Secondary Prevention of Coronary Artery Disease

Diabetes Mellitus

It is widely acknowledged that diabetes is a significant cardiovascular risk factor, being associated with accelerated and more severe CAD (see Chapter 24 ). Although type 1 and type 2 diabetes mellitus have many differences in pathogenesis, age of onset, and strategies for glucose-lowering, both types are associated with greatly increased cardiovascular event rates.

Because one of the hallmarks of diabetes is elevated glucose levels, and because prior epidemiologic studies showed an association between lower glucose levels and reduced cardiovascular events, intensive glucose lowering was postulated to have a beneficial effect on secondary prevention of CAD. Despite the epidemiologic evidence, however, randomized controlled clinical trials evaluating intensive glucose lowering in patients with diabetes to reduce cardiovascular events have not been convincing. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that a strategy of intensive glucose control (glycated hemoglobin [HbA1c] < 6% versus a goal of between 7% and 7.9%) did not reduce the primary endpoint, which was a composite of fatal and nonfatal cardiovascular events. Additionally, medications for intensive glucose control have often been associated with increased cardiovascular events, particularly heart failure events. In a meta-analysis including data from 14 trials and 95,502 patients, glucose-lowering drugs or strategies were associated with a 1.7-kg weight gain and an increased risk of heart failure compared with standard care (relative risk [RR] 1.14, 95% confidence interval [CI] 1.01–1.30; p = 0.041).

Of the currently available oral glucose lowering medications, metformin is perhaps the most studied. In the United Kingdom Prospective Diabetes Study (UKPDS), overweight patients with newly diagnosed type 2 diabetes mellitus were randomized to an intensive glucose control strategy that included metformin versus usual care. Whereas lowering blood glucose had no significant effect on cardiovascular complications in the overall trial, there was a 16% reduction (which was not statistically significant, p = 0.052) in the risk of combined fatal or nonfatal myocardial infarction (MI) and sudden death in the metformin arm. The current recommendation from the 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease (SIHD) recommends that patients with ischemic heart disease (IHD) and diabetes mellitus be treated to a HbA1c goal of less than 7% (LOE: B). These guidelines further specifically state that the drug rosiglitazone should not be initiated in patients with SIHD (LOE: C).

A potentially promising new class of oral hypoglycemic agents is the sodium/glucose cotransporter 2 (SGLT2) inhibitor class. In normal physiologic states, glucose is filtered from the blood by the kidney but is then “reclaimed” into the bloodstream via renal reabsorption of glucose (which has been postulated to be an evolutionary adaptation aimed at preserving calories). Renal SGLT2 is expressed in the proximal tubule and responsible for the majority (> 90%) of glucose reabsorption through active transport of glucose (against a concentration gradient) by coupling it to the downhill transport of sodium (Na ⁺ ). When SGLT2 is inhibited, less glucose is reclaimed and more Na ⁺ is excreted. For hypertensive patients with diabetes, these agents have demonstrated an additional benefit of blood pressure (BP) reduction compared with placebo through renal sodium loss.

The 2015 EMPA Reg trial showed beneficial results with the SGLT2 inhibitor empagliflozin. The EMPA Reg trial involved 7020 patients with type 2 diabetes and high cardiovascular risk who, in addition to receiving standard care, were randomized to receive empagliflozin or placebo. The individuals randomized to empagliflozin had a lower rate of the primary composite cardiovascular outcome and of death from any cause than did patients randomized to placebo.

Hypertension

Multiple randomized controlled trials have demonstrated that treating hypertension reduces cardiovascular events in patients both with and without known IHD, even in very-elderly hypertensive individuals. This has not been controversial. What has been controversial, however, is the optimal blood pressure goal to achieve this benefit. Whereas it is widely accepted that elevated blood pressure is a significant risk factor, excessively low blood pressure is also of concern, especially in patients with known CAD. According to the J-curve phenomenon, an excessive lowering of diastolic BP might impair coronary perfusion, leading to adverse cardiovascular events. In order to find the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD, the J-curve revisited study evaluated 10, 001 patients with CAD in the Treating to New Targets Trial. The investigators found a nonlinear relationship between BP and CVD events, with a higher risk of CVD at lower BPs (110–120/60–70 mm Hg). The adverse events which were higher with lower BP were all-cause mortality, cardiovascular mortality, nonfatal MI, and angina. Conversely, stroke outcomes were reduced with the lower BPs. In another recent post hoc analysis of data of 22,576 patients with hypertension and CAD studied in the International Verapamil-Trandolapril Study (INVEST), the relationship between BP and the primary outcome of all-cause mortality and total MI was found to be J-shaped, particularly for diastolic BP, with a nadir at 119/84 mm Hg. For the outcome of stroke, the investigators did not find a J-curve. However, other investigators note that there is no evidence of harm in treating BP down to a level of 115/75 mm Hg. The 2012 American College of Cardiology (ACC)/AHA SIHD guidelines recommend a BP goal of below 140/90 mm Hg (LOE: A).

