PCSK9 Inhibitors in the Treatment of Cardiovascular Diseases: A Narrative Review

2018/2019 Francisco Freire Barbas de Albuquerque Inibidores da PCSK9no tratamento de doenças cardiovasculares: uma revisão narrativa PCSK9 Inhibitors in the Treatment of Cardiovascular Diseases:ANarrative Review março, 2019 Mestrado Integrado em Medicina Área: Ciências Médicas e da Saúde –Medicina Clínica Tipologia: Monografia Trabalho efetuado sob a Orientação de: Doutor José Pedro Nunes Trabalho organizado de acordo com as normas da revista: Revista Portuguesa de Cardiologia Francisco Freire Barbas de Albuquerque Inibidores da PCSK9 no tratamento de doenças cardiovasculares: uma revisão narrativa PCSK9 Inhibitors in the Treatment of Cardiovascular Diseases:A Narrative Review março, 2019 PCSK9 Inhibitors in the Treatment of Cardiovascular Diseases: A Narrative Review Inibidores da PCSK9 no tratamento de doenças cardiovasculares: Uma revisão narrativa Francisco B Albuquerque Faculdade de Medicina, Universidade do Porto, Portugal Word Count: 4832 Corresponding author: Francisco B. Albuquerque Parque Residencial da Fonte Seca, lote 6B, 1º esquerdo 4715-229, Fraião, Braga e-mail: [email protected] Abstract Cardiovascular diseases are a main cause of morbidity and mortality worldwide and its prevention is a major concern in current practical guidelines. Reduction of low-density lipoprotein cholesterol (LDL-c) plasma levels lower than 70 mg/dL in patients with established cardiovascular disease, sometimes cannot be achieved, despite maximum-tolerated statin dose. The proprotein convertase subtilisin/kenin 9 inhibitors have recently emerged and showed an incremental reduction in LDL-c levels in this patient setting and a reduction of major adverse cardiovascular events have been clearly established. Several randomized controlled trials regarding the clinical effects of evolocumab, alirocumab and bococizumab have been published in the latest years and some of them are described in this article. Physicians might be looking towards a very useful lipid-lowering therapy for high cardiovascular risk patients. Key words: PCSK9 inhibitors, Evolocumab, Alirocumab, Bococizumab Resumo As doenças cardiovasculares são uma causa importante de morbimortalidade em todo o mundo e a sua prevenção constitui um assunto importante nas guidelines práticas atuais. A redução dos níveis plasmáticos de lipoproteínas de colesterol de baixa densidade (c-LDL) abaixo de 70 mg/dL em doentes com doença cardiovascular estabelecida, por vezes, não consegue ser alcançada, apesar da dose máxima tolerada de estatinas. Os inibidores proproteina convertase subtilisina/kenina 9 (PCSK9) emergiram recentemente mostrando uma redução adicional nos níveis de c-LDL neste grupo de doentes, assim como redução inequívoca nos eventos cardiovasculares major. Vários ensaios clínicos randomizados centrados nos efeitos clínicos do evolocumab, alirocumab e bococizumab têm sido publicados nos últimos anos e estando alguns deles são descritos neste artigo. A comunidade médica poderá estar a olhar em direção a uma terapêutica de redução lipídica muito útil em doentes com elevado risco cardiovascular. Palavras-chave: Inibidores PCSK9, Evolocumab, Alirocumab, Bococizumab Abbreviations Table Designation English Portuguese 3-hidroxi-3-methyl-glutaril-CoA HMG-CoA HMG-CoA Absolute risk reduction AAR RRA Acute coronary syndrome ACS SCA High-sensitivity C reactive protein hs-CRP PCR-as Cambridge Neuropsychological Test Automated battery CANTAB CANTAB Cardiovascular diseases CVD DCV Confidence interval CI IC Coronary heart disease CHD DAC Everyday cognition tool ECog ECog Hazard ratio HR HR LDL-cholesterol LDL-c c-LDL LDL receptor LDLR RLDL Major adverse limb events MALE EAMM Major adverse cardiovascular events MACE EACM Myocardial infarction MI EAM Number needed to treat NNT NNT Number n n Percent atheroma volume PAV VAP Peripheral artery disease PAD DAP Proprotein convertase subtilisin/kenin 9 PCSK9 PCSK9 Total atheroma volume TAV VAT Introduction Cardiovascular diseases (CVD) remain a leading cause of morbidity and mortality worldwide (1). Secondary CVD prevention is crucial in our society since more patients survive their first episode of cardiovascular event and are at higher risk of recurrence (2, 3). In this review, among the treatment targets and goals for CVD prevention, the author will focus only in hypercholesteremia. LDL-cholesterol (LDL-c) is a well-established and modifiable risk factor for CVD. Currently, an LDL-c goal of less than 70 mg/dl is recommended in very high-risk patients. To achieve these plasma levels, not only a lifestyle modification but also medical treatment is required (2). Statins remain the first-line drug for lipid management in patients with atherosclerotic CVD by inhibiting 3-hidroxi-3-methyl-glutaril-CoA (HMG-CoA) reductase (4). Although these drugs are safe, some patients experience adverse events or are intolerant to them, or do not achieve LDL-c goals despite maximum tolerated statin-dose (5). In either case, the second line therapy available is ezetimibe, a cholesterol absorption inhibitor, which