Cardiovascular disease (CVD) remains still the leading cause of death in the United States, and it is estimated to be the leading cause of death in the developing countries by 2020. In addition, the modifiable cardiovascular risk factors (CVRFs), hypertension, hypercholesterolemia, diabetes, and obesity, have increased significantly and by 2020 will account for 80% of all CVD deaths worldwide. Because the CVD and stroke risk increases significantly for subjects aged >50 years, it has been proposed to treat these subjects with a polypill containing 4 to 5 drugs, which is known to reduce the CVRFs for all subjects aged ≥55 years with an estimated reduction of CVD and stroke by 80%. However, this proposal is neither practical nor cost-effective, because it will involve a large number of subjects. Some investigators suggest to incorporate the coronary artery calcium score (CACS) with the Framingham Risk Score (FRS) to reduce the number of subjects who will benefit from the polypill. They have shown that patients with a CACS = 0 at age 50 years will derive no benefit from the polypill regardless of existing CVRFs, whereas those with a CACS of >100 will derive the best benefit. This strategy will reduce the number of qualified subjects for treatment with the polypill by 60%. Greater benefits will be derived with the combination of CACS and FRS. Additionally, other issues will have to be considered before approval of a polypill, and these issues will be discussed in this concise review. In conclusion, a polypill treatment strategy may be effective in the prevention of CVD and stroke, but, to be cost-effective, it may be reasonable to target patients with a high CACS and FRS.
Cardiovascular disease (CVD) remains still the leading cause of morbidity and mortality in the United States and the developed countries and is expected to be the leading cause of morbidity and mortality in the developing countries by the year 2020. In addition, the main cardiovascular risk factors (CVRFs), hypertension, hypercholesterolemia, diabetes, and obesity, which represent 90% of the modifiable CVRFs, have increased significantly in the United States and other countries and by the year 2020 they will account for 80% of all CVD deaths in the developing countries. Also, the decreased CVD burden that has been achieved with the implementation of effective preventive treatment strategies is threatened to be reversed. Epidemiologic studies show that the CVD risk begins to increase significantly after the age of 50 years for both men and women worldwide who are free of CVD at the age of 50 years. Therefore, these studies indicate that the treatment for the prevention of CVD should begin by the age of 50 years for both genders. However, the effectiveness of pharmacologic therapy for primary prevention is not yet well established, and several investigators have suggested the use of a polypill in subjects with moderate to high CVD risk. Regarding these issues, a MEDLINE search of the English-language literature was conducted from 2003 (the year of the first polypill publication) to the end of 2013. From this search, 7 pertinent publications using the polypill were selected from 40 abstracts reviewed, and they will be discussed in this concise review together with collateral literature.
Primary Cardiovascular Disease and Stroke Prevention
The concept of using a single polypill for primary CVD prevention has gained significant attention since the original publication by Wald and Law in 2003, who suggested that the daily use of a polypill with 6 component drugs (atorvastatin 10 mg/day or simvastatin 40 mg/day, folic acid 0.8 mg/day, aspirin 75 mg/day, and 1/2 the recommended dose of a thiazide diuretic, a β blocker, and angiotensin-converting enzyme [ACE] inhibitor) could significantly decrease the incidence of CHD and stroke. They estimated that the administration of this polypill in subjects aged >55 years would reduce the blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) and decrease the events from ischemic heart disease and stroke by an estimated level of 88% and 80%, respectively, based on the effects of the component drugs from previous publications. The publication of this study created a lot of interest among many investigators and resulted in the design and subsequent publication of 4 randomized studies using polypills with different drug combinations. The findings from these studies, including those from the study by Wald and Law, are summarized in Table 1 , and additional data will be provided here.
