Figure 1
Development and Implementation of Single Pill Combinations for Cardiovascular Disease.
Figure Legend. Milestones in the history of SPC for cardiovascular disease are listed chronologically and separated into two categories: scientific evidence to support the use of SPC in primary and secondary CVD prevention (bottom), and key events towards real-world adoption of SPC (top). The colour coding of the boxes is used to represent the progression in each of the two domains: from trials limited to intermediate outcomes (red) to trials evaluating clinical outcomes (yellow) to systematic meta-analyses (green) for the scientific evidence domain; and from SPC idea conceptualization (red) to manufacturing efforts (yellow) to policy implementation (green) for the real-world adoption domain.
Acronyms: Blood pressure (BP); cardiovascular disease (CVD); essential medicine list (EML); single pill combination (SPC); high-income countries (HIC); low- and middle-income countries (LMIC); low-density lipoprotein (LDL); major adverse cardiovascular events (MACE); randomized controlled trial (RCT); standard of care (SOC).
Table 1
Effects of SPC versus Control in Primary and Secondary CVD Prevention Trials.
| PRIMARY PREVENTION OF CVD* | ||||
|---|---|---|---|---|
| CONTROL GROUP N (%) | SPC GROUP N (%) | HR (95%CI) | p-VALUE | |
| SPC Strategy versus Control (Composite) | ||||
| Randomized | 9,088 | 9,074 | ||
| CV death, MI, stroke, revascularization | 445 (4.9) | 276 (3.0) | 0.62 (0.53–0.73) | <0.0001 |
| CV Death | 227 (2.5) | 144 (1.6) | 0.65 (0.52–0.81) | <0.0001 |
| MI | 139 (1.5) | 70 (0.8) | 0.52 (0.38–0.70) | <0.0001 |
| Stroke | 141 (1.6) | 83 (0.9) | 0.59 (0.45–0.78) | 0.0002 |
| Revascularization | 70 (0.8) | 39 (0.4) | 0.54 (0.36–0.80) | 0.002 |
| SPC Strategy versus Control (Subgroup: SPC with Aspirin)** | ||||
| Randomized | 4,489 | 4,462 | ||
| CV death, MI, stroke, revascularization | 217 (4.8) | 115 (2.6) | 0.53 (0.41–0.67) | <0.0001 |
| CV Death | 114 (2.5) | 58 (1.3) | 0.51 (0.37–0.72) | <0.0001 |
| MI | 89 (2.0) | 42 (0.9) | 0.47 (0.32–0.69) | 0.0001 |
| Stroke | 73 (1.6) | 36 (0.8) | 0.49 (0.32–0.73) | 0.0005 |
| Revascularization | 12 (0.3) | 5 (0.1) | 0.39 (0.13–1.12) | 0.08 |
| SPC Strategy versus Control (Subgroup: SPC without Aspirin)** | ||||
| Randomized | 6,020 | 6,041 | ||
| CV death, MI, stroke, revascularization | 292 (4.9) | 202 (3.3) | 0.68 (0.57–0.81) | <0.0001 |
| CV Death | 149 (2.5) | 110 (1.8) | 0.73 (0.57–0.93) | 0.01 |
| MI | 64 (1.1) | 38 (0.6) | 0.59 (0.39–0.88) | 0.009 |
| Stroke | 91 (1.5) | 57 (0.9) | 0.62 (0.44–0.86) | 0.005 |
| Revascularization | 70 (1.2) | 39 (0.6) | 0.55 (0.37–0.81) | 0.003 |
| SECONDARY PREVENTION OF CVD | ||||
| CONTROL GROUP N (%) | SPC GROUP N (%) | HR (95%CI) | p-VALUE | |
| SPC Strategy versus Standard of Care (Composite) | ||||
| Randomized | 1,229 | 1,237 | ||
| CV death, MI, stroke, revascularization | 156 (12.7) | 118 (9.5) | 0.76 (0.60–0.96) | <0.02 |
| CV Death | 71 (5.8) | 48 (3.9) | 0.67 (0.47–0.97) | – |
| MI | 62 (5.0) | 44 (3.6) | 0.71 (0.48–1.05) | – |
| Stroke | 27 (2.2) | 19 (1.5) | 0.70 (0.39–1.26) | – |
| Revascularization | 28 (2.3) | 27 (2.2) | 0.96 (0.57–1.63) | – |
[i] *Table adapted from Joseph (2021) (23). The table combines data from the three randomized clinical trials that were powered to detect clinical outcomes for the SPC strategy in primary CVD prevention: HOPE-3, PolyIran, and TIPS-3, although PolyIran also included a minority of patients (~10%) with pre-existing CVD.
**Patients from the HOPE-3 trial are not included in the subgroup analyses, as aspirin use was not part of this study.
Locations of enrolling sites for the primary prevention trials: Argentina, Australia, Bangladesh, Brazil, Canada, China, Colombia, Czech Republic, Ecuador, Hungary, India, Indonesia, Iran, Israel, Malaysia, Netherlands, Philippines, Russia, Slovakia, South Africa, South Korea, Sweden, Tanzania, Tunisia, United Kingdom, Ukraine (7, 8, 9).