not only provides an additional reduction in LDL-c levels when associated to a statin, but also significantly reduces major adverse cardiovascular events (MACE) (6). Even with an optimized regimen, some patients still do not reach their LDL-c goals. To accomplish that, a novel class of drugs, the proprotein convertase subtilisin/kenin 9 (PCSK9) inhibitors, had recently emerged (7). Evolocumab, alirocumab and bococizumab, are the three most studied PCSK9 inhibitors (8). PCSK9 is produced mostly in the liver and binds to LDL receptors (LDLR) on hepatic cell surface. It targets the LDLR for degradation inside hepatic cell endosome. Consequently, the LDLR is not recycled to the hepatic cell surface resulting in fewer LDLR available to capture LDL-c on plasma. Ultimately, a rise in LDL-c levels on plasma occurs (9). Thus, when using a PCSK9 inhibitor, the LDLR is not degraded and is able to return to the cell surface. This results in a decrease in LDL-c plasma levels (figure 1). Recently, Toth PP et al. showed that PCSK9 inhibitors were associated with a significant reduction in LDL-c plasma levels compared to either placebo and ezetimibe (10). It is important to establish if incremental reduction in LDL-c plasma levels prevents cardiovascular events and overall mortality (11). The main goal of this narrative review is to provide a summarized description of the major randomized controlled trials regarding the efficacy and clinical effects of evolocumab, alirocumab and bococizumab on CVD. The current report was not funded by any interested party, either governmental or industry, and the decision to carry out this review was taken exclusively by the author. In terms of MACE, in patients with PAD evolocumab reduced primary end-point by 21% (2.5-year Kaplan Meier rate, 13.3% versus 16.8%; HR, 0.79; 95% CI, 0.66-0.94; P=0.0098) and secondary endpoint by 27% (9.5% versus 13.0%; HR, 0.73; 95% CI, 0.59-0.91; P=0.0040) compared to placebo. This reduction was consistent even in patients with PAD without prior MI or stroke. Furthermore, LDL-c lowering with evolocumab reduced the risk of MALE by 42% in the overall population (0.27% versus 0.45%; HR, 0.58; 95% CI, 0.38-0.88; P=0.00093; ARR, 0.18%). Last, when looking at the composite of MACE or MALE in patients with PAD and no prior MI or stroke, evolocumab resulted in an ARR at 2.5 years of 6.3% yielding NNT of 16. Sabatine MS et al (29) analyzed the effects of evolocumab by severity and extent of coronary artery disease. The patients were stratified based on the number of prior MIs (more than 2 versus less than 2), the timing of prior MIs (less than 2 years versus more than 2 years) and the presence of residual multivessel coronary disease defined as ≥ 40% stenosis in ≥ 2 large vessels. When analyzing the placebo arm alone, both the primary and secondary end-point were significantly higher in all strata. When considering the benefit of evolocumab versus placebo, regarding timing of prior MI, evolocumab reduced primary end-point by 20% (HR, 0.80, 0.71-0.91) in those with a more recent MI versus 5% (HR, 0.95) in those without. This result was consistent in the rest strata, where evolocumab reduced the primary end-point by 18% in those with multiple prior MIs (HR, 0.82, 0.72-0.93) and 21% (HR 0.79, 0.69-0.91) in those with multivessel disease. Table 1 and 2 provide a compilation of the available data from the original articles regarding hazard ratios, absolute risk reductions and number need to treat with respect to primary and secondary endpoint of the FOURIER trial population. EBBINGHAUS (2017) The Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) study (30), assessed the cognitive function from a subgroup of patients from the FOURIER trial, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Patients were enrolled previously to the first dose administration in FOURIER trial. The inclusion criteria were the ones described previously in FOURIER trial. Patients were excluded if any condition could confound the study results, such as dementia or any cognitive impairment. A total of 1974 patients were enrolled. The primary end point was the score on the spacial working memory strategy index of executive function (scores range from 4 to 28, with lower scores representing more efficient use of strategy and planning). The three secondary end points were working memory, episodic memory and psychomotor speed. The primary analysis population included 1204 patients, out of the total 1974, who had baseline CANTAB assessment before or on the day of the first dose of evolocumab (n=586) or placebo (n=618) and had at least one follow-up CANTAB assessment. This analysis was a noninferiority comparison of the mean change in the primary end point from baseline over time. The median duration of follow-up was 19.4 months in the primary analysis population. In terms of outcomes, the mean change from baseline over time in the primary end-point did not differ significantly between the two study groups; the raw score at baseline was 17.8 in both groups, and mean change from baseline in the score was -0.21+/- 2.62 in evolocumab group and -0.29 +/- 2.81 in placebo group (P<0.001 for noninferiority and P=0.85 for superiority). With respect to the three secondary end points, the mean change in raw scores from baseline also did not differ significantly between two study groups. The full analysis population included the 1204 from the primary analysis population plus the 770 patients whose first CANTAB assessment occurred after the day on which the first dose of evolocumab (n=983) or placebo (n=990) was administered. No significantly differences were observed between two study groups. Between-group differences assessment showed no significantly differences favoring either the use of evolocumab or the use of placebo. At the final visit, a total of 1581 patients in the EBBINGHAUS study performed retrospective selfassessments of their executive and memory function comparing current level of everyday functioning with their level at the beginning of the trial, using the Everyday Cognition tool (ECog). No significant between-group differences were observed in scores on individual domains (P=0.83 for memory domain; P=0.28 for executive functioning domain) or total score (P=0.42). These results support either objectively (via CANTAB assessment) and subjectively (via ECog) that the use of evolocumab does not cause any cognitive impairment compared to placebo. Studies involving Bococizumab SPIRE (2017) The Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) program for the development of bococizumab consists of two parts: the six SPIRE lipid-lowering studies and the SPIRE1 and SPIRE-2 event-driven cardiovascular outcome trials (8, 31). The former did not meet the inclusion criteria for this report and the last is described in this article. The SPIRE-1 and SPIRE-2 studies are two randomized, placebo-controlled, multinational clinical trials which aim to evaluate the clinical efficacy and the safety of bococizumab. During the conduct of these two trials, the sponsor discontinued further development of bococizumab on November 1, 2016, because data from the six SPIRE lipid-lowering trial became available indicating that the drug was associated with the development antidrug antibodies that significantly attenuated LDL-c lowering over time. In addition, even among patients who were antibody negative, bococizumab was associated with a wide variation in LDL-c reduction(31). Despite the discontinuation of bococizumab and the prematurely stop of SPIRE-1 and SPIRE-2 trials, the unblinded data collected between October 2013 until November 2016 were analyzed and the results are described here (8). The inclusion criteria were to have either a previous cardiovascular event or history of diabetes, chronic kidney disease, or peripheral vascular disease with additional cardiovascular risk condition or a history of familial hypercholesteremia, to have one or more additional cardiovascular risk factors and age of at least 50 years for men and 60 years for women. Patients were also required to have an LDL-c level ≥70 mg/dl or non-HDL level ≥ 100 mg/dl in SPIRE-1 and to have a LDL-c level ≥ 100 mg/dl or non-HDL ≥ 130 mg/dl in SPIRE-2. Treatment with a statin during the previous 4 weeks was a condition met in all patients. At the time the sponsor stopped the trial a total of 16817 patients had been enrolled in SPIRE-1 trial to receive either bococizumab 150mg, twice a week, via subcutaneous injections (n=8408) or matching placebo (n=8392). A total of 10621 patients had enrolled in SPIRE-2 trial to received either bococizumab 150mg subcutaneously every two weeks (n=5312) or matching placebo (n=5309). By the time the trial was terminated, the median follow-up time was 7 months in SPIRE-1 and 12 months in SPIRE-2. The primary end-point of the two trials was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for unstable angina requiring urgent revascularization. In SPIRE-1 the primary end-point occurred in 173 patients each in bococizumab group and placebo group (HR 0.99; 95% CI, 0.80 to 1.22; P=0.94). In SPIRE-2 the primary end-point occurred in 179 patients in bococizumab group and in 224 patients in placebo group (HR, 0.79; 95% CI, 0.65 to 0.97; P=0.02). In the combined analysis, the primary end-point occurred in 352 patients in bococizumab group and in 397 in placebo group (HR, 0.88; 95% CI, 0.76 to 1.02; P=0.08). In summary, bococizumab significantly reduced cardiovascular events in the higher risk patient group (SPIRE-2) but did it not in the lower risk patient group (SPIRE-1). Studies involving Alirocumab ODYSSEY OUTCOMES (2018) The ODYSSEY OUTCOMES trial (32) tested whether adding alirocumab to standard high intensity statin therapy, in post-acute coronary syndrome (ACS) patients would improve their morbidity and mortality. In this multi-center, double-blind, placebo-controlled trial, the authors randomized 18924 patients, who were more than 40 years of age, had a recent ACS within 1 to 12 months prior to randomization and who had an LDL-c level more than 70 mg/dl, or non-HDL-c level more than 100 mg/dl or a apolipoprotein B more than 80 mg/dl, despite maximal intensity-statin therapy, to receive either alirocumab (n=9462) 75mg subcutaneously every two weeks or matching placebo (n=9462). Protocol-specific dose-adjustments were performed to target an LDL-c level of 25 to 50 mg/dl and to avoid sustained levels below 15mg/dl. If patients achieved LDL-c levels above 50 mg/dL alirocumab was up-titrated from 75mg to 150mg. If patients achieved levels below 15 mg/dL in two consecutives measurements, patients were switched to placebo arm. LDL-c levels were considered acceptable between 15-25 mg/dl with alirocumab 75mg, but down-titrated if alirocumab 150mg. Median duration of follow-up was 2.8 years. The primary efficacy end-point was a composite of death from coronary heart disease (CHD), nonfatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. A total of 903 patients (9.5%) in the alirocumab group and 1052 patients (11.1%) in the placebo group (HR 0.85, 95% CI, 0.78-0.93, P<0.001) experienced the primary end-point. A prespecified subgroup analysis demonstrated the greatest benefit in those with an LDL-c level higher than 100 mg/dL at baseline (HR 0.76, 95% CI, 0.65-0.87) compared to those with LDL-c levels lower than 100 mg/dl. The major secondary efficacy end-point included: any CHD event; major CHD event; any CV event; composite of death from any cause, non-fatal MI or non-fatal ischemic stroke; death from CHD; death from CV causes; death from any cause. The hierarchical analysis showed significant results in the first four secondary end-points, but it was stopped after the first nonsignificant P value observed in death from CHD end-point (P=0.38), in accordance with the hierarchical testing plan. A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (HR, 0.85; 95% CI, 0.73 to 0.98). Finally, the treatment was safe and well tolerated. The most frequent adverse event, which was rare, was local site-injection reactions (3.8% in alirocumab group versus 2.1% in placebo group, P<0.001). Table 3 provides a compilation of the studies previously described and summaries of their major findings. Limitations Several limitations regarding original studies described here should be considered. GLAGOV trial examined the effects of disease progression only on patients presenting for a clinically indicated coronary angiography and focused only on atheroma volume and did not characterized the effects on atheroma morphology (24). The major limitation of FOURIER trial is the relatively short follow-up period compared to other lipidlowering trials (11). Post-hoc analysis of FOURIER trials are not truly randomized controlled trial, once the results are interpreted in a post-randomization subgroup stratification. Even with adequate multivariable adjustment, residual confounding may remain. In SPIRE program, the major limitation was the prematurely stop of the trial and discontinuation of the drug. Besides, the differences in baseline LDL-c levels and follow-up duration between SPIRE-1 and - 2 populations also constitute a limitation. In ODYSSEY OUTCOME trial, whether the safety and efficacy of alirocumab were influenced by the blinded dose-adjustment strategy, which was designed to mitigate the occurrence of very low levels of LDL-c constitutes a major limitation. Like in FOURIER trial, this trial cannot predict longer-term safety of treatment with a PCSK9 inhibitor (32). A limitation in all these trials is the infrequent use of ezetimibe, for which cardiovascular efficacy is established. Conclusions CVD are a major problem in our society and many efforts are being made to attenuate this issue (1,2,3). Reduction of LDL-c has been proven to reduce overall mortality, but some patients still cannot achieve current LDL-c goals (2). PCSK9 inhibitors might be an important therapeutic weapon in this setting. Evolocumab, alirocumab and bococizumab all proved to produce an incremental reduction on LDL-c plasma levels in patients already taking statins and ezetimibe (10). However, the last drug was not able to maintain its effects overtime because of development of antidrug antibodies which led to its discontinuation (31). Still, an analysis made with available data from the SPIRE-1 and 2 trials before its ending, showed no benefits of bococizumab in MACE reduction compared to placebo in SPIRE-1 and combined SPIRE-1 and 2 analysis, but a significant reduction was observed in SPIRE-2 population (8,31). The GLAGOV trial demonstrated for the very first time a regression of atherosclerotic plaque in patients using evolocumab compared to placebo when added to a statin background (24). Yet, whether if incremental LDL-c level reduction and plaque regression using evolocumab would prevent MACE was still uncertain. Following this, FOURIER trial showed a significant reduction in the composite end-point of major CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization, but not on all-cause mortality (11). Importantly, these benefits came with no offsetting neurocognitive impairment, as demonstrated in EBBINGHAUS trial, or other adverse events (22,30). Subgroup analysis of FOURIER trial demonstrated that patients with baseline diabetes, hs-CRP baseline level >3 mg/dL, baseline PAD, more than two