- Email: [email protected]
A personalised or procrustean approach to treating hypertension?
Correspondence
Are ACE inhibitors acceptable ingredients in polypills? The Lancet suggested in their Editorial (March 11, p 984)1 that an affordable polypill would be welcomed in the more than 30 million people world wide who do not have access to appropriate secondary prevention. When considering such numbers, balance between benefits and harms becomes exceedingly important. As can be estimated by the number needed to treat, most people taking a polypill for years or decades will never be benefited by it. They nevertheless have to put up with adverse events, which are up to 16% higher (risk ratio 1·16, 95% CI 1·09–1·25) in participants randomly assigned polypills than in those assigned usual care.2 When looking at the ingredients of 15 various polypills in development, we note that 13 contained inhibitors of the angiotensin-converting enzyme (ACE) and only two contained angio tensin receptor blockers (ARBs). 3 Evidence from placebo-controlled trials, active-controlled trials, and head-to-head randomised trials all suggest ARBs are as efficacious and safe as ACE inhibitors, but ARBs have the advantage of better tolerability.4 Adverse events of ACE inhibitors, such as an irritating cough, have been extensively documented. For enalapril, pooled weighted incidence of cough was 11·48% (95% CI 9·54–13·41) and pooled weighted withdrawal rate due to cough was 2·57% (2·40–2·74).5 A much less common adverse event is angio-oedema, which is most prevalent in people with dark skin, and occasionally can be fatal. We estimated that exposing the 30 million people to ACE inhibitors, as The Lancet would welcome, could result in sev e ral hundred fatalities per year.6 Admit tedly, some of these numbers are extrapolations, but they still beg the question of whether ACE inhibitors are acceptable ingredients in polypills. 26
FHM has received personal fees from Menarini, Servier, Pfizer, Ipca, and American College of Cardiology, during the submitted work. SB has received grants and personal fees from Abbott Vascular; and personal fees from Merck, Pfizer, The Medicines Company, AstraZeneca, Daiichi Sankyo, and Boehringer Ingelheim, outside the submitted work. SFR has recevied personal fees from Servier and Menarini, outside the submitted work. JG has received personal fees from Servier and Sanofi Aventis, outside the submitted work. JN declares no competing interests.
*Franz H Messerli, Sripal Bangalore, Stefano F Rimoldi, Jerzy Gąsowski, Juerg Nussberger [email protected] Department of Cardiology, Mount Sinai Hospital, New York, NY 10029, USA (FHM); The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA (SB); Department of Cardiology and Clinical Research, University of Bern, Bern, Switzerland (FHM, SFR); Department of Internal Medicine and Gerontology, Jagiellonian University Kraków, Kraków, Poland (FHM, JG); and Centre Hospitalier Universitaire Vaudois, Lausanne University Hospital, Lausanne, Switzerland (JN) 1 2
3 4
5
6
The Lancet. Polypills: an essential medicine for cardiovascular disease. Lancet 2017; 389: 984. Bahiru E, de Cates AN, Farr MR, et al. Fixed-dose combination therapy for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2017; 3: CD009868. Huffman MD, Xavier D, Perel P. Uses of polypills for cardiovascular disease and evidence to date. Lancet 2017; 389: 1055–65. Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensinconverting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc 2016; 91: 51–60. Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians’ Desk Reference. Am J Med 2010; 123: 1016–30. Messerli FH, Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet 2000; 356: 608–09.
A personalised or procrustean approach to treating hypertension? Clara Chow and colleagues (Feb 9, p 1035)1 advocate initiating hyper tension treatment with combination therapy, using four drugs rather than two, which is currently suggested by some authorities.2 This approach contradicts deprescribing efforts to reduce polypharmacy.
