Review of the top 5 cardiology studies of 2017-18

Each year, numerous studies are published in the discipline of cardiology. Given that many of these interventions are specialized, relatively few are relevant to primary care practice. Therefore, it can be onerous to remain knowledgeable about the current literature. This article presents a brief synopsis of the top 5 (with 1 honorable mention) recently published cardiology-based studies identified by primary care practitioners as being relevant to their practice and thus likely to affect patient care.

Methods

The methodology for study selection was similar to previous publications.^1-3 Briefly, a group of hospital-based pharmacists practising in cardiology identified a list of 19 potentially relevant cardiology studies published in 2017-18. These studies, along with accompanying abstracts and citations, were included in an online survey emailed to all pharmacists subscribed to the Primary Care Pharmacy Specialty Network of the Canadian Pharmacists Association/Canadian Society of Hospital Pharmacists. This voluntary group of 411 members from across Canada uses an electronic mailing list to facilitate communication and networking among pharmacists practising in primary care. Respondents were instructed to select up to a maximum of 5 cardiology studies relevant to their practice area. The survey was open for 3 weeks, and 1 reminder email was sent.

Results

There were 39 respondents. Appendix 1 (available online at www.cpjournal.ca) lists the studies and voting frequency. The 3 trials receiving the most votes addressed the effect of acetylsalicylic acid (ASA) in patients without preexisting cardiovascular disease (CVD).^4-6 The next 2 addressed the prevention of cardiovascular events with sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus and anticoagulation for stable CVD, respectively.^7,8 For completeness, the sixth trial was chosen for inclusion since it also investigated the cardiovascular effect of an SGLT2 inhibitor.⁹

Primary Cardiovascular Prevention

The benefit of low-dose ASA in the secondary prevention of CVD is well established.^10,11 However, its role in primary prevention is controversial, as the benefits in cardiovascular risk reduction may not outweigh the increased risk of bleeding. Two meta-analyses of trials that investigated ASA in patients without CVD did not demonstrate an overall benefit.^11,12 However, a subsequent meta-analysis showed a modest decrease in all-cause mortality with low-dose ASA in primary prevention patients.¹³ This has led to discordance among guidelines: the 2011 Canadian Cardiovascular Society and 2016 European Society of Cardiology guidelines do not recommend the routine use of low-dose ASA in patients without CVD,^14,15 but the 2012 American College of Chest Physicians guidelines suggest low-dose ASA for patients ≥50 years of age.¹⁶ The 2018 Canadian Diabetes Association guidelines do not recommend the routine use of ASA for primary prevention of CVD in patients with diabetes but endorse that it may be considered in patients with additional cardiovascular risk factors.¹⁷ Older patients are of particular concern because they have an increased risk of both CVD and bleeding.^18,19 However, the benefit-risk ratio of ASA for primary prevention in older adults is unknown, as these patients have been underrepresented in clinical trials to date. Three highly anticipated trials were recently published to help clarify this long-standing controversy.

ASPREE: Effect of aspirin on cardiovascular events and bleeding in the healthy elderly (N Engl J Med 2018)

Background: The objective of this multicentre, double-blind randomized controlled trial (RCT) was to determine the effects of ASA in elderly patients with no history of CVD.⁴

Patients: Patients aged ≥70 years (or ≥65 years if black or Hispanic in the United States) were included. Exclusion criteria consisted of patients with established CVD, atrial fibrillation, uncontrolled hypertension, anemia, dementia, significant physical disability or life expectancy <5 years. Patients at high risk of bleeding or those currently taking an antiplatelet or anticoagulant agent were also excluded.

Intervention and control: Patients were randomized to enteric-coated ASA 100 mg daily or matching placebo.

Outcomes: The primary endpoint was a composite of death, dementia or persistent physical disability, which was reported in separate publications.^20,21 Secondary outcomes included a composite of major cardiovascular events (fatal coronary heart disease, nonfatal myocardial infarction [MI], fatal or nonfatal stroke or hospitalization for heart failure) and the composite of major bleeding (hemorrhagic stroke, symptomatic intracranial bleeding or clinically significant extracranial bleeding).⁴

Results: A total of 19,114 patients were enrolled (median age 74 years, 44% male) and followed for a median of 4.7 years. In the final year of the trial, adherence rates were low, at approximately 63% in both groups. The primary analysis showed that ASA did not prolong disability-free survival.²⁰ Furthermore, higher all-cause mortality with ASA was observed, but the analysis was not corrected for multiple comparisons and thus could have been a chance finding.²¹ There was no significant difference in major cardiovascular events with ASA versus placebo (10.7 vs 11.3 events per 1000 person-years; hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.83-1.08).⁴ Major hemorrhage was significantly higher with ASA (8.6 vs 6.2 events per 1000 person-years; HR, 1.38; 95% CI, 1.18-1.62), which was primarily driven by an increase in upper gastrointestinal and intracranial bleeding.

