Single-Pill Combination to Improve Hypertension Treatment: Pharmaceutical Industry Development
Abstract
:1. Introduction
2. Data Sources and Study Selection
- The Medline;
- PubMed®;
- The Science Direct;
- The Cochrane Library (a database with systematic reviews).
- CENTRAL clinical trials registry;
- Drugs.com—an international drug information database;
- DrugBank—an international drug information database. The database is used by scientists and healthcare professionals around the world.
- Publications unrelated to beta-blocker and ACE-I combinations (publications on monotherapy were excluded at the beginning);
- Publications on antihypertensive and other drug combinations that are not antihypertensive;
- Publications that describe circumstances that constitute indications for using combinations of the specified medications in a way that is overly vague and imprecise;
- Publications that were published prior to 1980;
- Publication of studies that were not randomized, placebo-controlled, or blinded (not meeting the GCP requirements). Selected publications were qualified in the third step based on the selection criteria applied. The papers included in the review were chosen based on whether the experiment was randomized, placebo-controlled, double-blind, or single-blind. They were carried out in accordance with good clinical practice (GCP) guidelines and designed in accordance with the Helsinki Declaration. In human research, they met medical, bioethical, and scientific requirements.
3. Hypertension Treatment
3.1. β-Adrenergic Receptors Blockers (Beta-Blocker)
3.2. Angiotensin-Converting Enzyme Inhibitors (ACE-I)
3.3. Single-Pill Combination
3.4. Combination Antihypertensive Therapy
- ACE-I + calcium channel blockers;
- ACE-I + thiazide or thiazide-like diuretic;
- ARB + thiazide diuretic;
- ARB + calcium antagonist.
- calcium channel blockers + beta-blocker;
- thiazide-like diuretic + calcium channel blockers;
- beta-blocker + ACE-I;
- thiazide diuretic + vasodilator beta-blocker.
3.5. Rationale of Combining Beta-Blockers with ACE-I
4. Combinations of Antihypertensive Drugs with Other Classes of Drugs
4.1. Combination Treatment of Hypertension and Hyperlipidemia
4.2. Combination Treatment of Hypertension and Blood Coagulation Problems
4.3. Combination Treatment of Hypertension and Diabetes Mellitus Type II
5. Single-Pill Combinations Drugs—Product Overview
6. Pharmacoeconomics
- valsartan/amlodipine;
- valsartan/hydrochlorothiazide;
- indapamide/amlodipine;
- olmesartan/amlodipine;
- amlodipine/valsartan/hydrochlorothiazide;
- atorvastatin/perindopril/amlodipine;
- olmesartan/amlodipine/hydrochlorothiazide.
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Non-Selective β1/β2 Agents | ||||
---|---|---|---|---|
Bucindolol 1 | carteolol | Carvedilol 1,3 | Labetalol 1,3 | nadolol |
Oxeprenolol 2 | Penbutolol 2 | Pindolol 2 | propranolol | timolol |
β1-selective agents | ||||
acebutolol | atenolol | betaxolol | bisoprolol | celiprolol |
esmolol | metoprolol | Nebivolol 3 |
Drugs Directly Inhibit the Activity of the Angiotensin Converting Enzyme | |||
---|---|---|---|
Prodrugs and its active forms | |||
Name of Clinical Trial | Randomized Patients | Studied Drugs | Effect | Literature |