Chow and colleagues1 compared four drugs against placebo, testing the null hypothesis that four drugs known to lower blood pressure individu ally would not lower blood pressure when combined. The small patient cohort (n=18), modest blood pressure elevation at baseline (systolic blood pressure 3·4 mm Hg above ambulatory target), and the observation that 39% of patients reached the ambulatory target with placebo make the results—87% of patients achieved the ambulatory blood pressure target with the four drug combination—seem less impressive. An alternative approach by Dickerson and colleagues3 examined rotation (serial monotherapy) be tween four different drugs in 56 patients with higher initial blood pressure than those included in the study by Chow and colleagues, reporting that 73% of patients reached the target on their best monotherapy (compared with 39% with first drug) and 83% were controlled using only two drugs. Stepped care has been highly effective in controlling blood pressure for large groups of patients in managed care4 in the USA and across Canada (85% of patients treated were controlled).5 The short treatment time and small patient cohort in the study by Chow and colleagues1 do not permit reliable estimates of safety. Smaller doses of individual drugs will have fewer doseassociated adverse effects than larger doses. However, adverse effects that stem from blood pressure lowering, as observed in the SPRINT study,6 might not be reduced by this immediate highly effective combination therapy. Adverse effects that are not doseassociated will only increase as ex posure to additional drugs occurs. Moreover, this approach contradicts the prevailing ideas around person alised medicine, which we advocate should also be adopted in the field of hypertension. GMG reports personal fees from Pfizer and AstraZeneca, outside the submitted work, and was a member of the Australian National Heart Foundation Committee that wrote the 2016 Australian National Blood Pressure Guideline.
www.thelancet.com Vol 390 July 1, 2017
Correspondence
Genevieve M Gabb, Peter G M Mol, *Leonard F Arnolda [email protected] Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia (LFA); Illawarra Shoalhaven Local Health District, Wollongong, NSW, Australia (LFA); Department of Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia (GMG); University of Adelaide, Adelaide, SA, Australia (GMG); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (PGMM); and Dutch Medicines Evaluation Board, Utrecht, Netherlands (PGMM) 1
2
3
4
5
6
Chow CK, Thakkar J, Bennett A, et al. Quarterdose quadruple combination therapy for initial treatment of hypertension: placebocontrolled, crossover, randomised trial and systematic review. Lancet 2017; 389: 1035–42. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens 2014; 32: 3–15. Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 1999; 353: 2008–13. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. Improved blood pressure control associated with a large-scale hypertension program. JAMA 2013; 310: 699–705. Statistics Canada. Blood pressure of adults, 2012 to 2013. 2014. http://www.statcan.gc. ca/pub/82-625-x/2014001/article/14101-eng. htm (accessed March 10, 2017). Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103–16.
Authors’ reply
We agree with the comments of Genevieve M Gabb and colleagues about our study1 with regard to the goals of therapy, but differ in our views on evidence interpretation and strategy in several areas. First, the use of fewer drugs does not necessarily result in fewer side-effects www.thelancet.com Vol 389 July 1, 2017
because of the steep side-effect dose responses observed for most drug classes: standard-dose or high-dose monotherapy could cause more sideeffects than low-dose combination therapy.2 The likelihood of idiosyncratic side-effects, such as anaphylaxis, will increase with more drugs, but these are extremely rare. Second, it is unlikely that mono therapy could achieve similar benefits to combination therapy if person alised medicine is used to select the best monotherapy for each patient. Standard-dose monotherapy reduces blood pressure by 9/5 mm Hg on average2 and if some patients did really achieve twice that benefit (ie, comparable to the effect of low-dose combination therapy1,3), this would imply that an equal number of patients are immune to blood pressure lowering drugs. True interindividual variability is likely to be much lower. Additionally, in view of the signal to noise ratio associated with blood pressure monitoring, the identification of true differences between individuals is not usually possible.4 Without a placebo control, differentiating between true treatment effect and changes that would have happened anyway is practically impossible in clinical trials and clinical practice. Overlooking the role of random variability leads to overestimation of the difference between drugs, which was illustrated in the Dickerson trial.5 In that trial, the comparatively low control rate in the first treatment period was partly because participants had a higher starting blood pressure, whereas starting blood pressure was closer to the target for the three subsequent treatment periods after regression to the mean. Statistically, comparison of the first treatment with the most effective of the subsequent three treatments would be expected to overestimate any true differences, because this would provide three opportunities to get a chance extreme finding. Third, it is implied that all side-effects in the SPRINT trial6 were due to
blood pressure lowering. However, some side-effects might have been due to the use of high doses, which provides minimal additional blood pressure reduction.2 Finally, Gabb and colleagues cite two examples of eventual success with stepped care, even though a key feature of the cited Kaiser Permanente programme 7 was increased use of initial combination therapy. However, these successes are the exception rather than the rule: undertreatment with monotherapy remains a domin ant issue globally and the impact of undertreated high blood pressure on public health is substantial.8 Additional effective, cost-effective, and scalable approaches are needed. Single pill, low-dose combinations hold promise and long-term random ised comparisons with usual care are now required. Some trials are in progress (trial registration numbers: SLCTR/2015/020, NCT01826019, ACTRN12616001144404, and NCT 02710552), but more are needed. CKC and AR report grants from the National Health and Medical Research Council during the conduct of the study; and the George Institute for Global Health received an investment to develop fixed-dose combinations containing aspirin, statin, and blood pressure lowering drugs, and applied for a patent compositions for the treatment of hypertension, on which AR is listed as an inventor, during the conduct of the study. JT received an Australian Postgraduate Award scholarship from the University of Sydney, during the conduct of the study. AB declares no competing interests.