Locations of enrolling sites for the secondary prevention trials: Czech Republic, France, Germany, Hungary, Italy, Poland, Spain (10).
Table 2
SPCs for CVD with three or more drugs.
| COMBINATIONS | BRAND & MANUFACTURER | COUNTRY OF MANUFACTURE |
|---|---|---|
| 1. Aspirin, simvastatin, ramipril, atenolol, hydrochlorothiazide | “Polycap” by Cadila | India |
| 2. Atorvastatin, perindopril, amlodipine | “Triveram” by Servier | France |
| 3. Aspirin, atorvastatin/simvastatin, ramipril |
| Spain |
| India | |
| India | |
| India | |
| India | |
| 4. Aspirin, atorvastatin, ramipril, metoprolol | “CV-Pill Kit” by Torrent Pharmaceutical “Zycad-4 kit” by Zydus Cadila | India India |
| 5. Aspirin, simvastatin, lisinopril, atenolol | “Red Heart Pill Version 1” by Dr. Reddy’s Laboratories | India |
| 6. Aspirin, losartan, atenolol, and atorvastatin | “Starpill” by Cipla | India |
| 7. Rosuvastatin, candesartan, hydrochlorothiazide | “Polilep” by Lepetit | Argentina |
| 8. Atorvastatin, ramipril, clopidogrel | “Atamra CV kit” by Amra Remedies | India |
| 9. Aspirin, simvastatin, lisinopril, hydrochlorothiazide | “Red Heart Pill Version 2” by Dr. Reddy’s Laboratories | India |
| 10. Aspirin, atorvastatin, hydrochlorothiazide, enalapril | “Polypill-E” by Alborz Darou Pharmaceutical Company | Iran |
| 11. Aspirin, atorvastatin, hydrochlorothiazide, valsartan | “Polypill-V” by Alborz Darou Pharmaceutical Company | Iran |
| 12. Ramipril, Atorvastatin, metoprolol | “Lifepill 3” by Zydus | India |
| 13. Ramipril, Atorvastatin, Aspirin | “Eze Pill” by Welcure Pharma | India |
[i] The data were collected from a previous survey conducted by the WHF (30), and supplemented with those identified in previous literature. Additionally, WHF conducted targeted consultations, which included experts from academia and industry.
Table 3
Roadblocks and Potential Solutions to SPC Implementation for CVDs.
| ACCESS CHALLENGES | ROADBLOCKS | PROPOSED SOLUTIONS |
|---|---|---|
| AVAILABILITY | Limited manufacturing | Financial incentives to attract manufacturers to the market e.g. subsidies, tax breaks, advanced purchase agreements Training and technology transfer programs from current manufacturers to new manufacturers, especially those in LMICs Investment in local manufacturing infrastructure through grants, loans, and partnerships Early engagement of manufacturers with regulatory agencies and technical assistance to manufacturers to navigate regulatory processes Harmonisation of guidelines across different health regulatory agencies |
| Others: Lack of data on need, supply, demand, and price-elasticity; supply chain weaknesses (excessive fragmentation, poor visibility of stock, erratic funding flows, poor governance) | Strengthen data systems and streamline supply chains, through sustainable financing mechanisms | |
| AFFORDABILITY | Higher cost of SPCs | Large scale-pooled procurement at the national or regional level to improve purchasing power and reduce costs* |
| Others: Gaps in health insurance scheme coverage of people with NCDs | Inclusion of SPCs in national insurance coverage or reimbursement lists | |
| ADOPTION | Inconsistent recommendations of SPCs in international and national guidelines and treatment protocols Prescriber inertia | Development of context-specific effectiveness and cost-effectiveness evidence Multi-stakeholder collaborations (e.g. researchers, advocacy organisations, policy makers, professional societies) to support the translation of clinical trial and real-world research evidence into clear policy that is consistent across policy institutions (62). For example, inclusion of SPCs on essential medicines lists and as recommended first line treatment in guidelines/treatment protocols Ongoing capacity strengthening and mentoring initiatives to support healthcare workers to integrate SPCs into existing practices Education and awareness campaigns by professional societies and Ministries of Health aimed at healthcare providers, using evidence (including feedback on prescribing patterns among peers) to show flexibility and benefits of SPCs to healthcare workers and patients |
| Others: Clinical or institutional inertia or barriers and lack of awareness of SPCs among patients | Use of implementation research tools to co-design context-specific implementation strategies in each country Inclusion of all relevant stakeholders (including health workers and pharmacists) in co-production and implementation research studies |
[i] *The recent HEARTS in the Americas initiative of the Pan-American Health Organization may offer some insights for pooled procurement of CVD medications. The initiative included centralised pooled procurement of SPCs for hypertension among several countries in Latin America through a Strategic Fund, aiming to consolidate regional demand and achieve competitively priced long term agreements for procurement of quality generic products (61).