impact of Niacin Therapy

AbstractBackground and objective: A common adverse effect of niacin therapy is flushing, manifested by cutaneous warmth, redness, itching and/or tingling. The Flushing ASsessment Tool (FAST©) was developed to assess flushing symptoms and their impact on patients receiving niacin therapy. This study evaluated the reliability, validity and responsiveness of the FAST©. The minimal important difference (MID) of the FAST© was also examined. Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group 8-week study conducted to evaluate the psychometric characteristics of the FAST©. The instrument is administered daily using an electronic patient diary. The study was conducted at 41 clinical sites in the US. 276 patients with dyslipidaemia were randomized to treatment and were at least 18 years of age, with fasting laboratory values of low-density lipoprotein cholesterol (LDL-C) <250 mg/dL and one of the following: high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males or <50 mg/dL for females; or triglycerides (TG) ≥150 and ≤400 mg/dL; or LDL-C ≥70 mg/dL for patients with a history of coronary heart disease (CHD) or CHD risk equivalents, or ≥ 100 mg/dL for subjects with two risk factors, or ≥ 160 mg/dL for subjects with 0–1 risk factors. Patients were randomized (1: 1: 1) to receive niacin extended-release (NER) 500 mg/day in week 1, 1000 mg/day in week 2 and 2000 mg/day in weeks 3–6/aspirin (acetylsalicylic acid [ASA]), NER/ASA placebo, or NER placebo/ASA placebo. Results: FAST© test-retest reliability in stable patients during the first 2 weeks was demonstrated for overall flushing severity using patient and physician overall treatment effect (OTE) ratings (intraclass correlation coefficients of >0.7 for mean overall and individual flushing severity scores). Over the 6-week treatment period, FAST© scores demonstrated significant correlations with individual symptoms, impact on daily activities and sleep, and dissatisfaction related to flushing (p < 0.01) . Changes in FAST© scores were associated with treatment satisfaction (p < 0.01) and patient- and physician-rated OTE (p<0.01). Using patient-rated OTE, the mean maximum flushing severity scores improved 1.85 points in responders and only 0.18 points in non-responders (p < 0.001); responders were defined by improved patient- or physician-rated OTE. Among patients with flushing, mean maximum overall flushing scores differed between patients who subsequently discontinued due to flushing (7.9 points) and those who did not discontinue (4.7 points; p < 0.001). The probable range in this study for a detectable change in flushing symptoms (MID) was 0.29–0.38 points for mean flushing severity and 0.66–0.86 points for maximum flushing severity. Conclusion: The FAST© exhibited test-retest reliability, good evidence of construct validity, and, overall, flushing severity was responsive to change over time. The FAST© is a reliable and valid instrument for assessing the impact of niacin-induced flushing in patients with dyslipidaemia.

Combination of niacin extended-release and simvastatin results in a less atherogenic lipid profile than atorvastatin monotherapy

Objective: To compare the effects of combination niacin extended-release + simvastatin (NER/S) versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia. Patients and methods: Patients (n = 137) with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4–5 weeks prior to the study) received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks) or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo) A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher’s exact test. Results: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B < 80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003). NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022), small LDL (55% versus 45%; P = 0.011), very low-density lipoprotein (VLDL) and total chylomicrons (63% versus 39%; P < 0.001), and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007) and VLDL (9.3% versus 0.1%; P < 0.001), compared with atorvastatin. Conclusion: NER/S treatment significantly improved apo A-I levels and the apo B:A-I ratio, significantly lowered the number of atherogenic LDL particles and VLDL and chylomicron particles, and increased the mean size of LDL and VLDL particles, compared with atorvastatin.

Niacin Extended-Release Therapy in Phase III Clinical Trials is Associated with Relatively Low Rates of Drug Discontinuation due to Flushing and Treatment-Related Adverse Events

Background and ObjectiveNiacin is a highly effective agent for increasing low high-density lipoprotein cholesterol (HDL-C) levels. It also has beneficial effects on key pro-atherogenic lipoprotein parameters. However, the side effect of flushing can challenge patient adherence to treatment. In this study, we pooled safety data from available trials of at least 16 weeks’ duration to evaluate the impact of flushing on patient adherence to niacin extended-release (NER) therapy.MethodsData were pooled from eight NER studies (administered as NER with a maximum dosage of 1000, 1500, and 2000 mg/day, either as monotherapy or in combination with simvastatin 20 or 40mg/day [NER/S], or lovastatin 20 or 40 mg/day [NER/L]) to evaluate rates of study discontinuation due to flushing or any treatment-related adverse events.ResultsWhile 66.6% of patients experienced flushing, only 5.2% of patients discontinued treatment due to flushing. Of the total number of patients treated with NER (n = 307), NER/S (n = 912), or NER/L (n = 928), 34 (11%), 105 (11%), and 127 (14%) patients discontinued due to any treatment-related adverse event, respectively, while 14 (5%), 43 (5%), and 55 (6%) discontinued due to flushing. Discontinuation for flushing did not differ with regard to maximum dose, or to the presence or type of statin combined with NER.ConclusionAlthough flushing was common with NER treatment, discontinuation due to flushing occurred in only 5–6% of patients in this pooled analysis. This could be due to several factors, including the fact that all patients in the NER trials were educated about flushing and its management. Translation of methodology employed in these trials into clinical practice may improve long-term adherence to NER therapy, which would enhance the therapeutic benefit of NER for reducing cardiovascular risk.