| Author | Polypill (Drugs) | Patients (no) | Age (yrs) | F-U (wks) | BP (mm Hg) | Change (mm Hg) | LDL-C (mg/dl) | Change (mg/dl) | Projected CHD | Decrease Stroke |
|---|---|---|---|---|---|---|---|---|---|---|
| Wald & Law | (Statin, aspirin, D, BB, ACEI ∗ ) | NA | ≥55 | NA | 150/90 | −20/11 | 186 | −70 | 86% | 74% |
| Yusuf | (Statin, D, BB, aspirin) | 412 | 45–80 | 12 | 134/85 | −7/6 | 116 | −27 | 62 | 48% |
| Malekzadeh | (Statin, D, ACEI, aspirin) | 241 | 50–79 | 48 | 128/79 | −5/2 | 116 | −19 | 34% | 21% |
| Rodgers | (Aspirin, lisinopril, HCTZ, simvastatin) | 189 | ≥18 | 12 | 134/81 | −10/5 | 143 | −31 | 60% | 50% |
| Wald | (Amlodipine, HCTZ, losartan, simvastatin) | 84 | 51–77 | 12 | 143/86 | −18/10 | 143 | −54 | 72% | 64% |
∗ Indicates that ACEI, BB, and D were given at 1/2 their recommended doses.
The study by Yusuf et al was a phase II, double-blind, proof-of-concept trial. The Indian Polypill Study (TIPS) included 2,053 Indian subjects aged 45 to 80 years, free of CVD at baseline and with 1 CVRF that included hypertension (systolic BP >140 mm Hg or diastolic BP >90 mm Hg, smoking within the past 5 years, waist/hip ratio >0.85 for women and >0.90 for men, LDL-C >120 mg/dl, and high-density lipoprotein cholesterol <40 mg/dl). The objectives of the study were to evaluate the effects of polypill on BP, heart rate, lipids, and 11-dehydrothromboxane B2. The patients were randomized into 9 groups as follows: (1) aspirin 100 mg/day (n = 205), (2) hydrochlorothiazide (HCTZ) 12.5 mg/day (n = 205), (3) simvastatin 20 mg/day (n = 202), (4) HCTZ/ramipril 12.5/5 mg/day (n = 209), (5) HCTZ/atenolol 12.5/50 mg/day (n = 207), (6) HCTZ/ramipril/atenolol 12.5/5/50 mg/day (n = 204), (7) HCTZ/ramipril/atenolol/aspirin 12.5/5/50/100 mg/day (n = 204), (8) simvastatin 20 mg/day (n = 202), and (9) Polycap containing HCTZ/ramipril/atenolol/simvastatin/aspirin 12.5/5/50/20/100 mg/day (n = 412), and they were followed up for 12 weeks. In addition to the data listed in Table 1 , the Polycap reduced the total cholesterol by 32.1 mg/dl, the heart rate by 7 beats/min, and 11-dehydrothromboxane B2 by 283.1/mmol creatinine.
The study by Malekzadeh et al was a double-blind, placebo-controlled trial of 475 Iranian subjects aged 50 to 79 years. The objectives of this study were to evaluate the effects and tolerability of a fixed-dose drug combination therapy with a polypill on BP and LDL-C in adults without elevated BP or lipid levels and free of CVD at baseline. These subjects were randomized to a polypill containing aspirin 81 mg, enalapril 2.5 mg, atorvastatin 20 mg, and HCTZ 12.5 mg (n = 241) or to a placebo (n = 234) and were followed up for 12 months. Additional data to Table 1 include a reduction in total cholesterol by 24 mg/dl (p <0.001), triglycerides by 14 mg/dl (p <0.005), blood glucose by 3.1 mg/dl (p = 0.008), and no change in high-density lipoprotein cholesterol.
The study by Rodgers et al was a randomized, double-blind, placebo-controlled trial of a polypill containing aspirin 75 mg, lisinopril 10 mg, HCTZ 12.5 mg, and simvastatin 20 mg. The objectives of the study were to evaluate the effects of the polypill on systolic BP, LDL-C, and tolerability. This study involved 378 adult subjects aged ≥18 years without an indication for any of the component drugs of the polypill, who had an estimated 5-year CVD risk of >7.5%. The subjects were randomized 1:1 to the Red Heart Pill or to identical placebo and were followed up for 12 weeks. In addition to data in Table 1 , the polypill decreased total cholesterol by 31 mg/dl (p <0.001) and triglycerides by 18 mg/dl (p <0.001).
