Summary Platelet-mediated thrombosis is a major pathophysiological mechanism that underlies acute coronary syndromes, and therefore, antiplatelet therapy is an important foundation in the treatment ...and prevention of recurrence of these syndromes. Nearly 30 years ago, aspirin was the first agent to show a benefit for acute coronary syndromes and is still a key therapeutic agent. The landmark CURE trial showed that the addition of a P2Y12 antagonist, clopidogrel, to aspirin was beneficial in the treatment of acute coronary syndromes. Despite substantial benefits with clopidogrel, limitations include the slow speed of onset, variable response, and a modest antiplatelet effect. Next-generation P2Y12 antagonists, prasugrel and ticagrelor, overcome these limitations and have been shown, in large-scale clinical trials for acute coronary syndromes, to reduce ischaemic events more than clopidogrel, at the expense of an increase in bleeding. Additional agents that target platelets by alternate mechanisms, including the protease-activated receptor-1 antagonist vorapaxar, have shown ischaemic benefit. These large-scale trials inform treatment decisions that need to balance ischaemic benefit and bleeding risk in patients with acute coronary syndromes. This Series paper describes major trial results, implications for clinical practice, and summarises continuing controversy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains ...undefined.
We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.
We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 95% CI 0·83–0·96, p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 0·80–0·93) and not in those without (1·00 0·87–1·16, p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 0·71–0·84, p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 0·48–0·64, p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.
SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In two randomized trials, evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), reduced LDL cholesterol levels by 61%. In an exploratory analysis, the ...incidence of cardiovascular events was reduced in the evolocumab group.
Reduction in low-density lipoprotein (LDL) cholesterol levels has proved to be highly effective in reducing rates of major cardiovascular events in numerous large outcome trials.
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For this reason, LDL cholesterol reduction has been incorporated into practice guidelines as a fundamental means of reducing cardiovascular morbidity and mortality.
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During the past 3 years, monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have emerged as a new class of drugs that very effectively lower LDL cholesterol levels.
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One of the members of this class is evolocumab, a fully human monoclonal antibody that typically achieves approximately a 60% reduction . . .
Abstract Background Acute myocardial infarction (AMI) has become a major cause of hospitalization and mortality in China. There has been limited data to date available to characterize AMI ...presentation, contemporary patterns of medical care, and outcomes in China. Aims The China acute myocardial infarction (CAMI) registry is a national project with the objectives to timely obtain real-world knowledge about AMI patients, and to provide the platform for clinical research, guide preventive measures and care quality improvement efforts in China. Methods and progress The CAMI registry is a prospective, nationwide, multicenter observational study for AMI patients. The registry includes three levels of hospitals (representing typical Chinese governmental and administrative models) from all provinces and municipalities throughout Mainland China. Sites were instructed to enroll consecutive patients with a primary diagnosis of AMI. Clinical data, treatments, outcomes and cost are collected by local investigators and captured electronically, with a standardized set of variables and standard definitions, and rigorous data quality control. Post-discharge patient follow-up to 2 years is planned. The CAMI Registry was launched in January 2013. A total of 108 hospitals have participated in the registry so far. As of September 2014, 26,103 patients with AMI were registered. Conclusions The CAMI registry represents a well-supported and the largest national long-term registry-research-education platform for surveillance, research, prevention and care improvement for AMI in China, the world’s most populous nation. The broad representation of all provinces and different-level hospitals will allow for the exploration of AMI across diverse geographic regions and economic circumstances.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background The benefits and risks of prolonged dual antiplatelet therapy may be different for patients with acute myocardial infarction (MI) compared with more stable presentations. ...Objectives This study sought to assess the benefits and risks of 30 versus 12 months of dual antiplatelet therapy among patients undergoing coronary stent implantation with and without MI. Methods The Dual Antiplatelet Therapy Study, a randomized double-blind, placebo-controlled trial, compared 30 versus 12 months of dual antiplatelet therapy after coronary stenting. The effect of continued thienopyridine on ischemic and bleeding events among patients initially presenting with versus without MI was assessed. The coprimary endpoints were definite or probable stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) moderate or severe bleeding. Results Of 11,648 randomized patients (9,961 treated with drug-eluting stents, 1,687 with bare-metal stents), 30.7% presented with MI. Between 12 and 30 months, continued thienopyridine reduced stent thrombosis compared with placebo in patients with and without MI at presentation (MI group, 0.5% vs. 1.9%, p < 0.001; no MI group, 0.4% vs. 1.1%, p < 0.001; interaction p = 0.69). The reduction in MACCE for continued