---|---|---|---|---|
EUROPA | 12,218 | Perindopril + beta-blocker | reduced cardiovascular disease and mortality | [32] |
Pol-Fokus | 12,375 | ACE-I + beta-blocker | the most commonly prescribed drug combination | [33] |
Name of Drugs | Date of Approval (FDA) | Date of Approval (DCG) |
---|---|---|
SPC with beta-blockers | ||
Atenolol 50 mg + Nifedipine 20 mg | - | 1990 |
Timolol maleate 25 mg + Hydrochlorothiazide 10 mg | 1981 * | - |
Metoprolol tartrate 50 mg + Hydrochlorothiazide 25 mg | 1984 | 1982 |
Propranolol hydrochloride 40/80 mg + Hydrochlorothiazide 25 mg | 1987 | 1982 |
Propranolol hydrochloride 80 mg + Bendrafluazide 2.5 mg | - | 1982 |
Nadolol 40/80 mg + Bendroflumethiazide 5 mg | 1983 | - |
Acebutolol hydrochloride 200 mg + Hydrochlorothiazide 12.5 mg | - | 1986 |
Labetalol hydrochloride 100/200/300/400 mg + Hydrochlorothiazide 25 mg | 1987 * | - |
Metoprolol tartrate 100/200 mg + Chlorthalidone 25 mg | 1987 * | - |
Atenolol 25/50/100 mg + Chlorthalidone 6.25/12.5/25 mg | 1990 | 2008 |
Betaxolol hydrochloride 5/10 mg + Chlorthalidone 12.5 mg | 1992 * | - |
Pindolol 5/10 mg + Hydrochlorothiazide 25 mg | 1995 * | - |
Atenolol 30 mg + Nitrendipine 10/20 mg | - | 1995 |
Atenolol 25/50 mg + Amlodipine besylate 2.5/5 mg | - | 1996 |
Bisoprolol fumarate 2.5/5/10 mg + Hydrochlorothiazide 6.25 mg | 2000 | 1999 |
Atenolol 50 mg + Lercanidipine 10 mg | - | 2003 |
Nabivolol hydrochloride 5 mg + Hydrochlorothiazide 12.5 mg | - | 2004 |
Atenolol 50 mg + Losartan 50 mg | - | 2005 |
Atenolol 25/50 mg + Hydrochlorothiazide 12.5/25 mg | - | 2005 |
Bisoprolol 2.5/5 mg + Amlodipine 5 mg | - | 2005 |
Metoprolol succinate 25/50/100 mg + Hydrochlorothiazide 12.5 mg | 2006 | 2005 |
Nebivolol hydrochloride 5 mg + Valsartan 80 mg | 2016 * | 2006 |
Nevibolol hydrochloride 5 mg + Amlodipine besylate 5/10 mg | - | 2006 |
Atenolol 25/50 mg + Indapamide 1.5 mg | - | 2007 |
Nebivolol 2.5/5 mg + Indapamide 1.5 mg | - | 2010 |
Metoprolol succinate 25/50 mg + Telmisartan 20/40 mg | - | 2010 |
Carvedilol 6.25/12.5/25 mg + Ivabradine hydrochloride 5/7.5 mg | - | 2018 |
SPC with ACE-I | ||
Enalapril maleate 5/10 mg + Hydrochlorothiazide 12.5/25 mg | 1986 | 1992 |
Captopril 25/50 mg + Hydrochlorothiazide 15/25 mg | - | 1989 |
Benazepril hydrochloride 5/10/20 mg + Hydrochlorothiazide 6.25/12.5/25 mg | 1992 | 1998 |
Fosinopril sodium 10/20 mg + Hydrochlorothiazide 12.5 mg | 1994 | - |
Benazepril hydrochloride 10/20/40 mg + Amlodipine besylate 2.5/5/10 mg | 1995 | 2002 |
Enalapril Maleate 2.5/5 mg + Amlodipine 2.5/5 mg/2.5 | - | 1995 |
Lisinopril 5/10/20 mg + Hydrochlorothiazide 12.5/25 mg | - | 1995 |
Enalapril maleate 5 mg + Felodipine 2.5/5 mg | 1996 | - |
Trandolapril 1/2/4 mg + Verapamil hydrochloride 180/240 mg | 1996 | 2006 |
Ramipril 2.5/5 mg + Hydrochlorothiazide 12.5/25 mg | - | 1996 |
Moexipril hydrochloride 7.5/15 mg + Hydrochlorothiazide 12.5/25 mg | 1997 | - |
Lisinoril 5 mg + Amlodipine besylate 2.5/5 mg | - | 1997 |
Perindopril 2/4 mg + Indepamide 0.625/1.25 mg | - | 1998 |
Quinapril hydrochloride 10/20 mg + Hydrochlorothiazide 12.5/25 mg | 1999 | 2003 |
Ramipril 2.5/5/10 mg + Amlodipine 2.5/5 mg | - | 2003 |
Ramipril 2.5/ 5 mg + Candesartan cilexatil 8 mg | - | 2003 |