Anthony Rodgers,*Clara K Chow, Jay Thakkar, Alexander Bennett [email protected] The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia (CKC, AR, AB); University of Sydney, Sydney, NSW, Australia (CKC, AR, JT); and Westmead Hospital, Westmead, NSW, Australia (CKC, JT) 1
2
3
Chow CK, Thakkar J, Bennett A, et al. Quarterdose quadruple combination therapy for initial treatment of hypertension: placebocontrolled, crossover, randomised trial and systematic review. Lancet 2017; 389: 1035–42. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003; 326: 1427–31. Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over. PLoS One 2012; 7: e41297.
SciencePhoto
The views expressed in this letter are her personal views and not necessarily those of the Australian National Heart Foundation. PGMM is employed by the Dutch Medicines Evaluation Board, but the views expressed are his personal views and do not necessarily reflect those of the Dutch Medicines Evaluation Board. LFA reports personal fees from Pfizer, outside the submitted work, and was chair of the Australian National Heart Foundation Committee that wrote the 2016 Australian National Blood Pressure Guideline. The views expressed in this letter are his personal views and not necessarily those of the Australian National Heart Foundation.
27
Are ACE inhibitors acceptable ingredients in polypills? The Lancet suggested in their Editorial (March 11, p 984)1 that an affordable polypill would be welcomed in the more than 30 million people world wide who do not have access to appropriate secondary prevention. When considering such numbers, balance between benefits and harms becomes exceedingly important. As can be estimated by the number needed to treat, most people taking a polypill for years or decades will never be benefited by it. They nevertheless have to put up with adverse events, which are up to 16% higher (risk ratio 1·16, 95% CI 1·09–1·25) in participants randomly assigned polypills than in those assigned usual care.2 When looking at the ingredients of 15 various polypills in development, we note that 13 contained inhibitors of the angiotensin-converting enzyme (ACE) and only two contained angio tensin receptor blockers (ARBs). 3 Evidence from placebo-controlled trials, active-controlled trials, and head-to-head randomised trials all suggest ARBs are as efficacious and safe as ACE inhibitors, but ARBs have the advantage of better tolerability.4 Adverse events of ACE inhibitors, such as an irritating cough, have been extensively documented. For enalapril, pooled weighted incidence of cough was 11·48% (95% CI 9·54–13·41) and pooled weighted withdrawal rate due to cough was 2·57% (2·40–2·74).5 A much less common adverse event is angio-oedema, which is most prevalent in people with dark skin, and occasionally can be fatal. We estimated that exposing the 30 million people to ACE inhibitors, as The Lancet would welcome, could result in sev e ral hundred fatalities per year.6 Admit tedly, some of these numbers are extrapolations, but they still beg the question of whether ACE inhibitors are acceptable ingredients in polypills. 26
FHM has received personal fees from Menarini, Servier, Pfizer, Ipca, and American College of Cardiology, during the submitted work. SB has received grants and personal fees from Abbott Vascular; and personal fees from Merck, Pfizer, The Medicines Company, AstraZeneca, Daiichi Sankyo, and Boehringer Ingelheim, outside the submitted work. SFR has recevied personal fees from Servier and Menarini, outside the submitted work. JG has received personal fees from Servier and Sanofi Aventis, outside the submitted work. JN declares no competing interests.