The study by Wald et al was a randomized, double-blind, placebo-controlled, crossover trial. The trial included 86 subjects (84 completed) aged >50 years without a history of CVD at baseline. They were randomized 1:1 to the polypill containing amlodipine 2.5 mg, losartan 25 mg, and HCTZ 12.5 mg or to placebo and were followed up for 12 weeks; then, they were crossed over to the other treatment for an additional 12 weeks. Additional data to Table 1 include the placebo-subtracted decrease by the polypill of total cholesterol by 62 mg/dl, triglycerides by 16 mg/dl, apolipoprotein B by 0.4 gm/L, and an increase in high-density lipoprotein cholesterol by 1.2 mg/dl.
The study by Bittencourt et al involved 6,814 patients aged 45 to 84 years from the Multi-Ethnic Study of Atherosclerosis, who were, supposedly, eligible to participate in the treatments used by 4 published polypill studies based on their coronary artery calcium scores (CACS) of 0, 1 to 100, and >100. These patients were allocated to these treatment regimens as follows: (1) Wald and Law (n = 4,416), (2) Yusuf et al and TIPS (n = 2,238), (3) Malekzadeh et al and Poly-Iran (n = 2,278), and (4) Rodgers et al and PILL collaboration (n = 3,911), and they were followed up for a hypothetical period of 7.6 years. The objectives of this study were to evaluate the effects the different polypills would have on subjects with minimal or no CVD risk and in those with higher CVD risk, identifying which subjects would benefit with the treatment with a polypill. The expected CHD and CVD event rates of the patients allocated to 4 polypill treatments according to their CACS are listed in Table 2 . The overall rates for the CHD events were low for those patients with CACS = 0, ranging from 1.2 to 1.9 per 1,000 person-years, increased by 2.9 to 4.1-fold for CACS 1 to 100, and by 6.0 to 11-fold per 1,000 person-years for CACS >100. Similarly the expected CVD event rates were low for those with CACS = 0, ranging from 2.5 to 4.0 and increased to 6.0 to 8.5 for CACS 1 to 100, and to 15.8 to 18.4 per 1,000 person-years for those with CACS >100 ( Table 2 ). The hazard ratios (95% confidence intervals) for CHD and CVD events for the participants in the 4 polypill studies based on their CACS are listed in Table 3 . A sensitivity analysis showed that the number needed to treat (NNT) to prevent 1 CVD event in 5 years for subjects with a CACS = 0 was >50 for all treatment regimens. For those with a CACS 1 to 100 the NNT was <50 and for those with a CACS >100 the NNT was <30. This study suggests that if the CACS and the FRS are combined, they would better identify those subjects who stand to benefit the most from the cardiovascular risk reduction with the polypill.
| Wald & Law | TIPS | Poly-Iran | PILL Collaboration | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CAC scores | Zero | 1–100, | >100 | Zero, | 1–100, | >100 | Zero, | 1–100, | >100 | Zero, | 1–100, | >100 |
| Patients (n) | 1718 | 1324 | 1374 | 1312 | 581 | 345 | 1241 | 628 | 409 | 1596 | 1361 | 1154 |
| (%) | (38.9) | (30) | (31.1) | (58.6) | (26) | (15.4) | (54.5) | (27.6) | (17.9) | (40.8) | (29.7) | (29.5) |
| CHD events (%) | 23 (1.3), | 46 (3.5), | 106 (7.7) | 11 (0.8), | 19 (3.3), | 31 (9.0) | 12 (1.0), | 18 (2.9), | 33 (8.1) | 19 (1.2), | 44 (3.8), | 96 (8.3) |
| CHD event | ||||||||||||
| Rate (1000 pr-yrs) | 1.9 | 5.1 | 11.6 | 1.2 | 4.6 | 13.3 | 1.3 | 4.1 | 12.0 | 1.7 | 5.5 | 12.5 |
| CVD events | 45 | 75 | 148 | 23 | 25 | 42 | 22 | 26 | 43 | 45 | 67 | 130 |
| (%) | (2.6) | (5.7) | (10.8) | (1.8) | (4.3) | (18.4) | (1.8) | (4.1) | (10.5) | (2.8) | (5.8) | (11.3) |
| CVD event | ||||||||||||
| Rate (1000 pr-yrs) | 3.7 | 8.3 | 16.5 | 2.5 | 6.1 | 18.4 | 2.5 | 6.0 | 15.8 | 4.0 | 8.5 | 17.2 |
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