Polycap

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Polycap is a specific five-in-one fixed dose combination polypill created by Cadila Pharmaceuticals Limited of Ahmedabad, India that combines moderate levels of five different medications in a single, one-a-day pill aimed at reducing/preventing heart attacks and strokes.

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Polycap containing three generic blood pressure medications and a statin dramatically reduces the risk of heart-related illness in people with no prior history of heart problems, according to the results of a recent clinical trial presented at the American Heart Association’s Scientific Sessions 2020.

This result comes as part of the International Polycap Study (TIPS)-3, a randomized, placebo-controlled trial to test the effectiveness of this fixed-dose combination therapy. The study investigators also examined the impact of aspirin alone and in combination with the polypill. When taken on its own, Polycap reduces by 20% the risk of heart attack, stroke, procedures to reopen clogged arteries and other heart disease, the researchers reported. The Polycap combined with daily low-dose aspirin is even more effective, reducing heart health problems by up to 40%. The study results were published online in the New England Journal of Medicine . [1]

Polycap combines 100 milligrams of aspirin, with simvastatin (a generic version of Zocor, the cholesterol-lowering statin; 20 mg) and low doses of three blood pressure medications, beta blocker atenolol (50 mg), ACE inhibitor ramipril (5 mg) and diuretic hydrochlorothiazide (12.5 mg). And despite containing multiple drugs, the pill has a fairly small size which can facilitate swallowing. [2]

The International Polycap Study - 3 (TIPS-3)

The International Polycap Study 3 (TIPS-3) was a 2x2x2 factorial design study presented in two parts during the late-breaking clinical trial session. In TIPS-3, investigators randomized 5713 participants across 9 countries to determine if a fixed-dose combination tablet reduced the risk of major cardiovascular outcomes in a primary prevention population. As part of the factorial design, the additional interventions included aspirin alone compared with placebo as well as polypill plus aspirin compared with double placebo.

To be included in the study, patients had to be at intermediate risk for myocardial infarction, stroke, and cardiovascular death. The participants’ average age was 64 years. Men 50 years and older and women 55 years and older with an INTERHEART risk score ≥ 10 (or men and women 65 years and older with an INTERHEART risk score ≥ 5) were included in the international study. Roughly 53% of study participants were women. Mean LDL cholesterol level and systolic blood pressure at baseline were 121 mg/dL and 144.5 mm Hg, respectively. [3] For the trial, participants were randomly assigned to one of four groups. They were asked to take one of the following daily: both the polypill and aspirin, the polypill alone, aspirin alone, or only a placebo. The top-enrolling countries were India, the Philippines, Columbia, and Bangladesh; Canada enrolled 131 patients. [3]

Medications included in the polypill were atenolol, 100 mg; ramipril, 10 mg; hydrochlorothiazide, 25 mg; and simvastatin, 40 mg.

Only 4.4% of those who took the polypill alone had a heart attack, stroke, artery-reopening procedure or died of heart disease, compared to 5.5% who took the placebo. About 4.1% of those who took aspirin alone developed heart-related illness, compared to 4.7% of those with the placebo.

Combining a polypill with aspirin provided the best benefits, the study authors said. The polypill/aspirin combination reduced heart problems and deaths by 31%, the researchers discovered. People who continued to take the pill without interruption for about four years saw a 40% reduced risk of heart problems. [4]

The trial included a follow-up period of 5 years. During which, participants were monitored for nonfatal myocardial infarctions, nonfatal strokes, heart failure, cardiac arrest, and cardiovascular death.

The study was 95% funded by charitable organizations like the Wellcome Trust UK , parent company Cadila Pharmaceuticals and other government agencies.

The Indian Polycap Study (TIPS)

A study called The Indian Polycap Study (TIPS) was sponsored by Cadila Pharmaceuticals Limited, (where the drug development program was coordinated by JP Parswani, President, and Dr. Arun Maseeh, Vice-President Medical Affairs), and led by Dr. Salim Yusuf of McMaster University in Hamilton, Ontario, and Dr. Prem Pais of St. John's Medical College in Bangalore, India. The results of the randomized, controlled, double-blind study, reported in March 2009 at an American College of Cardiology conference and published online by The Lancet , documented the outcome of 2,000 individuals with an average age of 54 given the medication, all of whom had at least one heart disease risk factor: diabetes, hypercholesterolemia, hypertension, obesity or smoking. [2] The study was registered with ClinicalTrials.gov, number NCT00443794. [5]

During a 12-week treatment period, 400 of the study participants were given Polycap. The remainder were divided into eight groups of 200 who were given either individual components or groups of them. [2] Three of the groups of 200 received only aspirin, simvastatin or thiazide respectively; Three groups received two of the three blood pressure medications; Another received all three blood pressure medications, while the last received all three combined with aspirin. [6]

The individuals who were given Polycap saw their blood pressure drop from six to seven points for both their systolic and diastolic levels. These reductions in blood pressure could cut the risk of heart disease by 62% and of stroke by 48% based on the results of other studies that showed risk reductions from cutting blood pressure levels. The combined pill was almost as effective as the individual pills with no increase in side effects. [2]

Generic versions of the five components cost $17 per month in the United States as of 2009. Estimates are that the combined dose would sell for far less while offering the psychological benefit of reducing the "pill burden" on patients taking multiple medications. Distribution would require approval by the U.S. Food and Drug Administration and other regulatory bodies worldwide. [2] Details of the polycap data were widely reported in the popular media, including USA Today, The Guardian (UK), BBC, CBS Healthwatch, ABC News, India Today.