thienopyridine was greater for patients with MI (3.9% vs. 6.8%; p < 0.001) compared with those with no MI (4.4% vs. 5.3%; p = 0.08; interaction p = 0.03). In both groups, continued thienopyridine reduced MI (2.2% vs. 5.2%, p < 0.001 for MI; 2.1% vs. 3.5%, p < 0.001 for no MI; interaction p = 0.15) but increased bleeding (1.9% vs. 0.8%, p = 0.005 for MI; 2.6% vs. 1.7%, p = 0.007 for no MI; interaction p = 0.21). Conclusions Compared with 12 months of therapy, 30 months of dual antiplatelet therapy reduced the risk of stent thrombosis and MI in patients with and without MI, and increased bleeding. (The Dual Antiplatelet Therapy Study The DAPT Study; NCT00977938 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Mechanical reperfusion with stenting for ST-elevation myocardial infarction (STEMI) is supported by dual antiplatelet treatment with aspirin and clopidogrel. Prasugrel, a potent ...and rapid-acting thienopyridine, is a potential alternative to clopidogrel. We aimed to assess prasugrel versus clopidogrel in patients undergoing percutaneous coronary intervention (PCI) for STEMI. Methods We undertook a double-blind, randomised controlled trial in 707 sites in 30 countries. 3534 participants presenting with STEMI were randomly assigned by interactive voice response system either prasugrel (60 mg loading, 10 mg maintenance n=1769) or clopidogrel (300 mg loading, 75 mg maintenance n=1765) and were unaware of the allocation. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Efficacy analyses were by intention to treat. Follow-up was to 15 months, with secondary analyses at 30 days. This trial is registered with ClinicalTrials.gov , number NCT00097591. Findings At 30 days, 115 (6·5%) individuals assigned prasugrel had met the primary endpoint compared with 166 (9·5%) allocated clopidogrel (hazard ratio 0·68 95% CI 0·54–0·87; p=0·0017). This effect continued to 15 months (174 10·0% vs 216 12·4%; 0·79 0·65–0·97; p=0·0221). The key secondary endpoint of cardiovascular death, myocardial infarction, or urgent target vessel revascularisation was also significantly reduced with prasugrel at 30 days (0·75 0·59–0·96; p=0·0205) and 15 months (0·79 0·65–0·97; p=0·0250), as was stent thrombosis. Treatments did not differ with respect to thrombolysis in myocardial infarction (TIMI) major bleeding unrelated to coronary-artery bypass graft (CABG) surgery at 30 days (p=0·3359) and 15 months (p=0·6451). TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments, and only TIMI major bleeding after CABG surgery was significantly increased with prasugrel (p=0·0033). Interpretation In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding. Funding Daiichi Sankyo and Eli Lilly.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
IMPORTANCE: The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE: To evaluate the association between lowering ...LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION: The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. MAIN OUTCOMES AND MEASURES: The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. RESULTS: A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L 122.3 mg/dL) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate 95% CI, 0.5%-2.6% per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate 95% CI, 2.9%-6.4% per each 1-mmol/L lower LDL-C level; P < .001). CONCLUSIONS AND RELEVANCE: In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.
Summary Background Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1 , also known as MDR1 ). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport ...and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON–TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. Methods We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON–TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19 . 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. Findings In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% 52 of 414 vs 7·8% 80 of 1057 participants; HR 1·72, 95% CI 1·22–2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38–2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. Interpretation Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. Funding Daiichi Sankyo Company Ltd and Eli Lilly and Company.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopidogrel and to relate platelet inhibition to ...systemic exposure to each active metabolite. Thienopyridines are prodrugs, metabolized in vivo to active metabolites that inhibit the platelet P2Y12 adenosine diphosphate (ADP) receptor. Methods This was an open-label, 2-way, crossover study that randomized healthy subjects (n = 68) to an oral loading dose (LD) of prasugrel 60 mg or clopidogrel 300 mg. Platelet aggregation response to 5 and 20 μmol/L of ADP was measured by turbidometric aggregometry. Plasma concentrations of the active metabolites of prasugrel and clopidogrel were quantified by liquid chromatography with tandem mass spectrometry detection methods. Results Inhibition of platelet aggregation (IPA) after prasugrel was significantly higher ( P < .01) than that after clopidogrel from 15 minutes through 24 hours (5 μmol/L ADP) and from 30 minutes through 24 hours (20 μmol/L ADP). For 20 μmol/L ADP, the median time to reach ≥20% IPA was 30 minutes for prasugrel and 1.5 hours for clopidogrel ( P < .001). The maximum IPA was 84.1% ± 9.5% with prasugrel versus 48.9% ± 27.0% with clopidogrel for 5 μmol/L ADP and 78.8% ± 9.2% versus 35.0% ± 24.5%, respectively, for 20 μmol/L ADP ( P < .001). Response to prasugrel was more consistent compared to clopidogrel ( P < .01). The lower IPA response to clopidogrel was associated with lower plasma concentrations of its active metabolite ( P < .001). Conclusions Prasugrel 60 mg LD results in more rapid, potent, and consistent inhibition of platelet function than clopidogrel 300 mg LD. Lower IPA responses to clopidogrel were associated with lower concentrations of its active metabolite.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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