ASCEND: Effects of aspirin for primary prevention in persons with diabetes mellitus (N Engl J Med 2018)

Background: This multicentre, double-blind RCT evaluated the effect of ASA on the incidence of vascular and bleeding events in diabetic patients with no history of CVD.⁵

Patients: Included were diabetic patients aged ≥40 years with no evidence of CVD. Excluded were those with a contraindication to ASA or clinically significant condition that could inhibit adherence.

Intervention and control: Patients were randomized to enteric-coated aspirin 100 mg daily or matching placebo.

Outcomes: The primary efficacy endpoint was the first serious vascular event, defined as a composite of nonfatal MI, nonfatal stroke (excluding intracranial hemorrhage) or transient ischemic attack (TIA) or death from any vascular cause. The primary safety endpoint was the first major bleeding event, defined as a composite of intracranial hemorrhage, sight-threatening eye bleeding, gastrointestinal bleeding or other serious bleeding that resulted in hospitalization, transfusion or death. Secondary outcomes included gastrointestinal cancer and the composite of any serious vascular event or arterial revascularization procedure.

Results: A total of 15,480 patients (mean age 63 years, 63% male) were randomized and followed for a mean of 7.4 years. At baseline, the median duration of diabetes was 7 years, mean glycosylated hemoglobin (A1c) was 7.2% and 36% were taking ASA. Compared with placebo, ASA reduced the primary efficacy endpoint (8.5% vs 9.6%; relative risk [RR], 0.88; 95% CI, 0.79-0.97; number needed to treat [NNT] 91) and secondary outcome of any serious vascular event or revascularization (10.8% vs 12.1%; RR, 0.88; 95% CI, 0.80-0.97; NNT 77). However, ASA also increased major bleeding events (4.1% vs 3.2%; RR, 1.29; 95% CI, 1.09-1.52; number needed to harm [NNH] 112), primarily gastrointestinal bleeding. There was no significant difference in the rate of gastrointestinal cancer between groups.

ARRIVE: Use of aspirin to reduce the risk of initial vascular events in patients at moderate risk of cardiovascular disease (Lancet 2018)

Background: The objective of this multicentre, double-blind RCT was to investigate the efficacy of ASA for the primary prevention of cardiovascular events in moderate-risk patients.⁶

Patients: Eligible men were aged ≥55 years with 2 to 4 cardiovascular risk factors (dyslipidemia, hypertension, current smoker or family history of CVD), and eligible women were aged ≥60 years with ≥3 cardiovascular risk factors. Patients were excluded if they had diabetes, were already receiving antiplatelet or anticoagulant therapy or were considered to be at high risk of bleeding.

Intervention and control: Patients were randomized to enteric-coated aspirin 100 mg daily or matching placebo.

Outcomes: The primary outcome was the first major vascular event, defined as a composite of MI, unstable angina, TIA, stroke or cardiovascular death. Secondary outcomes included all-cause mortality, a composite of the primary endpoint minus TIA and unstable angina and the individual components of the primary outcome. Safety endpoints were hemorrhagic events and other treatment-related adverse events.

Results: A total of 12,546 patients (mean age 64 years, 70% male) were included and followed for a median of 5 years. In the intention-to-treat analysis, there was no significant reduction in the primary composite outcome with ASA vs placebo (4.3% vs 4.5%; HR, 0.96; 95% CI, 0.81-1.13). In addition, there was no significant difference in any of the secondary outcomes. Regarding safety endpoints, the incidence of gastrointestinal bleeding was significantly higher in the ASA group (0.97% vs 0.46%; HR, 2.11; 95% CI, 1.36-3.28; NNH 197) as was the overall incidence of treatment-related adverse events (16.8% vs 13.5%, p < 0.0001; NNH 31).

Implications for practice: The ASCEND trial demonstrated that the use of ASA reduced vascular events in patients with diabetes but without CVD. However, in nondiabetic patients at moderate cardiovascular risk (i.e., the ARRIVE trial) and elderly patients without CVD (i.e., the ASPREE trial), the use of ASA did not significantly reduce cardiovascular events. Notably, the statistical power of these trials may have been limited due to the low event rates. Regardless, an increase in bleeding (primarily gastrointestinal) was demonstrated in all trials. In particular, the incidence of bleeding in the ASPREE trial was markedly higher than in previous trials that included younger patients.¹⁸ Use of ASA for primary prevention in patients with diabetes or nondiabetic patients with cardiovascular risk factors should be approached judiciously and based on a discussion of the benefits and risks of therapy, as well as the patient’s values and preferences. For healthy elderly patients without CVD, the use of ASA for primary prevention was harmful overall and should not be recommended.

