Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Yoga-Based Cardiac Rehabilitation After Acute Myocardial Infarction: A Randomized Trial

Background: Given the shortage of cardiac rehabilitation (CR) programs in India and poor uptake worldwide, there is an urgent need to find alternative models of CR that are inexpensive and may offer choice to subgroups with poor uptake (e.g., women and elderly). Objectives: This study sought to evaluate the effects of yoga-based CR (Yoga-CaRe) on major cardiovascular events and self-rated health in a multicenter randomized controlled trial. Methods: The trial was conducted in 24 medical centers across India. This study recruited 3,959 patients with acute myocardial infarction with a median and minimum follow-up of 22 and 6 months. Patients were individually randomized to receive either a Yoga-CaRe program (n = 1,970) or enhanced standard care involving educational advice (n = 1,989). The co-primary outcomes were: 1) first occurrence of major adverse cardiovascular events (MACE) (composite of all-cause mortality, myocardial infarction, stroke, or emergency cardiovascular hospitalization); and 2) self-rated health on the European Quality of Life–5 Dimensions–5 Level visual analogue scale at 12 weeks. Results: MACE occurred in 131 (6.7%) patients in the Yoga-CaRe group and 146 (7.4%) patients in the enhanced standard care group (hazard ratio with Yoga-CaRe: 0.90; 95% confidence interval [CI]: 0.71 to 1.15; p = 0.41). Self-rated health was 77 in Yoga-CaRe and 75.7 in the enhanced standard care group (baseline-adjusted mean difference in favor of Yoga-CaRe: 1.5; 95% CI: 0.5 to 2.5; p = 0.002). The Yoga-CaRe group had greater return to pre-infarct activities, but there was no difference in tobacco cessation or medication adherence between the treatment groups (secondary outcomes). Conclusions: Yoga-CaRe improved self-rated health and return to pre-infarct activities after acute myocardial infarction, but the trial lacked statistical power to show a difference in MACE. Yoga-CaRe may be an option when conventional CR is unavailable or unacceptable to individuals. (A study on effectiveness of YOGA based cardiac rehabilitation programme in India and United Kingdom; CTRI/2012/02/002408)

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Optical Coherence Tomography (OCT) evaluation of culprit lesions in patients with Non-ST Elevation Acute Coronary Syndromes (NSTE-ACS)

Abstract Funding Acknowledgements Type of funding sources: None. Background OCT is an excellent tool to determine plaque morphology in Acute Coronary Syndromes. While plaque rupture has been determined to be the dominant morphology in ST Elevation Myocardial Infarction, there is paucity of literature in NSTE-ACS, which includes Non–ST Segment Elevation Myocardial Infarction (NSTEMI) and Unstable angina (UA). Purpose To characterize culprit lesion morphology by OCT in NSTE-ACS and to evaluate the frequency of each type of lesion in patients presenting with NSTEMI and UA. Methods In this single-centre observational study, OCT imaging of culprit lesion was acquired during coronary angioplasty of culprit lesions of 50 patients presenting with NSTE-ACS between August 2020 to July 2021. A comparison of the frequency of each type of lesion between NSTEMI and UA was performed. Results OCT of culprit vessel in the entire cohort of NSTE-ACS showed plaque erosion in 32% (n=16), plaque rupture in 32% (n=16), tight stenosis in 26% (n=13) and calcific nodule in 10% (n= 5) patients. Lipid plaque was seen in a higher number of patients with plaque erosion and plaque rupture (93.8% and 87.5% respectively). Comparison of the frequency of these lesions in NSTEMI and UA, revealed that among NSTEMI patients (n=25), 48% had plaque erosion, 36% had plaque rupture, 12% had tight stenosis and 4% had calcific nodule whereas, among UA patients (n=25), 16% had plaque erosion, 28% had plaque rupture, 40% had tight stenosis and 16% had calcific nodule. There was a statistically significant increase in plaque erosion in NSTEMI compared to UA (p=0.015) while tight stenosis was significantly more common in UA (p=0.024). Similarly, red thrombus and spotty calcium (p=0.002 and 0.008 respectively) were higher in NSTEMI compared to UA. There was no significant difference in frequency of thin cap fibroatheroma, macrophages, cholesterol crystals, white thrombus, and neovascularization among the two groups. Conclusions OCT provides unique insights into the mechanisms of NSTE-ACS. In our study plaque erosion and plaque rupture were both equally seen in patients presenting with NSTE- ACS. However, NSTEMI patients had a higher frequency of plaque erosion, red thrombus, and spotty calcium when compared to UA. While UA patients had a higher incidence of tight stenosis. </jats:sec

A randomized controlled trial evaluating a theory driven, complex intervention centered on task sharing and mobile health to improve selfcare and outcomes in heart failure – The PANACEA-HF RCT: Design and rationale

