Carla Yunis

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BACKGROUND Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low‐density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow‐up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of ‐56.0% in the bococizumab group and +2.9% in the placebo group, for a between‐group difference of –59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower‐risk, shorter‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow‐up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher‐risk, longer‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow‐up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection‐site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower‐risk patients but did have a significant benefit in the trial involving higher‐risk patients. (Funded by Pfizer; SPIRE‐1 and SPIRE‐2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389.)

The Fagerström Test for Nicotine Dependence as a Predictor of Smoking Abstinence: A Pooled Analysis of Varenicline Clinical Trial Data

INTRODUCTION We explored the relationship between the Fagerström Test for Nicotine Dependence (FTND) and smoking abstinence rates in 10 randomized, double-blind placebo-controlled Phase 2-4 varenicline studies. METHODS Participants were adult smokers (≥10 cigarettes/day) who were motivated to quit. Efficacy end points included continuous abstinence rate (CAR) for weeks 9-24 analyzed, by baseline FTND and Heaviness of Smoking Index (HSI) scores, and treatment. Data were analyzed using logistic regression models. RESULTS Overall, 2,763 varenicline (M [SD] FTND score: 5.6 [2.2]) and 2,229 placebo subjects (5.5 [2.1]) were included in the analysis. An increase of one unit in baseline FTND or HSI score decreased the odds of abstinence at Week 24 by 11% (odds ratio [OR] 0.89, 95% CI 0.86-0.92, p < .0001) and 18% (OR 0.82, 95% CI 0.79-0.87, p < .0001), respectively. Treatment had a significant impact on CAR 9-24: odds of abstinence were increased threefold for varenicline versus placebo (OR 3.3, 95% CI 2.8-3.8, p < .0001). There was no interaction between treatment and FTND (p = .98) or HSI score (p = .97) for CAR 9-24. The HSI score predicted abstinence outcome as effectively as the FTND score. CONCLUSION Abstinence rates decreased with increasing dependence scores. There was no interaction between treatment and baseline FTND or HSI score, suggesting that they have no effect on the efficacy of varenicline versus placebo. These results also suggest that the HSI may be as effective at predicting smoking cessation outcome as the whole FTND questionnaire.

Effects of Varenicline on Smoking Cessation in Adults With Stably Treated Current or Past Major Depression: A Randomized Trial

UNLABELLED Chinese translation BACKGROUND Depression is overrepresented in smokers. OBJECTIVE To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo. DESIGN Phase 4, multicenter, parallel, 1:1 allocation, double-blind, randomization trial. Randomization, stratified by antidepressant use and depression score at baseline, was blocked in sizes of 4. (ClinicalTrials.gov: NCT01078298). SETTING 38 centers in 8 countries. PARTICIPANTS 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events. INTERVENTION Varenicline, 1 mg twice daily, or placebo for 12 weeks, with 40-week nontreatment follow-up. MEASUREMENTS Primary outcome was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood, anxiety, and suicidal ideation or behavior. RESULTS 68.4% versus 66.5% of the varenicline and placebo groups, respectively, completed the study. Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 (35.9% vs. 15.6%; odds ratio [OR], 3.35 [95% CI, 2.16 to 5.21]; P < 0.001), 9 to 24 (25.0% vs. 12.3%; OR, 2.53 [CI, 1.56 to 4.10]; P < 0.001), and 9 to 52 (20.3% vs. 10.4%; OR, 2.36 [CI, 1.40 to 3.98]; P = 0.001). There were no clinically relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group. The most frequent adverse event was nausea (varenicline, 27.0%; placebo, 10.4%). Two varenicline-group participants died during the nontreatment phase. LIMITATIONS Some data were missing, and power to detect differences between groups was low in rare events. Smokers with untreated depression, with co-occurring psychiatric conditions, or receiving mood stabilizers and antipsychotics were not included. CONCLUSION Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety. PRIMARY FUNDING SOURCE Pfizer.

Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab

BACKGROUND Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin–kexin type 9 (PCSK9), reduces levels of low‐density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. METHODS We conducted six parallel, multinational lipid‐lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period. RESULTS At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between‐group difference, ‐55.2 percentage points). Significant between‐group differences were also observed in total cholesterol, non–high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high‐titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection‐site reaction (12.7 per 100 person‐years). CONCLUSIONS In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954, NCT01968967, NCT01968980, NCT02100514, NCT02135029, and NCT02458287.)