MI, prior MI less than two years and multivessel residual coronary disease would benefit the most from evolocumab use (26-29). Give the currently high cost of the drug (33), such finding shall be taken into consideration regarding which patients would benefit the most from drug’s clinical potential. Alirocumab showed a significant reduction in MACE comparing to placebo, similarly to FOURIER trial. This benefit was more pronounced among patients who had an LDL-c baseline level of at least 100 mg/dL, like in SPIRE-2 trial population. This drug also had an impact on overall mortality (32). To conclude, evolocumab and alirocumab, consistently lowered LDL-c and reduced MACE (11,32) with no appreciable adverse events (22,30). Alirocumab showed a reduction in overall mortality (32). Bibliography 1. World Health Organisation. Global Health Estimates 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000-2016. Geneva, World Health Organization; 2018. 2018, May 24 [Available from: http://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. 2. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European Heart Journal. 2016;37(39):2999-3058. 3. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practiceThe Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). European Heart Journal. 2016;37(29):2315-81. 4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45. 5. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-22. 6. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015;372(25):2387-97. 7. Giugliano RP, Sabatine MS. Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? Journal of the American College of Cardiology. 2015;65(24):2638-51. 8. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. The New England journal of medicine. 2017;376(16):1527-39. 9. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. Journal of lipid research. 2009;50 Suppl:S172-7. 10. Toth PP, Worthy G, Gandra SR, et al. Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia. Journal of the American Heart Association. 2017;6(10). 11. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017;376(18):1713-22. 12. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. The New England journal of medicine. 2014;370(19):1809-19. 13. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet (London, England). 2012;380(9858):2007-17. 14. Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. Circulation journal : official journal of the Japanese Circulation Society. 2014;78(5):1073-82. 15. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. Journal of the American College of Cardiology. 2014;63(23):2531-40. 16. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet (London, England). 2012;380(9858):1995-2006. 17. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Table 3. Some of the major studies on clinical outcomes of PCSK9 Inhibitors and summaries of their conclusion Study n Intervention End-point Major Findings OSLER (2015) 4465 EVO SC plus SOC (420 mg Q1M) vs. SOC alone in OSLER-1 EVO SC (140mg Q2W or 420mg Q1M) plus SOC vs. SOC alone in OSLER-2 Incidence of adverse events Adverse events were reported more frequently in the EVO group EVO group had a significantly lower rates of all cardiovascular events than did the patients in the SOC group No differences between groups regarding glycaemia and new onset-diabetes GLAGOV (2016) 968 EVO SC (420mg Q1M) vs. PLA Nominal change in PAV and nominal change in TAV EVO significantly reduces PAV and TAV compared with PLA FOURIER (2017) 27564 EVO SC (140mg Q2W or 420 Q1M) vs. PLA Primary end-point: CV death, MI, stroke, hospitalization for UA or CR Secondary endpoint: CV death, MI, stroke EVO significantly reduced both the primary and secondary end-point compared to PLA EVO did not reduce all-cause mortality compared to PLA EVO was equally effective in reducing MACE in patients with LDL-c <70mg/dL vs >70mg/dL and maximal statin dose vs submaximal statin-dose EVO significantly reduced MACE in patients with and without diabetes EVO reduced MACE across hsCRP strata with greater ARR in patients with higher-baseline hsCRP levels EVO significantly reduced MACE and MALE with greater ARR in patients with PAD versus without EVO significantly reduced MACE in patients closer to their most recent MI, with multiple prior MI or with multivessel CAD with greater ARR in this subgroup of patients EBBINGHAUS (2017) 1974 EVO SC (140mg Q2W or 420 Q1M) vs. PLA Score on the spacial working memory strategy index of executive function No differences between groups regarding cognitive function SPIRE (2016) 27438 total 16817 in SPIRE-1 10621 in SPIRE-2 BOCO SC (150mg Q2W) vs. PLA Composite of CV death, non-fatal MI, non-fatal stroke or hospitalization for UA requiring urgent revascularization BOCO did not significantly reduced MACE in SPIRE-1 BOCO significantly reduced MACE in SPIRE-2 BOCO did not significantly reduced MACE in the combined groups ODYSSEY OUTCOMES (2018) 18924 ALI SC (75 or 150 mg Q2W) vs PLA Composite of CHD disease, nonfatal MI, fatal or nonfatal IS, or UA requiring hospitalization ALI significantly reduced MACE ALI reduced overall mortality