PREVENTION OF CARDIOVASCULAR DISEASE : A FEW THINGS WE ’ VE LEARNED THIS YEAR A new year is nearly here and with it will come the usual renewed focus by patients on improving their health. What have we learned over this past year to help patients lower their risk of heart disease and improve their heart health? Perhaps the most recent piece of information is that lower is better. Blood pressure, that is, and earlier treatment brings benefit. The 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults defines a normal blood pressure as <120/<80 mm Hg and a blood pressure between 120-129/<80 mm Hg as elevated.1 The new cut-off for hypertension is <130/80 mm Hg. Along with the new categories, there’s a strong emphasis on risk assessment and lifestyle interventions as the initial treatment in a large proportion of these patients. We’ve also learned that even small amounts of physical activity can provide true benefit. Just 30 minutes of physical activity five days a week could prevent one in 12 deaths and one in 20 cases of cardiovascular disease worldwide, according to the PURE study.2 A greater reduction was seen in those who were highly active (750 minutes weekly). At least 150 minutes of moderate-intensity aerobic physical activity throughout the week and muscle strengthening exercise at least two days a week is recommended by the Word Health Organization. Interestingly, the PURE study also found that the physical activity incorporated into our daily lives for traveling to and from work and within our jobs inside and outside the home had the same benefit as leisure activities. The STABILITY trial has shown that as little as 10 minutes a day of walking at a brisk pace (3.5 mph) or 15-20 minutes at a slower pace (2-2.5 mph) can reduce all-cause mortality by 33 percent in patients with stable coronary heart disease. With a doubling of the volume and duration of exercise there were reductions in all-cause and cardiovascular mortality." Elderly patients also benefit from modest levels of physical activity, such as walking, gardening and housework, according to the European Prospective Investigation into Cancer cohort study, with a graded reduction from 12-14 percent in cardiovascular events as activity levels increased." Two studies presented at AHA 2017 may give some insight into how physical activity affects the heart and vasculature. The CARDIA study presented by Henrique Doria de Vasconcellos, MD, et al., showed that as body mass index increases from early adulthood through middle age, there was adverse left atrial remodeling as shown by higher left volumes and lower left atrial function. In this study of 1,160 participants (half were women and half were African American), 3D echocardiography was used to evaluate cardiac structure and adjustments were made for demographics and traditional risk factors. In an analysis from the MESA study, Roberta Florido, MD, et al., found that higher levels of physical activity had salutary changes on cardiac structure and function. In 3,233 MESA participants without cardiovascular disease (half were women; a quarter were African American and a quarter Hispanic), over the 10-year follow-up there was a significant association between higher levels of physical activity, vs. lower, and increases in left ventricular mass and end-diastolic volume as well as stroke volume, but lower left ventricular mass to volume ratio. These findings led the investigators to suggest higher levels of physical activity may contribute to preventing heart failure. Earlier this year, Florido and colleagues published work in JACC: Heart Failure that showed physical activity may lower the risk of myocardial damage in people who are obese, with higher levels of activity associated with lower levels of high sensitivity troponin T after adjustment for traditional risk factors.5 In their accompanying editorial, Tariq Ahmad, MD, MPH, FACC, and Jeffrey M. Testani, MD, MTR, encourage cardiologists to promote healthy habits rather than simply treating heart failure after it has developed. We’re hearing more about the benefit of plantbased diets, including basketball players at the highest levels of the NBA saying it’s improved their performance on the court. The large-scale epidemiologic PURE study, reported in August, found a higher consumption of fruit, vegetable and legumes was associated with a lower risk of non-cardiovascular and total mortality.6 Three to four servings per day (equivalent to 375-500 g/day) appeared to provide the maximum benefits for both non-cardiovascular mortality and total mortality. At AHA 2017, the REGARDS study presented by Kyla M. Lara, MD, et al., found that a greater adherence to the