A novel programme to evaluate and communicate 10-year risk of CHD reduces predicted risk and improves patients' modifiable risk factor profile

Aims:  We assessed whether a novel programme to evaluate/communicate predicted coronary heart disease (CHD) risk could lower patients’ predicted Framingham CHD risk vs. usual care.

Proactive multiple cardiovascular risk factor management compared with usual care in patients with hypertension and additional risk factors: the CRUCIAL trial.

Abstract Objective: To investigate whether a proactive multifactorial risk factor intervention strategy using single-pill amlodipine/atorvastatin (5/10, 10/10 mg) in addition to other antihypertensive and lipid-lowering therapy, as required, resulted in greater reduction in calculated Framingham 10-year coronary heart disease (CHD) risk compared with usual care (UC) after 52-weeks treatment. Research design and methods: Prospective, multinational, open-label, cluster randomized trial, with the investigator as the unit of randomization. Eligible hypertensive patients were 35–79 years of age, with ≥3 additional cardiovascular risk factors, but no history of CHD and baseline total cholesterol (TC) ≤6.5 mmol/l. Clinical trial registration: Trial registration: ClinicalTrials.gov identifier: NCT00407537. Main outcome measure: The primary endpoint was calculated Framingham 10-year CHD risk at 52 weeks. Results: Of the 140 randomized sites, 136 sites contributed 1461 patients. Mean baseline age and low-density lipoprotein cholesterol (LDL-C) were comparable between treatment arms. Mean baseline BP (150.3/89.7 vs. 144.3/86.5 mmHg) and Framingham CHD risk (20.0 vs. 18.1%) were higher in the proactive intervention versus the UC arm (p < 0.002 for both). At week 52, mean CHD risk was 12.5% in the proactive intervention arm and 16.3% in the UC arm (p < 0.001). The difference, observed at weeks 16 and 52, was primarily driven by significant differences in systolic BP and in TC between the two arms. Overall, adverse events (AEs) were reported in 48.8% and 44.0% of patients in the proactive intervention and the UC arm, respectively. Although there were differences in the incidence of AEs between the treatment arms, the AE profile in the proactive intervention arm was consistent with previous safety experience for this medication. Conclusions: A proactive multifactorial risk factor intervention strategy that simultaneously treated both BP and cholesterol regardless of individual risk factors per se, is more effective in reducing calculated Framingham 10-year CHD risk than UC in patients with hypertension and additional risk factors.

The Use of a Single-Pill Calcium Channel Blocker/Statin Combination in the Management of Hypertension and Dyslipidemia: A Randomized, Placebo-Controlled, Multicenter Study

Poor control of hypertension or dyslipidemia may at least in part be due to these risk factors being treated in isolation. The Caduet in Untreated Subjects Population (CUSP) trial was an 8‐week, randomized, double‐blind, placebo‐controlled trial evaluating the efficacy/safety of the combination of a calcium channel blocker (amlodipine besylate) and a statin (atorvastatin calcium) in a single‐pill form (5/20 mg) plus therapeutic lifestyle changes (TLC) compared with placebo plus TLC in patients with comorbid hypertension and dyslipidemia without evidence of cardiovascular disease. At week 4, additional antihypertensive/lipid‐lowering medication was permitted. The primary end point was the proportion of patients in whom the dual goal of blood pressure (<140/90 mm Hg) and low‐density lipoprotein cholesterol control (<100 mg/dL) was met at week 4. This dual goal attainment was significantly greater with amlodipine/atorvastatin plus TLC compared with placebo plus TLC at week 4 (47.6% vs 1.7%; P<.001), with further improvements at week 8. Most adverse events were mild to moderate. Therapy with single‐pill amlodipine/atorvastatin plus TLC in these patients significantly increased dual blood pressure/low‐density lipoprotein cholesterol goal attainment compared with placebo plus TLC.

Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefit beyond lipid lowering?