Polycap PK Study

The Polycap (Cadila) has been found to be safe and effective for reducing multiple cardiovascular risk factors. Bioavailability of each component of PolycapTM and absence of their mutual interaction relative to single component reference formulations have been evaluated by a group of scientists led by Dr. Bhaswat Chakraborty. [7]

Bioavailability of the components of the Polycap (aspirin, ramipril, simvastatin, atenolol and hydrochlorothiazide) when formulated as a single capsule was compared to identical capsules with each of its components administered separately in a five arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least 2 week washout period in a total of 195 healthy humans. Plasma concentrations of each drug and where applicable its active metabolite were measured using validated LC-MS/MS and UPLC. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte. Comparative bioavailability and absence of drug-drug interaction for each component were computed based on a point estimate of test/reference (T/R) ratio of geometric means falling within 80-125% for Cmax, AUC0-t and AUC0-∞. [7]

The ratio of Cmax, AUC0-t and AUC0-∞ for Polycap and reference drugs was within 80-125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose normalized salicylic acid. However, for simvastatin the point estimate of Cmax, AUC0-t and AUC0-∞ for Ln-transformed data were significantly lower (~25%) and for its active metabolite, simvastatin acid, it was significantly higher (~60%). Thus, the increased bioavailability of active simvastatin acid compensated for the loss of bioavailability of simvastatin alone. There was no indication of kinetic drug-drug interaction in any of components. [7]

Related Research Articles

Aspirin Medication to reduce pain, fever, and inflammation

Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.

Heart Protection Study

The Heart Protection Study was a randomized controlled trial run by the Clinical Trial Service Unit, and funded by the Medical Research Council (MRC) and the British Heart Foundation (BHF) in the United Kingdom. It studied the use of the cholesterol lowering drug, simvastatin 40 mg and vitamin supplementation in people who were at risk of cardiovascular disease. It was led by Jane Armitage, an epidemiologist at the Clinical Trial Service Unit.

Hydrochlorothiazide Diuretic medication

Hydrochlorothiazide is a diuretic medication often used to treat high blood pressure and swelling due to fluid build up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is less effective than chlortalidone for prevention of heart attack or stroke. HCTZ is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

Atorvastatin Cholesterol-lowering medication

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

Simvastatin Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

Amlodipine Dihydropyridine Calcium Channel Blocker used to Treat Cardiovascular Diseases

Amlodipine is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. While not typically recommended in heart failure, amlodipine may be used if other medications are not sufficient for treating high blood pressure or heart-related chest pain. It is taken by mouth and has an effect that lasts for at least a day.

Chlortalidone Chemical compound

Chlortalidone, also known as chlorthalidone, is a diuretic medication used to treat high blood pressure, swelling including that due to heart failure, liver failure, and nephrotic syndrome, diabetes insipidus, and renal tubular acidosis. In high blood pressure it is a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

Ramipril ACE inhibitor

Ramipril, sold under the brand name Altace among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

A polypill is a medication that is a drug product in pill form that combines multiple active pharmaceutical ingredients. The prefix "poly" means "multiple", referring to the multiplicity of distinct drugs in a given "pill". An occasional synonym is combopill. It is commonly manufactured as a fixed-dose combination (FDC) drug product targeting treatment or prevention of chronic disease. Polypills may be aimed to be consumed by healthy people as a means of preventive medicine, and/or treating actual pathophysiological condition(s), the former typically involving lower dosages than the latter. Polypills can reduce the number of tablets or capsules that need to be taken, which in turn may facilitate handling and administration of pharmaceuticals as well as alleviate patient pill-burden. Sometimes the multiple drugs in a given polypill might all be aimed at a single underlying condition, partly because this expands the pool of potential patients for whom a given combination of drugs/dosages might be appropriate. The term polypill was first coined in the context of cardiovascular disease prevention, but has since gained broader acceptance, including now for combinatorial drug products that existed before the term was actually coined.

Losartan Blood pressure medication

Losartan, sold under the brand name Cozaar among others, is a medication used to treat high blood pressure. It is also used for diabetic kidney disease, heart failure, and left ventricular enlargement. It is taken by mouth. It may be used alone or in addition to other blood pressure medication. Up to six weeks may be required for the full effects to occur.

Valsartan

Valsartan, sold under the trade name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination valsartan/hydrochlorothiazide, valsartan/amlodipine, valsartan/amlodipine/hydrochlorothiazide, or valsartan/sacubitril.