Abbreviations:ALI, alirocumab; ARR, absolute risk reduction; BOCO, bococizumab; CAD, coronary artery disease; CHD, coronary heart disease death; CR, cardiac revascularization; CV, cardiovascular; EVO, evolocumab; IS, ischemic stroke; MACE, major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; PAD, peripheral artery disease; PAV, percent atheroma volume; PLA, placebo; Q1M, every one month; Q2W, every two weeks; SC, subcutaneous; SOC, standard of care; TAV, normalized total atheroma volume; UA, unstable angina; hsCRP, high-sensitivity C-reactive protein Agradecimentos Em primeiro lugar quero agradecer ao meu orientador, Professor José Pedro Nunes, pela sua disponibilidade durante todo o processo deste trabalho e pela sua sabedoria e motivação. Aos meus colegas e amigos, que de uma forma indireta, e por tudo aquilo que representam, são também importantes neste trabalho. Por último, expresso a minha profunda gratidão à minha família, pais, irmão e irmã, pelo seu apoio incondicional durante todo o meu percurso académico. ANEXO Normas de Publicação da Revista Portuguesa de Cardiologia A Revista Portuguesa de Cardiologia, órgão oficial da Sociedade Portuguesa de Cardiologia, é uma publicação científica internacional destinada ao estudo das doenças cardiovasculares. Publica artigos em português na sua edição em papel e em português e inglês na sua edição online, sobre todas as áreas da Medicina Cardiovascular. Se os artigos são publicados apenas em inglês, esta versão surgirá simultaneamente em papel e online. Inclui regularmente artigos originais sobre investigação clínica ou básica, revisões temáticas, casos clínicos, imagens em cardiologia, comentários editoriais e cartas ao editor. Para consultar as edições online deverá aceder através do link www.revportcardiol.org. Todos os artigos são avaliados antes de serem aceites para publicação por peritos designados pelos Editores (peer review). A submissão de um artigo à Revista Portuguesa de Cardiologia implica que este nunca tenha sido publicado e que não esteja a ser avaliado para publicação noutra revista. Os trabalhos submetidos para publicação são propriedade da Revista Portuguesa de Cardiologia e a sua reprodução total ou parcial deverá ser convenientemente autorizada. Todos os autores deverão enviar a Declaração de Originalidade, conferindo esses direitos à RPC, na altura em que os artigos são aceites para publicação. Envio de manuscritos Os manuscritos para a Revista Portuguesa de Cardiologia são enviados através do link http://www.ees.elsevier.com/repc. Para enviar um manuscrito, é apenas necessário aceder ao referido link e seguir todas as instruções que surgem. Responsabilidades Éticas Os autores dos artigos aceitam a responsabilidade definida pelo Comité Internacional dos Editores das Revistas Médicas (consultar www.icmje.org). Os trabalhos submetidos para publicação na Revista Portuguesa de Cardiologia devem respeitar as recomendações internacionais sobre investigação clínica (Declaração de Helsínquia da Associação Médica Mundial, revista recentemente) e com animais de laboratório (Sociedade Americana de Fisiologia). Os estudos aleatorizados deverão seguir as normas CONSORT. Informação sobre autorizações A publicação de fotografias ou de dados dos doentes não devem identificar os mesmos. Em todos os casos, os autores devem apresentar o consentimento escrito por parte do doente que autorize a sua publicação, reprodução e divulgação em papel e na Revista Portuguesa de Cardiologia. Do mesmo modo os autores são responsáveis por obter as respectivas autorizações para reproduzir na Revista Portuguesa de Cardiologia todo o material (texto, tabelas ou figuras) previamente publicado. Estas autorizações devem ser solicitadas ao autor e à editora que publicou o referido material. Conflito de interesses Cada um dos autores deverá indicar no seu artigo se existe ou não qualquer tipo de Conflito de Interesses. Declaração de originalidade O autor deverá enviar uma declaração de originalidade. Ver anexo I Protecção de dados Os dados de carácter pessoal que se solicitam vão ser tratados num ficheiro automatizado da Sociedade Portuguesa de Cardiologia (SPC) com a finalidade de gerir a publicação do seu artigo na Revista Portuguesa de Cardiologia (RPC). Salvo indique o contrário ao enviar o artigo, fica expressamente autorizado que os dados referentes ao seu nome, apelidos, local de trabalho e correio electrónico sejam publicados na RPC, bem como no portal da SPC (www.spc.pt) e no portal online www.revportcardiol.org, com o intuito de dar a conhecer a autoria do artigo e de possibilitar que os leitores possam comunicar com os autores. INSTRUÇÕES AOS AUTORES Todos os manuscritos deverão ser apresentados de acordo com as normas de publicação. Pressupõe-se que o primeiro autor é o reponsável pelo cumprimento das normas e que os restantes autores conhecem, participam e estão de acordo com o conteúdo do manucrito. 