Diabetes Mellitus

CANVAS: Canagliflozin and cardiovascular and renal events in type 2 diabetes (N Engl J Med 2017)

Background: Since 2008, the US Food and Drug Administration has required manufacturers of all new antidiabetic drugs to conduct trials to demonstrate cardiovascular safety.²² The “CANVAS Program” analyzed data from 2 separate multicentre, double-blind RCTs (CANVAS and CANVAS-R) using a noninferiority progressing to superiority analysis. Both compared the effect of canagliflozin, an SGLT2 inhibitor, to placebo in adults with type 2 diabetes and at high risk of cardiovascular events.⁷

Patients: Eligible patients were ≥30 years of age with a history of symptomatic atherosclerotic CVD or ≥50 years of age with ≥2 cardiovascular risk factors (e.g., systolic blood pressure >140 mmHg on treatment, diabetes for >10 years or current smoker) and an A1c between 7% and 10.5%. Patients were excluded if they had type 1 diabetes or a stroke, acute coronary syndrome or revascularization procedure within 3 months of screening.

Intervention and control: Patients were randomized to canagliflozin 100 mg or 300 mg daily or matching placebo, in addition to standard care.

Outcomes: The primary outcome for noninferiority was a composite of death from cardiovascular causes, nonfatal MI or nonfatal stroke. Secondary outcomes included all-cause mortality, cardiovascular mortality and a composite outcome of cardiovascular mortality or hospitalization for heart failure.

Results: A total of 10,142 patients (median age 63 years, 64% male) were randomized and followed for a mean of 3.6 years. Approximately 66% had established CVD, with a mean A1c of 8.2%. Compared with placebo, the addition of canagliflozin to standard care significantly reduced the primary composite outcome (26.9 vs 31.5 participants per 1000 patient-years; HR, 0.86; 95% CI, 0.75-0.97), as well as the secondary composite of cardiovascular mortality or hospitalization for heart failure (16.3 vs 20.8 participants per 1000 patients-years; HR, 0.78; 95% CI, 0.67-0.91). However, there was no significant difference in any of the individual components of the primary composite outcome or all-cause mortality. With respect to safety, canagliflozin had a higher rate of genital infections, volume depletion and fractures (all of which are known adverse effects of canagliflozin) compared with placebo, as well as an unexpected increase in the risk of amputations (6.3 vs 3.4 participants per 1000 patient-years; HR, 1.97; 95% CI, 1.41-2.75).

Implications for practice: The CANVAS trials demonstrated that in patients with type 2 diabetes at high risk of CVD, the addition of canagliflozin to standard therapy significantly lowered the risk of death from cardiovascular causes, nonfatal MI or nonfatal stroke. Accordingly, the 2018 Canadian Diabetes Association guidelines now recommend the use of SGLT2 inhibitors for patients with clinical CVD and unmet glycemic targets while on existing antihyperglycemic therapy.²³ However, the risk of adverse effects, as well as other practical considerations (e.g., cost), need to be considered and discussed with patients before initiating therapy.

DECLARE-TIMI 58: Dapagliflozin and cardiovascular outcomes in type 2 diabetes (N Engl J Med 2018)

Background: This multicentre, double-blind, noninferiority RCT compared dapagliflozin, another SGLT2 inhibitor, to placebo in patients with type 2 diabetes and established or at risk for atherosclerotic CVD.⁹ If noninferiority was confirmed, then a superiority analysis was performed.

Patients: Patients ≥40 years of age with type 2 diabetes, an A1c between 6.5% and 11.9% and creatinine clearance ≥60 mL/minute were eligible for inclusion. Patients also had to have established CVD or multiple cardiovascular risk factors (e.g., hypertension, dyslipidemia or tobacco use).

Intervention and control: Patients were randomized to dapagliflozin 10 mg daily or matching placebo, in addition to standard care.