204: Aspirin Use Prior to Initiation of Therapy with a Proprietary Niacin Extended-Release Reduces Discontinuation Rates Due to Flushing

Synopsis: Niacin has beneficial effects across all elements of the lipid profile; however, flushing can limit long-term adherence to therapy. Aspirin (ASA) can mitigate niacininduced flushing. Purpose: To evaluate the effect of ASA use prior to initiation of niacin therapy on tolerability of a novel combination of a proprietary, niacin extended-release with simvastatin (NER/S) as determined by discontinuation rates due to flushing. Methods: Data from 403 patients, who reported aspirin use prior to randomization to NER/S 1000/20, 2000/20, 1000/40, or 2000/40 mg/d for 24 weeks from two international studies, SEACOAST I and II, were pooled for this analysis. All patients had mixed dyslipidemia, including elevated cardiac risk-adjusted non-HDL-C, and were niacin-treatment-naive. After the end of the study, patients were retrospectively categorized based on ASA use prior to randomization: (1) those taking any dose of ASA (ASA ) at randomization and (2) those not taking ASA (ASA ). Results: The ASA subgroup included 192 of the 403 patients (47.6%), of whom 40 patients (9.9%) used 325 mg/d ASA, 101 (25.1%) used 81 or 100 mg/d ASA, and 51 (12.7%) used other doses. Most ASA patients reported that the ASA was being taken for cardiovascular disease prevention, therefore, frequency of ASA use at baseline differed based on coronary heart disease (CHD) risk (p 0.001 compared with ASA ). Of 271 patients with CHD or its risk equivalent, 164 (60.5%) used ASA; 24 of 100 patients (24.0%) with 2 risk factors used ASA; and 4 of 32 patients (12.5%) with 0 –1 risk factors used ASA. During NER/S treatment, fewer ASA than ASA patients experienced 1 flushing episode, 54.2% and 62.1%, respectively. Discontinuation rates due to flushing at week 24 were lower in ASA versus ASA patients, 4.2% and 7.6%, respectively. Of the 40 patients using 325 mg/d ASA at baseline, only one (2.5%) discontinued NER/S due to flushing. Treatment-emergent adverse events classified within the gastrointestinal system-organ class occurred with similar frequency in ASA and ASA patients (17.7% and 13.3%, respectively; p 0.27); no individual gastrointestinal adverse events occurred more frequently in ASA versus ASA patients (all p 0.1). Conclusions: Flushing and discontinuation due to flushing tended to be reduced in subjects reporting use of cardioprotective ASA before niacin therapy, suggesting that prior experience with ASA improves niacin tolerability. Relationships between ASA use and niacin persistence should be further explored in prospective studies.

216: Incidence of Flushing Decreases Over Time During Long-Term Therapy with a Novel Combination of Niacin Extended-Release with Simvastatin

Synopsis: Current evidence-based guidelines identify niacin as an important adjunct intervention, along with a statin, in high-risk patients with multiple lipid abnormalities. Perceptions regarding niacin-induced flushing limit its use. To date, however, no study has examined the extent to which patients who flush upon initiation of niacin continue to do so with continued therapy. Purpose: In this 52-week study (OCEANS), the incidence of flushing was evaluated over the duration of treatment in patients who experienced flushing during the initial 12 weeks of therapy with a novel, proprietary, niacin extendedrelease (NER) and simvastatin combination (NER/S). Methods: Patients were randomized to a variable titration schedule of NER/S, attaining a maximum dose of 2000/40 mg/day at 13 weeks. Total treatment duration was 24 to 52 weeks. Only patients who flushed during weeks 1–12 and completed a flushing log for weeks 1–12 and either weeks 13–24 or 41–52 were included in this post-hoc analysis. Concomitant treatment with aspirin/NSAIDS was allowed, though not mandated. Results: Flushing during the first 12 weeks of therapy occurred in 351 of 509 (71%) of patients. Of these patients, 45.8% (108 out of 236) did not experience flushing during weeks 13–24 although the dose of NER/S was increased to 2000/40 mg/day at the beginning of week 13 for 50% of patients. Further, 62.5% (75 out of 120) of patients did not experience flushing during weeks 41–52 [Figure]. Notably, 92% of the total flushing episodes in each titration group were rated as mild or moderate in intensity over the 52-week study. Conclusions: The majority of patients who experienced flushing during the initial 12 weeks of NER/S did not continue to experience flushing over the long-term despite continuing to receive NER/S. These results suggest that concerns with flushing over the long-term may be addressed and tolerance to NER-related flushing commonly occurs.