1. Artigos Originais Apresentação do documento: • Com espaço duplo, margens de 2,5 cm e páginas numeradas. • Não deverão exceder 5.000 palavras, contadas desde a primeira à última página, excluindo as tabelas. • Consta de dois documentos: primeira página e manuscrito • O manuscrito deve seguir sempre a mesma ordem: a) resumo estruturado em português e palavras-chave; b) resumo estruturado em inglês e palavras-chave; c) quadro de abreviaturas em português e em inglês; d) texto; e) bibliografia; f) legendas das figuras; g) tabelas (opcional) e h) figuras (opcional)- Primeira página Título completo (menos de 150 caracteres) em português e em inglês. Nome e apelido dos autores pela ordem seguinte: nome próprio, seguido do apelido (pode conter dois nomes) Proveniência (Serviço, Instituição, cidade, país) e financiamento caso haja. Endereço completo do autor a quem deve ser dirigida a correspondência, fax e endereço electrónico. Faz-se referência ao número total de palavras do manuscrito (excluindo as tabelas). Resumo estruturado O resumo, com um máximo de 250 palavras, está dividido em quatro partes: a) Introdução e objectivos; b) Métodos; c) Resultados e d) Conclusões. Deverá ser elucidativo e não inclui referências bibliográficas nem abreviaturas (excepto as referentes a unidades de medida). Inclui no final três a dez palavras-chave em português e em inglês. Deverão ser preferencialmente seleccionadas a partir da lista publicada na Revista Portuguesa de Cardiologia, oriundas do Medical Subject Normas de publicação da Revista Portuguesa de Cardiologia Headings (MeSH) da National Libray of Medicine, disponível em: www.nlm.nihgov/mesh/meshhome.html. O resumo e as palavras-chave em inglês devem ser apresentados da mesma forma. Texto Deverá conter as seguintes partes devidamente assinaladas: a) Introdução; b) Métodos; c) Resultados; d) Discussão e e) Conclusões. Poderá utilizar subdivisões adequadamente para organizar cada uma das secções. As abreviaturas das unidades de medida são as recomendadas pela RPC (ver Anexo II). Os agradecimentos situam-se no final do texto. Bibliografia As referências bibliográficas deverão ser citadas por ordem numérica no formato ‘superscript’, de acordo com a ordem de entrada no texto. As referências bibliográficas não incluem comunicações pessoais, manuscritos ou qualquer dado não publicado. Todavia podem estar incluídos, entre parêntesis, ao longo do texto. São citados abstracts com menos de dois anos de publicação, identificando-os com [abstract] colocado depois do título. As revistas médicas são referenciadas com as abreviaturas utilizadas pelo Index Medicus: List of Journals Indexed, tal como se publicam no número de Janeiro de cada ano. Disponível em: http://www. ncbi.nlm.nih.gov/entrez/citmatch_help.html#JournalLists. O estilo e a pontuação das referências deverão seguir o modelo Vancouver 3. Revista médica: Lista de todos os autores. Se o número de autores for superior a três, incluem-se os três primeiros, seguidos da abreviatura latina et al. Exemplo: 17. Sousa PJ, Gonçalves PA, Marques H et al. Radiação na AngioTC cardíaca; preditores de maior dose utilizada e sua redução ao longo do tempo. Rev Port cardiol, 2010; 29:1655-65 Capítulo em livro: Autores, título do capítulo, editores, título do livro, cidade, editora e páginas. Exemplo: 23. Nabel EG, Nabel GJ. Gene therapy for cardiovascular disease. En: Haber E, editor. Molecular cardiovascular medicine. New York: Scientific American 1995. P79-96. Livro: Cite as páginas específicas. Exemplo: 30. Cohn PF. Silent myocardial ischemia and infarction. 3rd ed. New York: Mansel Dekker; 1993. P. 33. Material electrónico: Artigo de revista em formato electrónico. Exemplo: Abood S. Quality improvement initiative in nursing homes: the ANA acts it an advisory role. Am J Nurs. [serie na internet.] 2002 Jun citado 12 Ago 2002:102(6): [aprox. 3] p. Disponível em: http:// www.nursingworld.org/AJN/2002/june/Wawatch.htm . A Bibliografia será enviada como texto regular, nunca como nota de rodapé. Não se aceitam códigos específicos dos programas de gestão bibliográfica. 1. Figuras As figuras correspondentes a gráficos e desenhos são enviadas no formato TIFF ou JPEG de preferência, com uma resolução nunca inferior a 300 dpi e utilizando o negro para linhas e texto. São alvo de numeração árabe de acordo com a ordem de entrada no texto. • A grafia, símbolos, letras, etc, deverão ser enviados num tamanho que, ao ser reduzido, os mantenha claramente legíveis. Os detalhes especiais deverão ser assinalados com setas contrastantes com a figura. • As legendas das figuras devem ser incluídas numa folha aparte. No final devem ser identificadas as abreviaturas empregues por ordem alfabética. • As figuras não podem incluir dados que dêem a conhecer a proveniência do trabalho ou a identidade do paciente. As fotografias das pessoas devem ser feitas de maneira que estas não sejam identificadas ou incluir-se-á o consentimento por parte da pessoa fotografada. Tabelas São identificadas com numeração árabe de acordo com a ordem de entrada no texto. Cada tabela será escrita a espaço duplo numa folha aparte. • Incluem um título na parte superior e na parte inferior são referidas as abreviaturas por ordem alfabética. • O seu conteúdo é auto-explicativo e os dados que incluem não figuram no texto nem nas figuras. 2. Cartas ao Editor Devem ser enviadas sob esta rubrica e referem-se a artigos publicados na Revista. Serão somente consideradas as cartas recebidas no prazo de oito semanas após a publicação do artigo em questão. • Com espaço duplo, com margens de 2,5 cm. • O título (em português e em inglês), os autores (máximo quatro), proveniência, endereço e figuras devem ser especificados de acordo com as normas anteriormente referidas para os artigos originais. • Não podem exceder as 800 palavras. • Podem incluir um número máximo de duas figuras. As tabelas estão excluídas. 3. Casos Clínicos Devem ser enviados sob esta rubrica. • A espaço duplo com margens de 2,5 cm. • O título (em português e em inglês) não deve exceder 10 palavras Os autores (máximo oito) proveniência, endereço e figuras serão especificados de acordo com as normas anteriormente referidas para os artigos originais. O texto explicativo não pode exceder 3.000 palavras e contem informação de maior relevância. Todos os símbolos que possam constar nas imagens serão adequadamente explicados no texto. Contêm um número máximo de 4 figuras e pode ser enviado material suplementar, como por exemplo vídeoclips. 4. Imagens em Cardiologia • A espaço duplo com margens de 2,5 cm. • O título (em português e em inglês) não deve exceder oito palavras • Os autores (máximo seis), proveniência, endereço e figuras serão especificados de acordo com as normas anteriormente referidas para os artigos originais. • O texto explicativo não pode exceder as 250 palavras e contem informação de maior relevância, sem referências bibliográficas. Todos os símbolos que possam constar nas imagens serão adequadamente explicados no texto. • Contêm um número máximo de quatro figuras. 5. Material adicional na WEB A Revista Portuguesa de Cardiologia aceita o envio de material electrónico adicional para apoiar e melhorar a apresentação da sua investigação científica. Contudo, unicamente se considerará para publicação o material electrónico adicional directamente relacionado com o conteúdo do artigo e a sua aceitação final dependerá do critério do Editor. O material adicional aceite não será traduzido e publicar-se-á electronicamente no formato da sua recepção. Para assegurar que o material tenha o formato apropriado recomendamos o seguinte: Normas de publicação da revista portuguesa de cardiologia ANEXO II Símbolos, abreviaturas de medidas ou estatística Formato Extensão Detalhes Texto Word .doc ou docx Tamanho máximo 300 Kb Imagem JPG .jpg Tamanho máximo 10MB Audio MP3 .mp3 Tamanho máximo 10MB Vídeo WMV .wmv Tamanho máximo 30MB Os autores deverão submeter o material no formato electrónico através do EES como arquivo multimédia juntamente com o artigo e conceber um título conciso e descritivo para cada arquivo. Do mesmo modo, este tipo de material deverá cumprir também todos os requisitos e responsabilidades éticas gerais descritas nessas normas. O Corpo Redactorial reserva-se o direito de recusar o material electrónico que não julgue apropriado. ANEXO I DECLARAÇÃO Declaro que autorizo a publicação do manuscrito: Ref.ª ........................................................................................ Título ........................................................................................... ........................................................................................................ ......................................................................................................... ........................................................................................................ do qual sou autor ou c/autor. Declaro ainda que presente manuscrito é original, não foi objecto de qualquer outro tipo de publicação e cedo a inteira propriedade à Revista Portuguesa de Cardiologia, ficando a sua reprodução, no todo ou em parte, dependente de prévia autorização dos editores. Nome dos autores: ............................................................................................. .................................................................................................. ......................................................................................................... Assinaturas: Normas de publicação da revista portuguesa de cardiologia Designação Ampere Ano Centímetro quadrado Contagens por minuto Contagens por segundo Curie Electrocardiograma Equivalente Grau Celsius Grama Hemoglobina Hertz Hora Joule Litro Metro Minuto Molar Mole Normal (concentração) Ohm Osmol Peso Pressão parcial de CO2 Pressão parcial de O2 Quilograma Segundo Semana Sistema nervoso central Unidade Internacional Volt Milivolt Volume Watts Estatística: Coeficiente de correlação Desvio padrão (standard) Erro padrão (standard) da média Graus de liberdade Média Não significativa Número de observações Probabilidade Teste «t» de Student Português A ano cm2 cpm cps Ci ECG Eq °C g Hb Hz h J L ou L m min M mol N Ω osmol peso pCO2 pO2 kg s Sem SNC UI V mV Vol W r DP EPM gl χ NS n p teste t Inglês A yr cm2 cpm cps Ci ECG Eq °C g Hb Hz h J I ou L m min M mol N Ω osmol WT pCO2 pO2 kg sec Wk CNS IU V mV Vol W r SD SEM df χ NS n p t test