plant-based dietary pattern was associated with a lower risk of heart failure, but no association was found for the four other dietary patterns (convenience, sweets, Southern, alcohol/ salads). None of the 15,569 participants had known coronary artery disease or heart failure at baseline. In another study, presented by Rami S. Najjar, MD, et al., lipoprotein(a) and other atherogenic lipoproteins and particles were significantly reduced after only four weeks of a defined plant-based diet. We’re reminded again that lowering the risk of heart disease can be as easy as eating a variety of nuts. Data from 210,000 people including women from the Nurses’ Health Study and Nurses’ Health Study II and men from the Health Professionals Follow-up Study, with up to 32 years of follow-up, found that regularly supplementing the diet with peanuts, walnuts and tree nuts lowered the risk of developing cardiovascular disease or coronary heart disease.7 Compared with people who never or almost never eat nuts, participants who consumed five or more servings of nuts a week had a 14 percent lower risk of cardiovascular disease and a 20 percent lower risk of coronary heart disease. Even eating walnuts only once a week was associated with reductions of 19 percent and 21 percent, respectively, and eating peanuts at least twice a week had reductions of 13 percent and 15 percent. The late-breaking science in prevention session at AHA 2017 was dominated by studies of drugs. In the first randomized trial to compare high-dose vs. low-dose statin therapy in Asia, the REAL-CAD study showed in Japanese patients that high-dose pitavastatin was superior in reducing cardiovascular events. At 733 centers across Japan, patients with established stable coronary artery disease were randomized to high-dose (4 mg) pitavastatin (n = 6,526) or low-dose (1 mg) (n = 6,528) pitavastatin. Their mean age was 68 years and 83 percent were men. With the high-dose of pitavastatin there was a 19 percent reduction in the primary composite outcome of cardiovascular death, myocardial infarction (MI), ischemic stroke and unstable angina (incidence of 4.3 percent vs. 5.4 percent; hazard ratio [HR], 0.81; 95 percent confidence interval [CI], 0.69-0.95; p = 0.01). The number needed to treat (NNT) for five years to prevent one primary outcome was 63. lower is better. Blood pressure, that is, and earlier treatment brings benefit. Just 30 minutes of physical activity five days a week could prevent one in 12 deaths and one in 20 cases of cardiovascular disease worldwide, according to the as little as 10 minutes a day of walking at a brisk pace … can reduce all-cause mortality by 33 percent in patients with stable coronary heart disease. The results of REAL-CAD are directionally consistent with trials such as PROVE-IT, IDEAL and TNT, which resulted in a Class I indication for high-dose statin therapy among patients with established coronary artery disease, wrote Dharam J. Kumbhani, MD, SM, FACC, on ACC.org. In Japan, moderate doses of statins are most commonly used and there had not been any clear evidence to establish whether doses lower than those recommended in the guidelines were effective in reducing mortality. The REAL-CAD study was terminated two years early because a substantial number of centers were reluctant to continue, thus the final follow-up was not completed in a substantial proportion of patients. Concerns about safety of the higher dose of statins in Asian populations contributes to the reluctance to use it. In this study, only muscle complaints were more frequent in the high-dose vs. low-dose dose group (1.9 percent vs. 0.7 percent; p < 0.001). Rhabdomyolysis was diagnosed in two patients in the high-dose and one patient in the low-dose group. There were significant reductions in the high-dose vs. low-dose groups in the primary outcome plus coronary revascularization (HR, 0.83; p = 0.0002), with an NNT of 41, as well as coronary revascularization, non-target lesion revascularization and all-cause death. New analyses from the FOURIER study presented at AHA 2017 suggest more benefits with evolocumab. In patients with symptomatic lower extremity peripheral arterial disease (PAD) – even in those without a history of MI or stroke – evolocumab added to statin therapy reduced major adverse cardiovascular events and limb events.8 In FOURIER, 3,642 (13.2 percent) patients had PAD, including 1,505 patients without a history of MI or stroke. PAD was defined as intermittent claudication and an ankle brachial index of <0.85 or a history of a peripheral vascular procedure. Results showed that evolocumab consistently and significantly reduced the primary endpoint — a composite of