Olmesartan

Olmesartan, sold under the trade name Benicar among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination olmesartan/hydrochlorothiazide and olmesartan/amlodipine.

Perindopril High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

Nebivolol

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

The Thrombolysis In Myocardial Infarction, or TIMI Study Group, is an Academic Research Organization (ARO) affiliated with Brigham and Women's Hospital and Harvard Medical School dedicated to advancing the knowledge and care of patients suffering from cardiovascular disease. The TIMI Study Group provides robust expertise in the key aspects of a clinical trial, including academic leadership, global trial management, biostatistics, clinical event adjudication, safety desk, medical hotline, and core laboratories. The group has its headquarters in Boston, Massachusetts.

Vorapaxar

Vorapaxar is a thrombin receptor antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co.

Valsartan/hydrochlorothiazide

Valsartan/hydrochlorothiazide, sold under the brand name Diovan HCT among others, is an medication used to treat high blood pressure when valsartan is not sufficient. It is a combination of valsartan, an angiotensin receptor blocker with hydrochlorothiazide, a diuretic. It is taken by mouth.

The PolyIran study is a pragmatic open-labeled randomized trial being conducted within Golestan cohort study (GCS) on 31000 subjects in 305 villages of Golestan Province, northeastern Iran. The pill used in this study namely "Polypill", has been successfully evaluated in a pilot study and consists of 4 components. It is estimated to decrease the death rate due to myocardial infarction and stroke by 30-53%. Participants were enrolled to the study during February 2011 and April 2013. The study will directly evaluate effect of Polypill tablet on cardiovascular death and hospitalizations compared to life style modification during 5 years of follow-up; unlike most of the studies that only investigate the impact of Polypill on indirect surrogate markers of cardiovascular diseases such as blood pressure or lipid profile. The study includes three arms. The first and largest arm are being just followed and receive no particular care other than care provided by governmental health system in Iran. The second arm receive recommendation about healthy lifestyle in face to face interviews and pamphlets, undergo blood pressure measurements in 6 months regular intervals and are referred to secondary or tertiary medical centers for treatment upon necessity(minimal care arm). The third arm receive Polypill once daily in addition to care provided to minimal care arm. In case of a substantial decrease in mortality in Polypill arm at the end of the study, Polypill might be offered to all individuals above 50 years old as a cheap preventive alternative for cardiovascular diseases.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

References

  1. ↑ Yusuf, Salim; Joseph, Philip; Dans, Antonio; Gao, Peggy; Teo, Koon; Xavier, Denis; López-Jaramillo, Patricio; Yusoff, Khalid; Santoso, Anwar; Gamra, Habib; Talukder, Shamim (2020-11-13). "Polypill with or without Aspirin in Persons without Cardiovascular Disease". New England Journal of Medicine. 384 (3): 216–228. doi:10.1056/NEJMoa2028220. ISSN   0028-4793. PMC   7116860 . PMID   33186492.
  2. 1 2 3 4 5 Marchione, Marilynn via Associated Press . "Study says one combo pill does work of five", The Record (Bergen County) , March 31, 2009. Accessed March 31, 2009.
  3. 1 2 "One Pill to Treat Them All: Polycap Strategy Sees Success in TIPS-3". TCTMD.com. Retrieved 2020-12-02.
  4. ↑ Yusuf, Salim & Pais, Prem & Sigamani, Alben & Xavier, Denis & Afzal, Rizwan & Gao, Peggy & Teo, Koon. (2012). Comparison of Risk Factor Reduction and Tolerability of a Full-Dose Polypill (With Potassium) Versus Low-Dose Polypill (Polycap) in Individuals at High Risk of Cardiovascular Diseases The Second Indian Polycap Study (TIPS-2) Investigators. Circulation. Cardiovascular quality and outcomes. 5. 463-71. 10.1161/CIRCOUTCOMES.111.963637.
  5. ↑ Clinical trial number NCT00443794 for "The Indian POLYCAP Study (TIPS)" at ClinicalTrials.gov
  6. ↑ Xavier, Denis; Pais, Prem; Sigamani, Alben; Pogue, Janice; Afzal, Rizwan; Yusuf, Salim (2008). "The need to test the theories behind the Polypill: Rationale behind the Indian Polycap Study". Nature Clinical Practice Cardiovascular Medicine. 6 (2): 96–97. doi:10.1038/ncpcardio1438. PMID   19104516. S2CID   26305238.
  7. 1 2 3 Patel, Anil; Shah, Tarang; Shah, Gaurang; Jha, Vijay; Ghosh, Chinmoy; Desai, Jagruti; Khamar, Bakulesh; Chakraborty, Bhaswat S (2010). "Preservation of Bioavailability of Ingredients and Lack of Drug-Drug Interactions in a Novel Five-Ingredient Polypill (Polycap™)". American Journal of Cardiovascular Drugs. 10 (2): 95–103. doi:10.2165/11532170-000000000-00000. PMID   20334446. S2CID   31754902.

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