Nonetheless, since these guidelines were released, a new study suggests that a lower BP goal will provide even better outcomes for high cardiovascular–risk patients. The Systolic Blood Pressure Intervention Trial (SPRINT) randomized 9361 patients at high cardiovascular risk (61% with a Framingham 10-year CVD risk score ≥ 15%, 20% with CVD, 28% with chronic kidney disease, and 28% older than 75 years) to either a standard BP treatment arm or an intensive BP treatment arm. A total of 4678 patients were assigned to the intensive arm with a goal systolic BP of less than 120 mm Hg, and 4683 were assigned to the standard treatment arm with a goal systolic BP of less than 140 mm Hg. The participants were followed for an average of 3.2 years before the trial was prematurely terminated due to benefit. The investigators found a 25% reduction in the primary outcome (a composite of MI, heart failure, stroke, and total mortality) and a 27% reduction in all-cause mortality among participants who were randomized to the more intensive systolic BP goal of less than 120 mm Hg, compared to participants assigned to the standard treatment arm with a goal of less than 140 mm Hg.

Of note, there were more side effects associated with tighter BP control in SPRINT. Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury were higher in the intensive-treatment group than in the standard-treatment group. An important caveat is that SPRINT was an open-label study, i.e., was not blinded. In addition, patients with diabetes or prior stroke were excluded from this trial, so these results may not be generalizable to these populations. Finally, the elevated risk profile seen in SPRINT was largely driven by advancing age and chronic kidney disease. Notwithstanding these caveats, current evidence suggests that, in patients with CAD, a systolic BP goal of less than 120 mm Hg may improve outcomes. Consistent with these findings, a 2015 meta-analysis by Ettehad et al. analyzed 123 studies with 613, 815 participants and came to similar conclusions. These investigators found that for every 10 mm Hg reduction in systolic BP there was a significant reduction in the risk of major cardiovascular disease events (RR 0.80, 95% CI 0.77–0.83), coronary heart disease (0.83, 0.78–0.88), stroke (0.73, 0.68–0.77), and heart failure (0.72, 0.67–0.78), and a significant 13% reduction in all-cause mortality (0.87, 0.84–0.91). The investigators concluded that there is “strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg.”

In patients with hypertension and chronic CAD, most will require a combination of medications, including a thiazide-type diuretic, to achieve optimal BP control. Angiotensin-converting enzyme inhibitors (ACE-I) may also improve outcomes in patients with CAD, especially in those with a history of MI, left ventricular (LV) dysfunction, chronic kidney disease (CKD) or diabetes mellitus. Angiotensin receptor blockers (ARBs) may improve outcomes in the same groups of patients but should be avoided in combination with ACE-I due to an increase in serious adverse events with this combination. β-Blockers improve outcomes in specific populations such as patients with angina pectoris, a history of MI, or LV dysfunction. Aldosterone antagonists improve outcomes in patients with LV dysfunction and heart failure, and calcium antagonists may be useful in the treatment of angina.

Dyslipidemia

Dyslipidemia is a powerful risk factor for atherosclerotic cardiovascular disease (ASCVD). In 2013, the ACC and AHA published guideline recommendations on managing blood cholesterol to reduce ASCVD risk. As with prior cholesterol guidelines, these new recommendations were written with the goal of reducing the risk of atherosclerotic disease, but unlike prior recommendations these guidelines were written using only the highest quality evidence base (randomized controlled trials, or high quality systematic reviews, and meta-analyses). This evidence base was used to specifically define which lipid-modulating strategies were most effective at reducing hard cardiovascular outcomes such as MI, stroke, and cardiovascular death and concluded that the most powerful strategy, with the greatest evidence base, was statin therapy. This is distinct from prior guidelines, which offered several options for pharmacotherapies to reduce cholesterol. These guidelines also stressed that the appropriate intensity of statin therapy should be used with the recommended intensity being defined by an individual’s cardiovascular risk rather than the absolute low-density lipoprotein cholesterol (LDL-C) level. These guidelines further define which patients are expected to benefit from statin therapy, and these are known as the statin benefit groups. The four statin benefit groups are:

• 1.

  adults with clinical established ASCVD,

• 2.

  adults with LDL-C > 190 mg/dL,

• 3.

  adults (40–75 years of age) with either type 1 or type 2 diabetes with LDL-C of 70–189 mg/dL,

• 4.

  adults (40–75 years of age) with > 7.5% 10-year ASCVD risk with LDL-C of 70–189 mg/dL.

At the time of writing of the 2013 cholesterol guidelines, no other lipid-altering medications had been shown in randomized controlled clinical trials to provide additional cardiovascular risk reduction above and beyond statin therapy for secondary prevention and some therapies had demonstrated potential harms.

The Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial tested a strategy of adding niacin-based therapy to statin therapy and found that there was no clinical benefit from the addition of niacin to simvastatin. More recently, the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial confirmed similar findings with the use of extended-release niacin–laropiprant added to the background of simvastatin 40 mg. In this trial there was a significant increase in serious adverse events such as an increased incidence of diabetes and gastrointestinal and musculoskeletal side effects with the addition of the niacin-based therapy to statin therapy. Similarly, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial demonstrated no additional benefit of adding fenofibrate to statin therapy in patients with diabetes.

Since these guidelines were released, however, the results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) were released. IMPROVE-IT showed that the combination of simvastatin and ezetimibe compared to simvastatin alone had a 2% absolute risk reduction in the primary composite cardiovascular outcome in patients with recent acute coronary syndrome (ACS). Subgroup analysis showed that the benefits were greatest in the subgroup of patients with diabetes. Given that this trial took approximately 7 years to complete, the results also showed the excellent safety of this combination therapy in patients with prior ACS.

The 2013 ACC/AHA guidelines for management of blood cholesterol in the United States departed from a prior paradigm focused on lipid levels, toward a new paradigm focused primarily on cardiovascular risk. By contrast, the current European guidelines for the management of hyperlipidemia rely on a combination of lipid levels and CVD risk to identify adults in need of statin therapy. In 2011, the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) released guidelines for the management of dyslipidemias. These EAS/ESC dyslipidemia guidelines recommend a “treat to risk group” approach and categorize patients into four risk levels: very high risk, high risk, moderate risk, and low risk. Very-high-risk patients include any of the following: (1) documented CVD by invasive or noninvasive testing; (2) previous MI, ACS, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), ischemic stroke, or peripheral arterial disease; (3) diabetes mellitus type 2 or type 1 with target organ damage; (4) moderate to severe chronic kidney disease (defined as glomerular filtration rate < 60 mL/min per 1.73m ² ); or (5) a calculated 10-year risk SCORE (Systematic Coronary Risk Estimation) of greater than or equal to 10%. Table 30.1 displays the ESC and ACC/AHA guidelines for secondary prevention.

Another promising class of cholesterol-lowering agents for CAD secondary prevention is the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies. The two currently Food and Drug Administration (FDA)-approved PCSK9 inhibitors are alirocumab and evolocumab, which have been shown to produce LDL-C reductions of up to 73%. While we await outcomes studies with these two agents, there is currently no specific place for routine use of these agents in secondary prevention, but these agents may ultimately have a role in: (1) ASCVD patients on maximally tolerated statin therapy with inadequate LDL-C reduction, (2) ASCVD patients with recurrent cardiovascular (CV) events while on maximally tolerated statin therapy, and (3) patients with statin intolerance. The guidelines also emphasize the importance of long-term therapeutic lifestyle changes in addition to pharmacologic therapy.

Smoking Cessation

Tobacco use greatly increases the risk of a first or a recurrent cardiac event. Patients with CAD who continue to smoke are more likely to have postinfarction angina and are twice as likely to suffer a subsequent MI as those who quit. Observational studies suggest that smoking cessation will reduce the risk of cardiovascular mortality by up to 50% over the ensuing years; thus smoking cessation remains one of the most effective secondary prevention interventions available. A 2004 systematic review from the Cochrane database reviewed twenty studies that evaluated the effect of smoking cessation on subsequent cardiac events. This analysis found that there was a 36% reduction in the RR of mortality for patients who quit smoking compared with those who continued smoking (RR 0.64, 95% CI 0.58–0.71). There was also a significant reduction in nonfatal MIs (RR 0.68, 95% CI 0.57–0.82). The authors concluded that smoking cessation is associated with a substantial reduction in all-cause mortality among patients with CHD and that this 36% risk reduction compares favorably with other secondary preventive strategies.

In addition to cessation of active smoking, avoidance of exposure to second-hand smoke (SHS) is also important as a secondary preventive measure. Several reports, including two recent separate meta-analyses of 17 and 18 individual studies, assessed the association of SHS with heart disease. Both estimated that nonsmoking spouses of smoking partners experience an increased risk of heart disease of approximately 25% (95% CI 17%–32%). A review of six studies examining the association between workplace SHS and CVD found a positive association in five of the six studies and a significant dose (exposure)–response relationship between the intensity of exposure to SHS (number of cigarettes smoked by coworkers) and coronary risk. Finally, studies in which coronary event rates were assessed in municipalities that have instituted complete outdoor smoking bans, before and after the bans took place, have revealed impressive reductions in MIs within months of initiation of the smoking bans. These data strongly suggest that avoidance of all environmental smoke is prudent as a secondary prevention measure (LOE: B).

Lifestyle Risk Factors

All patients with chronic CAD should be counseled about the need for lifestyle modification including smoking cessation, weight control, increased physical activity, alcohol moderation, and sodium reduction, along with emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products (LOE: B).