cardiovascular death, MI, stroke, hospital admission for unstable angina, or coronary revascularization – in patients with PAD (HR, 0.79; p = 0.0098) and without PAD (HR, 0.86; p = 0.0003). The key secondary composite endpoint of cardiovascular death, MI or stroke also was significantly reduced in those with and without PAD (HR, 0.73 and 0.81, respectively). Larger absolute risk reductions were seen in PAD patients than non-PAD patients for the primary endpoint (3.5 percent vs. 1.6 percent) and the key secondary endpoint (3.5 percent vs. 1.4 percent). The risk of major adverse limb events also was consistently reduced with evolocumab in patients with and without PAD (HR, 0.58; p = 0.0093). A consistent relationship between lower achieved LDL-C and lower risk of limb events was found and this extended down to <10 mg/dL. Marc P. Bonaca, MD, MPH, et al., write that “the relationship between achieved LDL-C and lower risk of limb events extended down to very low achieved levels of LDL-C.” And these “benefits come with no offsetting safety concerns.” According to Bonaca and colleagues, their data support reducing LDL-C levels to very low targets as a “core focus of preventive therapy in patients with symptomatic lower extremity peripheral artery disease, including those without concomitant coronary or cerebrovascular disease.” In a separate FOURIER trial analysis that looked at 22,351 patients with a history of MI, Marc S. Sabatine, MD, MPH, FACC, et al., found that patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease were at a 34-90 percent greater risk for major vascular events. In addition, these patients experience “substantial relative risk reductions (21-30 percent) and absolute risk reductions (2.6-3.4 percent over three years) with intensive LDL-C lowering with the PCSK9 [inhibitor] evolocumab.” The researchers conclude that “a patient’s history of coronary disease offers a way to tailor PCSK9 inhibitor use to maximize benefit.” An analysis from the CANTOS study found an association between canakinumab therapy, highsensitivity C-reactive protein (hsCRP) and event reduction. In patients with a prior MI, the magnitude of reduction in hsCRP, in the absence of any change in LDL-C, was “strongly related to cardiovascular event reduction and all-cause mortality reduction following canakinumab therapy.” The results were also published in The Lancet." Paul M. Ridker, MD, MPH, FACC, et al., looked at 10,061 men and women post MI with established atherosclerosis and hsCRP ..2 mg/L in 39 countries. Patients randomly received placebo or either 50 mg, 150 mg or 300 mg of canakinumab – a monoclonal antibody targeting interleukin-1.. – given subcutaneously every three months. The median follow-up time was three and four years. Results showed that patients in the canakinumab group who achieved hsCRP concentrations less than 2 mg/L had a 25 percent reduction in major adverse cardiac events, whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or higher. In addition, for those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality and all-cause mortality were both reduced by 31 percent, whereas no significant reduction in the endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or higher. The authors conclude that “the magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment.” In the year ahead, there will be plenty more clinical trials of drug therapy to address primary and secondary prevention of cardiovascular disease. ODYSSEY OUTCOMES, for one, leaps to mind and surely will be on the agenda of a scientific meeting sooner than later. Yet, lifestyle changes, including stopping smoking and moderating alcohol along with diet and physical activity, must be a firm cornerstone of treatment. The accumulating evidence showing sizable and tangible benefits may help with engaging patients in this approach. REFERENCES 1. Whelton PK, Carey RM, Aronow WS, et al. J Am Coll Cardiol; 2017:Nov 13:[Epub ahead of print]. 2. Lear SA, Hu W, Rangarajan S, et al. Lancet 2017;Sept 21:[Epub ahead of print]. 3. Stewart RAH, Held C, Hadziosmanovic N, et al. J Am Coll Cardiol 2017;70:1689-1700. 4. Lachman S, Boekholdt SM, Luben RN, et al. Eur J Prev Cardiol 2017;Nov 22:[Epub ahead of print]. 5. Florido R, Ndumele CE, Kwak L, et al. JACC: Heart Failure 2017;5(5):377-384. 6. Miller V, Mente A, Dehghan M, et al. Lancet 2017;390:2037-49. 7. Guasch-Ferré M, Liu X, Malik VS, et al. J Am Coll Cardiol 2017;70:2519-32. 8. Bonaca MP, Nault P, Giugliano RP, et al. Circulation 2017;Nov 13:[Epub ahead of print]. 9. Ridker PM, MacFayden JG, Everett BM, et al. Lancet 2017;Nov 13:[Epub ahead of print].
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