*Franz H Messerli, Sripal Bangalore, Stefano F Rimoldi, Jerzy Gąsowski, Juerg Nussberger [email protected] Department of Cardiology, Mount Sinai Hospital, New York, NY 10029, USA (FHM); The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA (SB); Department of Cardiology and Clinical Research, University of Bern, Bern, Switzerland (FHM, SFR); Department of Internal Medicine and Gerontology, Jagiellonian University Kraków, Kraków, Poland (FHM, JG); and Centre Hospitalier Universitaire Vaudois, Lausanne University Hospital, Lausanne, Switzerland (JN) 1 2
3 4
5
6
The Lancet. Polypills: an essential medicine for cardiovascular disease. Lancet 2017; 389: 984. Bahiru E, de Cates AN, Farr MR, et al. Fixed-dose combination therapy for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2017; 3: CD009868. Huffman MD, Xavier D, Perel P. Uses of polypills for cardiovascular disease and evidence to date. Lancet 2017; 389: 1055–65. Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensinconverting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc 2016; 91: 51–60. Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians’ Desk Reference. Am J Med 2010; 123: 1016–30. Messerli FH, Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet 2000; 356: 608–09.
A personalised or procrustean approach to treating hypertension? Clara Chow and colleagues (Feb 9, p 1035)1 advocate initiating hyper tension treatment with combination therapy, using four drugs rather than two, which is currently suggested by some authorities.2 This approach contradicts deprescribing efforts to reduce polypharmacy.
Chow and colleagues1 compared four drugs against placebo, testing the null hypothesis that four drugs known to lower blood pressure individu ally would not lower blood pressure when combined. The small patient cohort (n=18), modest blood pressure elevation at baseline (systolic blood pressure 3·4 mm Hg above ambulatory target), and the observation that 39% of patients reached the ambulatory target with placebo make the results—87% of patients achieved the ambulatory blood pressure target with the four drug combination—seem less impressive. An alternative approach by Dickerson and colleagues3 examined rotation (serial monotherapy) be tween four different drugs in 56 patients with higher initial blood pressure than those included in the study by Chow and colleagues, reporting that 73% of patients reached the target on their best monotherapy (compared with 39% with first drug) and 83% were controlled using only two drugs. Stepped care has been highly effective in controlling blood pressure for large groups of patients in managed care4 in the USA and across Canada (85% of patients treated were controlled).5 The short treatment time and small patient cohort in the study by Chow and colleagues1 do not permit reliable estimates of safety. Smaller doses of individual drugs will have fewer doseassociated adverse effects than larger doses. However, adverse effects that stem from blood pressure lowering, as observed in the SPRINT study,6 might not be reduced by this immediate highly effective combination therapy. Adverse effects that are not doseassociated will only increase as ex posure to additional drugs occurs. Moreover, this approach contradicts the prevailing ideas around person alised medicine, which we advocate should also be adopted in the field of hypertension. GMG reports personal fees from Pfizer and AstraZeneca, outside the submitted work, and was a member of the Australian National Heart Foundation Committee that wrote the 2016 Australian National Blood Pressure Guideline.
www.thelancet.com Vol 390 July 1, 2017
Correspondence
Genevieve M Gabb, Peter G M Mol, *Leonard F Arnolda [email protected] Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia (LFA); Illawarra Shoalhaven Local Health District, Wollongong, NSW, Australia (LFA); Department of Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia (GMG); University of Adelaide, Adelaide, SA, Australia (GMG); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (PGMM); and Dutch Medicines Evaluation Board, Utrecht, Netherlands (PGMM) 1
2
3
4
5
6
Chow CK, Thakkar J, Bennett A, et al. Quarterdose quadruple combination therapy for initial treatment of hypertension: placebocontrolled, crossover, randomised trial and systematic review. Lancet 2017; 389: 1035–42. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens 2014; 32: 3–15. Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 1999; 353: 2008–13. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. Improved blood pressure control associated with a large-scale hypertension program. JAMA 2013; 310: 699–705. Statistics Canada. Blood pressure of adults, 2012 to 2013. 2014. http://www.statcan.gc. ca/pub/82-625-x/2014001/article/14101-eng. htm (accessed March 10, 2017). Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103–16.
Authors’ reply
We agree with the comments of Genevieve M Gabb and colleagues about our study1 with regard to the goals of therapy, but differ in our views on evidence interpretation and strategy in several areas. First, the use of fewer drugs does not necessarily result in fewer side-effects www.thelancet.com Vol 389 July 1, 2017
because of the steep side-effect dose responses observed for most drug classes: standard-dose or high-dose monotherapy could cause more sideeffects than low-dose combination therapy.2 The likelihood of idiosyncratic side-effects, such as anaphylaxis, will increase with more drugs, but these are extremely rare. Second, it is unlikely that mono therapy could achieve similar benefits to combination therapy if person alised medicine is used to select the best monotherapy for each patient. Standard-dose monotherapy reduces blood pressure by 9/5 mm Hg on average2 and if some patients did really achieve twice that benefit (ie, comparable to the effect of low-dose combination therapy1,3), this would imply that an equal number of patients are immune to blood pressure lowering drugs. True interindividual variability is likely to be much lower. Additionally, in view of the signal to noise ratio associated with blood pressure monitoring, the identification of true differences between individuals is not usually possible.4 Without a placebo control, differentiating between true treatment effect and changes that would have happened anyway is practically impossible in clinical trials and clinical practice. Overlooking the role of random variability leads to overestimation of the difference between drugs, which was illustrated in the Dickerson trial.5 In that trial, the comparatively low control rate in the first treatment period was partly because participants had a higher starting blood pressure, whereas starting blood pressure was closer to the target for the three subsequent treatment periods after regression to the mean. Statistically, comparison of the first treatment with the most effective of the subsequent three treatments would be expected to overestimate any true differences, because this would provide three opportunities to get a chance extreme finding. Third, it is implied that all side-effects in the SPRINT trial6 were due to
blood pressure lowering. However, some side-effects might have been due to the use of high doses, which provides minimal additional blood pressure reduction.2 Finally, Gabb and colleagues cite two examples of eventual success with stepped care, even though a key feature of the cited Kaiser Permanente programme 7 was increased use of initial combination therapy. However, these successes are the exception rather than the rule: undertreatment with monotherapy remains a domin ant issue globally and the impact of undertreated high blood pressure on public health is substantial.8 Additional effective, cost-effective, and scalable approaches are needed. Single pill, low-dose combinations hold promise and long-term random ised comparisons with usual care are now required. Some trials are in progress (trial registration numbers: SLCTR/2015/020, NCT01826019, ACTRN12616001144404, and NCT 02710552), but more are needed. CKC and AR report grants from the National Health and Medical Research Council during the conduct of the study; and the George Institute for Global Health received an investment to develop fixed-dose combinations containing aspirin, statin, and blood pressure lowering drugs, and applied for a patent compositions for the treatment of hypertension, on which AR is listed as an inventor, during the conduct of the study. JT received an Australian Postgraduate Award scholarship from the University of Sydney, during the conduct of the study. AB declares no competing interests.
Anthony Rodgers,*Clara K Chow, Jay Thakkar, Alexander Bennett [email protected] The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia (CKC, AR, AB); University of Sydney, Sydney, NSW, Australia (CKC, AR, JT); and Westmead Hospital, Westmead, NSW, Australia (CKC, JT) 1
2
3
Chow CK, Thakkar J, Bennett A, et al. Quarterdose quadruple combination therapy for initial treatment of hypertension: placebocontrolled, crossover, randomised trial and systematic review. Lancet 2017; 389: 1035–42. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003; 326: 1427–31. Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over. PLoS One 2012; 7: e41297.
SciencePhoto
The views expressed in this letter are her personal views and not necessarily those of the Australian National Heart Foundation. PGMM is employed by the Dutch Medicines Evaluation Board, but the views expressed are his personal views and do not necessarily reflect those of the Dutch Medicines Evaluation Board. LFA reports personal fees from Pfizer, outside the submitted work, and was chair of the Australian National Heart Foundation Committee that wrote the 2016 Australian National Blood Pressure Guideline. The views expressed in this letter are his personal views and not necessarily those of the Australian National Heart Foundation.
27