Aims The DoUble-blind Atorvastatin AmLodipine (DUAAL) trial investigated whether atorvastatin decreases ischaemia by a vascular benefit, independent of low-density lipoprotein cholesterol lowering, in patients with coronary artery disease (CAD), both alone and in combination with the traditional anti-anginal therapy, amlodipine. Methods and results Randomized, double-blind, parallel-group, multicountry trial (2 weeks run-in and 24 weeks active therapy) comparing three treatments: amlodipine, atorvastatin, and amlodipine + atorvastatin; in 311 patients (78% male; mean age 62 years) with stable angina (≥2 attacks/week), CAD history, ≥3 transient myocardial ischaemia (TMI) episodes, and/or ≥15 min ischaemia on 48 h ambulatory electrocardiographic (AECG) monitoring. Efficacy variables were change in TMI by AECG, exercise ischaemia, angina diary data, and inflammatory biomarkers at Week 26. There was a comparable, highly significant decrease in TMI with amlodipine and atorvastatin, but no additional benefit for the combination. More than 50% of patients became TMI-free in all three groups and this was accompanied by a comparable, marked reduction in angina and nitroglycerin consumption. High-sensitivity C-reactive protein fell by 40% in patients receiving atorvastatin but there was no change with amlodipine. Adverse events were comparable among groups. Conclusion Atorvastatin was as potent an anti-ischaemic agent as amlodipine. Future studies of combination therapies will be instructive. Clinical trial registration information: National clinical trial number: NCT00159718, protocol number A0531031 listed on http://clinicaltrials.gov/.

Design and Rationale of a Real-Life Study to Compare Treatment Strategies for Cardiovascular Risk Factors: The CRUCIAL Study

Abstract The CRUCIAL trial was designed to compare the relative reduction in calculated Framingham coronary heart disease risk when a multiple risk factor intervention strategy, based on single-pill amlodipine besylate/atorvastatin calcium, was compared with a usual-care strategy. Eligible patients had treated or untreated hypertension, ≥ 3 additional cardiovascular risk factors, and baseline total cholesterol ≤ 6.5 mmol/L, but no coronary heart disease. The CRUCIAL trial was a 12-month, international, multicenter, prospective, stratified, cluster-randomized, parallel-design, open-label trial conducted in 20 countries in Asia, the Middle East, Europe, and Latin America. We anticipate the results of this study will be available in mid to late 2010. In this article we report the rationale for and design of the CRUCIAL trial and discuss how the challenges in the design and conduct of this cluster-randomized trial were addressed. The cluster-randomized trial design, with the investigator as the unit of randomization, was chosen to minimize contamination between the trial arms. The intent of the study was to compare the new therapeutic strategy with customary treatment practices, so no recommendation was made regarding the choice of antihypertensive or lipid-lowering drugs in the usual-care arm. It was considered that if the investigator managed both arms of the trial it would be difficult to prevent crossover of treatment strategies. Patients were enrolled in the study before the investigators were randomized to avoid selection bias. Investigators were randomized in a 1:1 ratio within each country to explicitly balance the treatment arms with respect to potential confounding factors. The cluster effect was taken into account in the sample size calculation. The findings from the CRUCIAL trial have the potential to inform current thinking on how to effectively reduce the cardiovascular risk of patients with hypertension and additional risk factors but only modestly elevated total cholesterol.

Proactive Multifactorial Intervention Strategy Reduces the Risk of Cardiovascular Disease Estimated with Region-Specific Risk Assessment Models in Pacific Asian Patients Participating in the CRUCIAL Trial

Despite race, ethnic, and regional differences in cardiovascular disease risk, many worldwide hypertension management guidelines recommend the use of the Framingham coronary heart disease (CHD) risk equation to guide treatment decisions. This subanalysis of the recently published CRUCIAL trial compared the treatment-related reductions in calculated CHD and stroke risk among Pacific Asian (PA) patients using a variety of region-specific risk assessment models. As a result, greater reductions in systolic and diastolic blood pressure, low-density lipoprotein cholesterol, and triglycerides were observed in the proactive multifactorial intervention (PMI) arm compared with the usual care arm at Week 52 for PA patients. The relative percentage change in 10-yr CHD risk between baseline and Week 52 in the PMI versus usual care arms was greatest using the NIPPON DATA80 fatal CHD model (LS [least square] mean difference -42.6%), and similar in the SCORE fatal CHD and Framingham total CHD models (LS mean difference -29.4% and -30.8%, respectively). The single-pill based PMI approach is consistently effective in reducing cardiovascular disease risk, evaluated using a variety of risk assessment models. (ClinicalTrials.gov registration number: NCT00407537)