Ramipril 2.5/5 mg + Losartan Potassium 50 mg | - | 2003 |
Ramipril 2.5/5 mg + Telmisartan 40 mg | - | 2005 |
Enalapril 2.5/5 mg + Hydrochlorothiazide 12.5 mg | - | 2005 |
Perindopril arginine 3.5/7/14 mg + Amlodipine besylate 2.5/5/10 mg | 2015 | 2007 |
Ramipril 2.5/5 mg + Atorvastatin Calcium 10/20 mg | - | 2007 |
Ramipril 5 mg + Olmesartan medoximil 20/40 mg | - | 2007 |
Ramipril 2.5/5 mg + Metolazone 2.5 mg | - | 2008 |
Ramipril 2.5 mg + Indapamide 1.5 mg | - | 2009 |
SPC with beta-blockers and ACE-I | ||
Metoprolol succinate 25/50 mg + Ramipril 2.5/5 mg | - | 2007 |
Metoprolol 25/50 mg + Ramipril 2.5/5/10 mg + Atorvastatin 10/20 mg | - | 2009 |
Atenolol 50 mg + Ramipril 5 mg + Simvastatin 20 mg + Hydrochlorothiazide 12.5 mg | - | 2009 |
Atenolol 25/50 mg + Lisinopril 5/10 mg + Simvastatin 10/20 mg | - | 2010 |
Bisoprolol 5/10 mg + Perindopril 5/10 mg | Available in EU from 2015 | |
SPC with beta-blockers and/or ACE-I and statins | ||
Metoprolol 25/50 mg + Atorvastatin 10 mg | - | 2010 |
Metoprolol Succinate 25/50 mg + Atorvastatin 10 mg | - | 2008 |
Metoprolol 50/50/25 mg + Atorvastatin 20/10/10 mg + Ramipril 10/5/2.5 mg | - | 2009 |
Simvastatin 20 mg + Ramipril 5 mg + Atenolol 50 mg + HCTZ 12.5 mg + Aspirin 100 mg | - | 2009 |
Metoprolol Succinate 25/50 mg + Atorvastatin 10 mg | - | 2008 |
Atorvastatin 10 mg + Ramipril 5 mg + Aspirin 75/150 mg + Metoprolol 25 mg | - | 2010 |
Aspirin 75 mg + Simvastatin 10/20 mg + Lisinopril 5/10 mg + Atenolol 25/50 mg | - | 2010 |
Atorvastatin Calcium 10 mg + Ramipril 2.5/5 mg | - | 2007 |
Atorvastatin 20 mg + Ramipril 2.5/5 mg | - | 2010 |
SPC with beta-blockers and/or ACE-I and anticoagulant drugs | ||
Simvastatin 20 mg + Ramipril 5 mg + Atenolol 50 mg + HCTZ 12.5 mg + Aspirin 100 mg | - | 2009 |
Atorvastatin 10 mg + Ramipril 5 mg + Aspirin 75/150 mg + Metoprolol 25 mg | - | 2010 |
Metoprolol tartarate 25/50 mg + Clopidogrel 75 mg | - | 2010 |
SPC with beta-blockers and/or ACE-I and antidiabetic drugs | ||
No formulation has been accepted | - | - |
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Paczkowska-Walendowska, M.; Sip, S.; Staszewski, R.; Cielecka-Piontek, J. Single-Pill Combination to Improve Hypertension Treatment: Pharmaceutical Industry Development. Int. J. Environ. Res. Public Health 2022, 19, 4156. https://doi.org/10.3390/ijerph19074156
Paczkowska-Walendowska M, Sip S, Staszewski R, Cielecka-Piontek J. Single-Pill Combination to Improve Hypertension Treatment: Pharmaceutical Industry Development. International Journal of Environmental Research and Public Health. 2022; 19(7):4156. https://doi.org/10.3390/ijerph19074156
Chicago/Turabian StylePaczkowska-Walendowska, Magdalena, Szymon Sip, Rafał Staszewski, and Judyta Cielecka-Piontek. 2022. "Single-Pill Combination to Improve Hypertension Treatment: Pharmaceutical Industry Development" International Journal of Environmental Research and Public Health 19, no. 7: 4156. https://doi.org/10.3390/ijerph19074156
APA StylePaczkowska-Walendowska, M., Sip, S., Staszewski, R., & Cielecka-Piontek, J. (2022). Single-Pill Combination to Improve Hypertension Treatment: Pharmaceutical Industry Development. International Journal of Environmental Research and Public Health, 19(7), 4156. https://doi.org/10.3390/ijerph19074156