Outcomes: The primary outcome for noninferiority was a composite of cardiovascular death, MI or ischemic stroke. An additional composite outcome of cardiovascular death or hospitalization for heart failure was added in response to the results of the EMPA-REG OUTCOME trial.²⁴

Results: A total of 17,160 patients (mean age 64 years, 63% male) were included and followed for a median of 4.2 years. Most patients (59%) had multiple cardiovascular risk factors, while the remaining 41% had established CVD. Dapagliflozin was noninferior, but not superior, to placebo for the primary composite outcome (8.8% vs 9.4%; HR, 0.93; 95% CI, 0.84-1.03). However, there was a significant reduction in the composite outcome of cardiovascular death or hospitalization for heart failure (4.9% vs 5.8%; HR, 0.83; 95% CI, 0.73-0.95; NNT 112), which was primarily driven by a reduction in heart failure hospitalizations. Cardiovascular death and all-cause death were not significantly different between groups. Regarding safety, there was an increase in genital infections and diabetic ketoacidosis with dapagliflozin compared with placebo (NNH 125 and 500, respectively). Rates of major hypoglycemia and acute kidney injury were lower in the dapagliflozin group, while rates of amputation and fracture were similar between groups.

Implications for practice: This trial showed that dapagliflozin was noninferior (but not superior) to placebo with respect to major cardiovascular events in patients with type 2 diabetes. This is contrary to evidence for canagliflozin and empagliflozin, both of which reduced cardiovascular events when compared with placebo.^7,24 Of note, dapagliflozin reduced the rate of hospitalizations for heart failure versus placebo, which is consistent with the other agents. The 2018 Canadian Diabetes Association guidelines do not recommend a specific SGLT2 inhibitor(s) over another.²³ Thus, patient-specific factors need to be considered when contemplating therapy. However, an indirect comparison of the clinical trials to date shows that dapagliflozin has less favorable cardiovascular safety data compared with the 2 aforementioned SGLT2 inhibitors.

Stable Cardiovascular Disease

COMPASS: Rivaroxaban with or without aspirin in stable cardiovascular disease (N Engl J Med 2017)

Background: The COMPASS trial was a multicentre, double-blind RCT that assessed the safety and efficacy of rivaroxaban with or without low-dose ASA, as compared with low-dose ASA alone, in patients with stable atherosclerotic CVD.⁸

Patients: Included were adult patients with established coronary artery disease (CAD) and/or peripheral artery disease (PAD). Patients with CAD were also required to be ≥65 years of age or have ≥1 of the following: atherosclerosis in ≥2 vascular beds or ≥2 additional high-risk characteristics (current smoker, diabetes, heart failure, estimated glomerular filtration rate <60 mL/minute or non-lacunar ischemic stroke >1 month earlier). Those at a high risk of bleeding or with a need for ongoing antithrombotic therapy other than ASA, stroke ≤1 month, any prior hemorrhagic or lacunar stroke, severe heart failure or an estimated glomerular filtration rate <15 mL/minute were excluded.

Intervention and control: Patients were randomized to receive 1 of 3 regimens: ASA 100 mg daily, rivaroxaban 5 mg twice daily or rivaroxaban 2.5 mg twice daily plus ASA 100 mg daily (i.e., dual pathway therapy). Furthermore, patients not already on a proton pump inhibitor at baseline were also randomized to pantoprazole or placebo, the results of which have not yet been published.

Outcomes: The primary efficacy outcome was a composite of cardiovascular death, stroke or MI. The primary safety outcome was major bleeding based on modified International Society of Thrombosis and Haemostasis criteria (fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation or any bleeding that led to hospitalization).

Results: A total of 27,395 patients were included (mean age 68 years, 78% male). Ninety-one percent had CAD while 27% had PAD. The study was terminated prematurely after a mean follow-up of 23 months owing to efficacy with the dual-pathway therapy regimen. There was a 1.3% absolute risk reduction in the primary efficacy outcome with low-dose rivaroxaban plus ASA as compared with ASA alone (HR, 0.76; 95% CI, 0.66-0.86; NNT 77), which was mainly driven by a reduction in stroke. However, there was also a 1.2% absolute increase in major bleeding (HR, 1.70; 95% CI, 1.40-2.05; NNH 84), which was largely attributable to an increase in gastrointestinal bleeding. Rivaroxaban monotherapy did not reduce the primary efficacy outcome compared with ASA monotherapy, but it increased major bleeding.

Implication for practice: The COMPASS trial demonstrated that a dual-pathway therapy regimen of low-dose rivaroxaban and ASA reduced thrombotic outcomes in high-risk patients with CAD and/or PAD, although at the expense of a comparable increase in major bleeding events. Thus, the net clinical benefit is questionable and likely dependent on the patient’s baseline cardiovascular and bleeding risk—this necessitates a careful assessment of the patient’s risk factors, as well as their values and preferences. Use of a dual-pathway therapy regimen should be considered in patients with stable CAD and/or PAD with a high thrombotic risk, low bleeding risk and the ability to adhere to a twice-daily regimen. ■