Background: We developed a three-pronged complex intervention to improve selfcare and deliver whole person care for patients with heart failure, underpinned by the ‘extant cycle’ theory – a theory based on our formative work. Methods: This is a 3 centre, 2-arm, 1:1, open, adaptive stratified, randomized controlled trial. We included patients aged ≥ 18 years with heart failure, taking any of the key guideline directed medical treatments, with a history of or currently on a high ceiling diuretic. We excluded end stage renal disease, clinically diagnosed severe mental illness or cognitive dysfunction and having no caregivers. Interventions included, (i) trained hospital based lay health worker mediated assessment of patients' current selfcare behaviour, documenting barriers and facilitators and implementing a plan to ‘transition’ the patient toward optimal selfcare. (ii) m-health mediated remote monitoring and (iii) dose optimization through a ‘physician supervisor’. Results: We recruited 301 patients between Jan 2021 and Jan 2022. Mean age was 59.8 (±11.7) years, with 195 (64.8 %) from rural or semi-urban areas and 67.1 % having intermediate to low health literacy. 190 (63.1 %) had an underlying ischemic cardiomyopathy. In the intervention arm, 142 (94.1 %) had a Selfcare in Heart Failure Index (SCHFI) score of ≤70, with significant barriers being ‘lack of knowledge’ 105 (34.5 %) and ‘behavioural passivity’ 23 (7.5 %). Conclusion: This is the first South Asian trial evaluating a complex intervention underpinned by behaviour change theory for whole person heart failure care. These learnings can be applied to heart failure patient care in other resource constrained health systems

Rationale, study design and methodology of the hypertension registry: a Pan-India, prospective, longitudinal study to assess management and real-world outcomes of high-risk essential hypertension

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; India contributes significantly towards a large part of the worldwide epidemic of hypertension (HTN) and its associated complications. As, there are limited longitudinal studies available in India to understand its occurrence over time, this Pan-India longitudinal study will aid to assess the real world outcomes of HTN across the country.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This was a prospective, multi-centered, longitudinal, observational study investigating a large COHORT of people with HTN across India over a period of one year. The primary objective of this study was to evaluate blood pressure (BP) control and clinical outcomes in high-risk hypertensive patients distributed over 5 visits (including baseline visit). The secondary objective is to assess the co-morbidities/risk factors in different clinical settings across India. Participants (4,000) with HTN will be included from 200 centres across India and data will be recorded for the use of anti-hypertensives, demographics, socio-economic status, anthropometric measurements, family history, personal history, risk factors, co-morbid conditions and physician treatment preferences. Overall, clinical practice patterns were assessed for their relationship with clinical outcomes.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study is expected to reveal the trends in complications associated with HTN, treatment strategies used by physicians, and correlation among treatment, control and complications of HTN within the Indian context. The outcome of this study will help to identify the burden of HTN, along with pin-pointing the emergence of early-onset complications and dose titration patterns. This will eventually help to develop person-centred care and facilitate public health agencies to invest appropriate resources in the management of high-risk HTN across India.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Trial registration:&lt;/strong&gt; Since this is a real world evidence study no trial registration was needed as per Indian regulations.&lt;/p&gt;</jats:p

Health-related quality of life at 30 days among Indian patients with acute myocardial infarction results from the ACS QUIK trial

Background: Despite a high cardiovascular disease burden, data on patient-reported health status outcomes among individuals with cardiovascular disease in India are limited. Methods and Results: Between November 2014 and November 2016, we collected health-related quality of life data among 1261 participants in the ACS QUIK trial (Acute Coronary Syndrome Quality Improvement in Kerala). We used a translated, validated version of the Seattle Angina Questionnaire administered 30 days after discharge for acute myocardial infarction, wherein higher scores represent better health status. We compared results across sex, myocardial infarction type, and randomization status using regression models that account for clustering and temporal trends. Mean (SD) age was 60.8 (13.7) years, 62% were men, and 63% presented with ST-segment–elevation myocardial infarction. More than 2 out of 5 respondents (44%) experienced angina 30 days after hospitalization, but most (68% of respondents with angina; 27% of the total sample) experienced it less than once per week (Seattle Angina Questionnaire angina frequency score 60). Respondents rated high median (interquartile range [IQR]) scores for angina frequency (100.0 [80.0–100.0]) overall with similar unadjusted scores by sex, but between-hospitality variability was high. Median (IQR) physical limitation scale response was 58.3 (41.7–77.8), which is consistent with limitations in moderate- and high-intensity activities at 30-day follow-up. Older respondents had more angina frequency and physical limitations and lower treatment satisfaction and quality of life. Women had greater physical limitations (median [IQR], 52.8 [38.9–72.2] for women versus median [IQR], 61.1 [44.4–80.6] for men; P<0.01). Overall treatment satisfaction was high with median (IQR) score, 81.3 (75.0–93.8), but overall quality of life was lower with median (IQR) score, 66.7 (50.0–83.3). Allocation to the quality improvement intervention group had the strongest direct association with higher quality of life (difference, 4.2; P=0.03), but overall effects were modest. Conclusions: This study represents the largest report of quality of life among myocardial infarction survivors in India with variability across age, sex, and quality improvement intervention status. Wide variability demonstrated across hospitals warrants further study. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02256657

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUND Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-highdensity lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS Among patients who had a previous acute coronary syndrome and who were receiving highintensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo