Retour sur le congrès de l AHA 2017

Transcription

1 Retour sur le congrès de l AHA 2017 Paul Poirier MD, PhD, FRCPC, FACC, FAHA, FCCS Professeur Faculté de pharmacie Université Laval Responsable du programme de prévention/réadaptation cardiaque

2 Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program Kenneth W. Mahaffey, Bruce Neal, Vlado Perkovic, Dick de Zeeuw, Greg Fulcher, Ngozi Erondu, Wayne Shaw, Elisa Fabbrini, Tao Sun, Qiang Li, Mehul Desai, David R. Matthews, on behalf of the CANVAS Program collaborative group Mahaffey KW, et al. Circulation

3 Introduction Patients with type 2 diabetes mellitus (T2DM) suffer substantial morbidity and mortality from cardiovascular (CV) and renal disease 1,2 Elevated relative and absolute risks of serious outcomes have been observed for both primary and secondary prevention cohorts While the largest absolute benefits of interventions for individual patients are achieved amongst those with established CV disease (secondary prevention), the very large number of diabetes patients without overt CV disease (primary prevention) makes knowledge about the effects of therapies on first events an additional priority 1. Guariguata L, et al. Diabetes Res Clin Pract. 2014;103(2): Liyanage T, et al. Lancet. 2015;385(9981):

4 The CANVAS Program The CANagliflozin cardiovascular Assessment Study (CANVAS) Program was designed to assess the CV safety and efficacy of canagliflozin compared with placebo in a broad range of patients with T2DM 1-4 Canagliflozin reduced the relative risk of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke by 14% (p = 0.02 for superiority) 4 Hospitalized heart failure and serious declines in renal function were reduced by 33% and 40%, respectively 4 An unanticipated ~2-fold increase in risk of amputation was also observed 4 By design, the CANVAS Program enrolled patients with and without prior CV disease to provide insight into the effects of canagliflozin in the primary and secondary prevention settings These analyses describe the efficacy and safety of canagliflozin separately for the primary and secondary prevention cohorts enrolled in the CANVAS Program 1. Neal B, et al. Am Heart J. 2013;166(2): Neal B, et al. Diabetes Obes Metab. 2017;19(3): Neal B, et al. Diabetes Obes Metab. 2017;19(7): Neal B, et al. N Engl J Med. 2017;377(7):

5 Efficacy and Safety Outcomes The following outcomes were evaluated in the primary and secondary prevention cohorts: CV death, nonfatal MI, or nonfatal stroke Individual components of CV death, nonfatal MI, or nonfatal stroke Hospitalization for heart failure All-cause mortality Renal composite outcome of 40% reduction in egfr, requirement for renal replacement therapy, or renal death Safety events of interest, including AEs attributable to genital infection, urinary tract infection, volume depletion events, hypoglycemia, diabetic ketoacidosis, acute pancreatitis, renal AEs, thromboembolism, cancer, fracture, and lower extremity amputation All major CV events, renal outcomes, and deaths as well as selected safety outcomes (diabetic ketoacidosis, acute pancreatitis, and fracture) were assessed by Endpoint Adjudication Committees

6 Participants Discontinuation of study drug similar with placebo and canagliflozin in the overall population (30% vs 29%) in the secondary prevention (29% vs 30%) In the primary prevention cohorts (31% vs 28%) Participant characteristics were well-balanced between treatment groups in the primary and secondary prevention cohorts

7 Outcomes in Secondary and Primary Prevention Cohorts Secondary prevention participants had higher rates of the CV composite outcome compared with the primary prevention participants There were more hospitalizations for heart failure, more deaths, and more of the composite renal outcome in the secondary prevention compared with the primary prevention group Rates of safety outcomes were not different except for lower extremity amputation and volume depletion events, which were more frequent among secondary prevention participants, and urinary tract infection, which was less common in secondary prevention participants

8 Effects of Canagliflozin on CV and Renal Outcomes The primary endpoint of CV death, nonfatal MI, or nonfatal stroke was reduced with canagliflozin compared to placebo (26.9 vs 31.5/1000 patient-years; HR 0.86, 95% CI: 0.75, 0.97; p <0.001 for noninferiority; p = 0.02 for superiority) in the total cohort 1 There was no statistical evidence of heterogeneity (p = 0.18) between the primary and secondary prevention groups There was no statistical evidence of heterogeneity between the primary and secondary prevention cohorts for hospitalization for heart failure, all-cause mortality, and the composite renal outcome (all p values for homogeneity 0.10) 1. Neal B, et al. N Engl J Med. 2017;377(7):

9 Effects of Canagliflozin Versus Placebo on CV and Mortality Outcomes Secondary prevention Primary prevention Overall population CV death, nonfatal MI, or nonfatal stroke CV death Nonfatal MI Nonfatal stroke Hospitalization for any cause Hospitalization for heart failure CV death or hospitalization for heart failure All-cause mortality Hazard ratios and 95% CIs were estimated by using Cox regression models, with stratification by trial for all canagliflozin groups combined versus placebo. *p <0.001 for noninferiority and p = 0.02 for superiority in the overall population. Patients per 1000 patient-years Number Hazard ratio of patients Canagliflozin Placebo (95% CI) p-interaction (0.72, 0.95) (0.74, 1.30) (0.75, 0.97)* (0.70, 1.06) (0.60, 1.43) (0.72, 1.06) (0.63, 0.99) (0.73, 2.00) (0.69, 1.05) (0.67, 1.16) (0.59, 1.61) (0.71, 1.15) (0.84, 0.99) (0.88, 1.15) (0.88, 1.00) (0.51, 0.90) (0.35, 1.15) (0.52, 0.87) (0.65, 0.92) (0.58, 1.19) (0.67, 0.91) (0.75, 1.07) (0.58, 1.07) (0.74, 1.01) Favors Canagliflozin Favors Placebo

10 Effects of Canagliflozin Versus Placebo on Renal Outcomes Secondary prevention Primary prevention Overall population Progression of albuminuria Number of patients Patients per 1000 patient-years Canagliflozin Placebo Hazard ratio (95% CI) p-interaction (0.67, 0.82) (0.60, 0.79) (0.67, 0.79) 40% reduction in egfr, renal replacement therapy, or renal death 40% reduction in egfr Renal replacement therapy Renal death* Hazard ratios and 95% CIs were estimated by using Cox regression models, with stratification by trial for all canagliflozin groups combined versus placebo. *Incidence rates and hazard ratios not calculated due to the small number of events (0.44, 0.79) (0.39, 1.02) (0.47, 0.77) (0.44, 0.81) (0.37, 1.00) (0.47, 0.78) (0.18, 2.64) (0.25, 3.53) (0.30, 1.97) Favors Canagliflozin Favors Placebo 0.85

11 CV Death, Nonfatal MI, or Nonfatal Stroke Secondary Prevention Primary Prevention

12 CV Death Secondary Prevention Primary Prevention

13 Hospitalization for Heart Failure Secondary Prevention Primary Prevention

14 Effects of Canagliflozin on Safety Outcomes Rates of AEs including genital infections, urinary tract infections, fractures, diabetic ketoacidosis and acute pancreatitis were not statistically different between treatment groups in the primary and secondary prevention participants The AE profile for canagliflozin compared with placebo was consistent in the primary and secondary prevention participants (all interaction p values 0.07)

15 Secondary prevention Primary prevention Overall population Male genital infection Female genital infection* Effects of Canagliflozin Versus Placebo on Safety Outcomes Patients per 1000 patient-years Number of patients Canagliflozin Placebo Hazard ratio (95% CI) p-interaction (2.72, 4.98) (2.60, 6.10) (2.12, 7.48) (2.51, 9.24) Urinary tract infection* Lower-extremity amputation All fracture Low-trauma fracture Diabetic ketoacidosis (0.75, 1.29) (0.94, 1.74) (1.43, 3.00) (0.70, 3.29) (0.99, 1.59) (0.94, 1.75) (0.94, 1.61) (0.86, 1.75) (0.56, 38.03) (0.40, 6.16) *For these adverse events, the annualized event rates are reported with data from CANVAS alone through January 7, 2014, because, after this time, only serious adverse events or adverse events leading to discontinuation were collected. In CANVAS-R, only serious adverse events or adverse events leading to discontinuation were collected. Owing to the differences between the 2 trials in methods of collection of the data, an integrated analysis of these adverse events is not possible Favors Canagliflozin Favors Placebo

16 Risk Differences for CV, Renal, and Amputation Outcomes Secondary prevention Primary prevention Overall population CV death, nonfatal MI, or nonfatal stroke Hospitalization for heart failure 40% reduction in egfr, renal replacement therapy, or renal death Lower extremity amputation Number of patients Patients per 1000 patient-years Canagliflozin Placebo Excess number of active patients experiencing the event in 1000 patients over 5 years (95% CI) ( 63, 9) ( 20, 23) ( 42, 4) ( 33, 7) ( 18, 2) ( 25, 7) ( 33, 8) ( 25, 0.5) ( 27, 8) (11, 31) ( 3, 13) (8, 22) Benefit Harm

17 Discussion The CANVAS Program included patients with established CV disease (~2/3) and patients at risk for CV disease (~1/3) Overall CV and renal event rates were higher in secondary prevention compared with primary prevention participants Canagliflozin provided numerically greater reductions in CV and renal outcomes in secondary prevention participants, with no statistical evidence of heterogeneity in relative reductions between groups Rates of common AEs were generally similar between cohorts The rate of lower extremity amputation was ~3-fold higher in the secondary prevention compared with the primary prevention group A statistically significant 2-fold increase in amputation was observed with canagliflozin versus placebo in the secondary prevention group; the result was statistically similar result between groups in the primary prevention cohort, which only reported 33 events Until further information is available on the potential mechanism for amputations with canagliflozin, caution should be used in patients at risk for amputations

18 Benefits and Risks The balance of CV and renal benefits compared with the major safety event of amputations was evaluated by calculating the number of patients with events prevented or caused over 5 years for 1000 treated patients As expected, there were numerically more events prevented in the secondary prevention compared with the primary prevention participants In both cohorts, the number of excess amputation events was numerically lower than the number of prevented cardiorenal outcomes

19 Conclusions In the CANVAS Program that evaluated patients with T2DM and elevated CV risk, participants with prior CV events (secondary prevention) compared with those without prior CV events (primary prevention) had greater absolute rates of CV, renal, and death outcomes Canagliflozin reduced CV and renal outcomes overall, with no statistical evidence of heterogeneity of canagliflozin effects between the primary and secondary prevention participants

20 POISE-2 PeriOperative ISchemic Evaluation-2 Trial Aspirin in patients with previous percutaneous coronary intervention (PCI) undergoing noncardiac surgery: The POISE-2 PCI Substudy Dr. Michelle M. Graham University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, Canada on behalf of POISE-2 Investigators

21 Background Globally >200 million noncardiac surgeries annually 10 million suffer major vascular complication increased mortality, hospitalization, costs Providers commonly encounter patients with previous PCI undergoing surgery increased risk of major perioperative complications Uncertainty remains regarding effects of aspirin in patients with prior PCI who are undergoing noncardiac surgery

22 POISE-2 POISE-2 randomized 10,010 patients having noncardiac surgery to aspirin vs. placebo aspirin did not prevent primary outcome of death/mi but increased risk of major bleeding Steering Committee did not expect randomization of patients with prior PCI and did not pre-specify PCI subgroup analysis however, 470 prior PCI patients were randomized We therefore undertook analyses to determine whether subgroup effect was present among patients with prior PCI

23 Methods Design blinded 2 X 2 factorial RCT Aspirin versus placebo and clonidine versus placebo Eligibility criteria undergoing noncardiac surgery, 45 yrs, at risk of vascular complication Excluded patients BMS <6 weeks before surgery DES <1 year before surgery took aspirin within 72 hrs before surgery

24 Methods 2 aspirin strata initiation stratum continuation stratum Intervention aspirin/placebo (200 mg) just before surgery continued daily (100 mg) 30 days in initiation stratum and 7 days in continuation stratum Primary outcome death or nonfatal MI at 30 days

25 Outcome definitions MI universal definition of MI Major bleed bleeding event Hb 70 g/l and 2 units RBCs; Hb drop 50 g/l and 2 units of RBCs; 4 units of RBCs within 24 hr period; intervention (e.g., embolization); or retroperitoneal, intraspinal, or intraocular bleed

26 Prior PCI subgroup 470 patients with prior PCI randomized at 82 centres in 21 countries 234 randomized to aspirin 236 randomized to placebo 30-day follow-up 99.9% complete

27 PCI characteristics PCI characteristics N (%) Bare-metal stent 255 (54.3) drug-eluting stent 119 (25.3) unknown type of stent 55 (11.7) no stent 41 (8.7) PCI with uncertainty regarding whether stent was used median duration from PCI to noncardiac surgery 2 (0.4%) 64 months (IQR )

28 Outcomes Outcome Aspirin n/n (%) Placebo n/n (%) HR (95% CI) Interaction P Value Death/MI overall trial No Prior PCI Prior PCI 351/4998 (7.0) 337/4764 (7.1) 14/234 (6.0) 355/5012 (7.1) 328/4776 (6.9) 27/236 (11.4) 0.99 ( ) 1.03 ( ) 0.50 ( ) 0.036

29 Outcomes Outcome Aspirin n/n (%) Placebo n/n (%) HR (95% CI) Interaction P Value Death/MI overall trial No Prior PCI Prior PCI 351/4998 (7.0) 337/4764 (7.1) 14/234 (6.0) 355/5012 (7.1) 328/4776 (6.9) 27/236 (11.4) 0.99 ( ) 1.03 ( ) 0.50 ( ) MI overall trial No Prior PCI Prior PCI 309/4998 (6.2) 297/4764 (6.2) 12/234 (5.1) 315/5012 (6.3) 289/4776 (6.1) 26/236 (11.0) 0.98 ( ) 1.03 ( ) 0.44 ( ) 0.021

30 Death/MI in prior PCI patients

31 Outcomes Outcome Aspirin n/n (%) Placebo n/n (%) HR (95% CI) Interaction P Value Major bleeding overall trial No Prior PCI Prior PCI 230/4998 (4.6) 222/4764 (4.7) 8/234 (3.4) 189/5012 (3.8) 180/4776 (3.8) 9/236 (3.8) 1.22 ( ) 1.24 ( ) 0.85 ( ) 0.50

32 Conclusions For every 1000 patients with prior PCI, perioperative aspirin will prevent 59 MIs but cause 8 major bleeds Among those with prior PCI undergoing noncardiac surgery, preoperative aspirin may be more likely to benefit than harm patients

33 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/ APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults American College of Cardiology Foundation and American Heart Association, Inc.

34 Systematic Review Questions on High BP in Adults Question Number Question 1 Is there evidence that self-directed monitoring of BP and/or ambulatory BP monitoring are superior to office-based measurement of BP by a healthcare worker for 1) preventing adverse outcomes for which high BP is a risk factor and 2) achieving better BP control? 2 What is the optimal target for BP lowering during antihypertensive therapy in adults? 3 In adults with hypertension, do various antihypertensive drug classes differ in their comparative benefits and harms? 4 In adults with hypertension, does initiating treatment with antihypertensive pharmacological monotherapy versus initiating treatment with 2 drugs (including fixed-dose combination therapy), either of which may be followed by the addition of sequential drugs, differ in comparative benefits and/or harms on specific health outcomes? BP indicates blood pressure.

35 2017 Hypertension Guideline Classification of BP

36 Definition of High BP COR LOE Recommendation for Definition of High BP I B-NR BP should be categorized as normal, elevated, or stage 1 or 2 hypertension to prevent and treat high BP.

37 Categories of BP in Adults* BP Category SBP DBP Normal <120 mm Hg and <80 mm Hg Elevated mm Hg and <80 mm Hg Hypertension Stage mm Hg or mm Hg Stage mm Hg or 90 mm Hg *Individuals with SBP and DBP in 2 categories should be designated to the higher BP category. BP indicates blood pressure (based on an average of 2 careful readings obtained on 2 occasions, as detailed in DBP, diastolic blood pressure; and SBP systolic blood pressure.

38 Prevalence of Hypertension Based on 2 SBP/DBP Thresholds* SBP/DBP 130/80 mm Hg or Self-Reported Antihypertensive Medication SBP/DBP 140/90 mm Hg or Self- Reported Antihypertensive Medication Overall, crude 46% 32% Men (n=4717) Women (n=4906) Men (n=4717) Women (n=4906) Overall, age-sex 48% 43% 31% 32% adjusted Age group, y % 19% 11% 10% % 44% 33% 27% % 63% 53% 52% % 75% 64% 63% % 85% 71% 78% Race-ethnicity Non-Hispanic White 47% 41% 31% 30% Non-Hispanic Black 59% 56% 42% 46% Non-Hispanic Asian 45% 36% 29% 27% Hispanic 44% 42% 27% 32% The prevalence estimates have been rounded to the nearest full percentage. *130/80 and 140/90 mm Hg in 9623 participants ( 20 years of age) in NHANES BP cutpoints for definition of hypertension in the present guideline. BP cutpoints for definition of hypertension in JNC 7. Adjusted to the 2010 age-sex distribution of the U.S. adult population. BP indicates blood pressure; DBP, diastolic blood pressure; NHANES, National Health and Nutrition Examination Survey; and SBP, systolic blood pressure.

39 2017 Hypertension Guideline Measurement of BP

40 Accurate Measurement of BP in the Office COR I LOE C-EO Recommendation for Accurate Measurement of BP in the Office For diagnosis and management of high BP, proper methods are recommended for accurate measurement and documentation of BP.

41 Out-of-Office and Self-Monitoring of BP COR I LOE A SR Recommendation for Out-of-Office and Self- Monitoring of BP Out-of-office BP measurements are recommended to confirm the diagnosis of hypertension and for titration of BP-lowering medication, in conjunction with telehealth counseling or clinical interventions. SR indicates systematic review.

42 Corresponding Values of SBP/DBP for Clinic, HBPM, Daytime, Nighttime, and 24- Hour ABPM Measurements Clinic HBPM Daytime ABPM Nighttime ABPM 24-Hour ABPM 120/80 120/80 120/80 100/65 115/75 130/80 130/80 130/80 110/65 125/75 140/90 135/85 135/85 120/70 130/80 160/ /90 145/90 140/85 145/90 ABPM indicates ambulatory blood pressure monitoring; BP, blood pressure; DBP diastolic blood pressure; HBPM, home blood pressure monitoring; and SBP, systolic blood pressure.

43 2017 Hypertension Guideline Treatment of High BP

44 Blood Pressure (BP) Thresholds and Recommendations for Treatment and Follow-Up BP thresholds and recommendations for treatment and follow-up Normal BP (BP <120/80 mm Hg) Elevated BP (BP /<80 mm Hg) Stage 1 hypertension (BP /80-89 mm Hg) Stage 2 hypertension (BP 140/90 mm Hg) Promote optimal lifestyle habits Nonpharmacologic therapy (Class I) Clinical ASCVD or estimated 10-y CVD risk 10%* No Yes Reassess in 1 y (Class IIa) Reassess in 3 6 mo (Class I) Nonpharmacologic therapy (Class I) Nonpharmacologic therapy and BP-lowering medication (Class I) Nonpharmacologic therapy and BP-lowering medication (Class I) Reassess in 3 6 mo (Class I) Reassess in 1 mo (Class I)

45 1 y (Class IIa) 3 6 mo (Class I) therapy (Class I) BP-lowering medication (Class I) BP-lowering medication (Class I) Reassess in 3 6 mo (Class I) Reassess in 1 mo (Class I) BP goal met No Assess and optimize adherence to therapy Yes Reassess in 3 6 mo (Class I) Consider intensification of therapy Colors correspond to Class of Recommendation in Table 1. *Using the ACC/AHA Pooled Cohort Equations. Note that patients with DM or CKD are automatically placed in the highrisk category. For initiation of RAS inhibitor or diuretic therapy, assess blood tests for electrolytes and renal function 2 to 4 weeks after initiating therapy. Consider initiation of pharmacological therapy for stage 2 hypertension with 2 antihypertensive agents of different classes. Patients with stage 2 hypertension and BP 160/100 mm Hg should be promptly treated, carefully monitored, and subject to upward medication dose adjustment as necessary to control BP. Reassessment includes BP measurement, detection of orthostatic hypotension in selected patients (e.g., older or with postural symptoms), identification of white coat hypertension or a white coat effect, documentation of adherence, monitoring of the response to therapy, reinforcement of the importance of adherence, reinforcement of the importance of treatment, and assistance with treatment to achieve BP target.

46 2017 Hypertension Guideline Hypertension in Patients With Comorbidities

47 Stable Ischemic Heart Disease COR I I LOE SBP: B-R DBP: C-EO SBP: B-R DBP: C-EO Recommendations for Treatment of Hypertension in Patients With Stable Ischemic Heart Disease (SIHD) In adults with SIHD and hypertension, a BP target of less than 130/80 mm Hg is recommended. Adults with SIHD and hypertension (BP 130/80 mm Hg) should be treated with medications (e.g., GDMT beta blockers, ACE inhibitors, or ARBs) for compelling indications (e.g., previous MI, stable angina) as first-line therapy, with the addition of other drugs (e.g., dihydropyridine CCBs, thiazide diuretics, and/or mineralocorticoid receptor antagonists) as needed to further control hypertension.

48 Stable Ischemic Heart Disease (cont.) COR I IIa IIb LOE B-NR B-NR C-EO Recommendations for Treatment of Hypertension in Patients With Stable Ischemic Heart Disease (SIHD) In adults with SIHD with angina and persistent uncontrolled hypertension, the addition of dihydropyridine CCBs to GDMT beta blockers is recommended. In adults who have had a MI or acute coronary syndrome, it is reasonable to continue GDMT beta blockers beyond 3 years as long-term therapy for hypertension. Beta blockers and/or CCBs might be considered to control hypertension in patients with CAD (without HFrEF) who had an MI more than 3 years ago and have angina.

49 Diabetes Mellitus COR I I IIb LOE SBP: B-R SR DBP: C-EO A SR B-NR Recommendations for Treatment of Hypertension in Patients With DM In adults with DM and hypertension, antihypertensive drug treatment should be initiated at a BP of 130/80 mm Hg or higher with a treatment goal of less than 130/80 mm Hg. In adults with DM and hypertension, all first-line classes of antihypertensive agents (i.e., diuretics, ACE inhibitors, ARBs, and CCBs) are useful and effective. In adults with DM and hypertension, ACE inhibitors or ARBs may be considered in the presence of albuminuria. SR indicates systematic review.

50 2017 Hypertension Guideline Summary of BP Thresholds and Goals for Pharmacological Therapy Plan of Care for Hypertension

51 BP Thresholds for and Goals of Pharmacological Therapy in Patients With Hypertension According to Clinical Conditions Clinical Condition(s) BP Threshold, mm Hg BP Goal, mm Hg General Clinical CVD or 10-year ASCVD risk 10% 130/80 <130/80 No clinical CVD and 10-year ASCVD risk <10% 140/90 <130/80 Older persons ( 65 years of age; noninstitutionalized, 130 (SBP) <130 (SBP) ambulatory, community-living adults) Specific comorbidities Diabetes mellitus 130/80 <130/80 Chronic kidney disease 130/80 <130/80 Chronic kidney disease after renal transplantation 130/80 <130/80 Heart failure 130/80 <130/80 Stable ischemic heart disease 130/80 <130/80 Secondary stroke prevention 140/90 <130/80 Secondary stroke prevention (lacunar) 130/80 <130/80 Peripheral arterial disease 130/80 <130/80 ASCVD indicates atherosclerotic cardiovascular disease; BP, blood pressure; CVD, cardiovascular disease; and SBP, systolic blood pressure.