Canadian Journal of Cardiology 30 (2014) 513e516
Point/Counterpoint
A Single Fixed-Dose Combination for All Patients Is Bad Medicine J. David Spence, MD, FRCPCa,b,c a
Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada b
c
Robarts Research Institute, London, Ontario, Canada
Division of Neurology, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
See article by Feldman and Nattel, pages 517-519 of this issue. ABSTRACT
RESUM E
It has been proposed that cardiovascular risk could be markedly reduced by prescribing a single daily pill to all patients at risk. This concept is bad medicine, because each constituent has problems, and the problems are different for each patient. A key principle of clinical pharmacology is individualization of therapy. Patients are not all the same, so a single polypill cannot work for all of them. For patients with resistant hypertension, at least 3 different versions would be needed for patients with different causes of hypertension, and even then not one pill would be suitable for all patients.
te avance que le risque cardiovasculaire pourrait nettement être Il a e duit en prescrivant une pilule à prise monoquotidienne à tous les pare s à un risque. On ne peut pas dire que ce concept relève de tients expose decine puisque chaque composant pre sente des probla bonne me rents d’un patient à l’autre. Un lèmes, et que les problèmes sont diffe de la pharmacologie clinique est l’individualisation du principe cle tant tous diffe rents, une seule polypilule ne traitement. Les patients e peut fonctionner pour tous. En ce qui concerne les patients souffrant rielle re fractaire, au moins 3 versions diffe rentes d’une hypertension arte cessaires chez ceux dont les causes d’hypertension arte rielle seraient ne jà une seule pilule ne conviendrait pas à tous les patients. diffèrent, et de
Wald and Law first proposed in 20031 that a single polypill containing a combination of fixed doses of a number of drugs for cardiovascular prevention could markedly reduce cardiovascular risk. This concept has engendered much discussion, including proposals that exercise or diet would be more appropriate, and concerns about cost-effectiveness and the difficulties of regulatory approval. These discussions have led to calls for action, and clinical trials2-4 that showed some promise. Unfortunately, the very construct is wrong: a single pill cannot and will not be best for all patients. A fundamental principle of clinical pharmacology is individualization of therapy: the right treatment, in the right dose, in the right regimen, for each individual. This is the basis of personalized medicine, an approach that shows increasing promise with the advent of genomic chips that can scan a large number of polymorphisms determining absorption, distribution, and metabolism of drugs, and response to drugs.
Even without resorting to genomic chips, it is possible to individualize much of cardiovascular therapy on the basis of clinical features and readily available laboratory tests. Table 1 shows the constituents of the polypill described by Wald and Law,1 the Polycap Plus that was used by Yusuf and colleagues in a clinical trial,3 and the polypill used by Thom et al.4 in the UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) trial. As detailed herein, there are problems with each and every one of these constituents, for some patientsdand importantly, the problems are not the same for each individual patient.
Received for publication December 2, 2013. Accepted January 29, 2014. Corresponding author: Dr J. David Spence, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, 1400 Western Rd, London, Ontario N6G 2V2, Canada. Tel.: þ1-519-931-5731; fax: þ1-519-931-5737. E-mail: [email protected] See page 515 for disclosure information.
Problems With b-Blockers All b-receptor antagonists (b-blockers) in clinical use cause adverse events due to blockade of the b-1 receptord bradycardia and impairment of ventricular contraction that can cause or aggravate heart failure. In addition, the nonselective b-blockers (propranolol, nadolol, timolol) cause adverse effects due to blockade of b-2 receptorsdimpaired muscle blood flow, cold extremities, and impairment of metabolism of glucose and lipids (an increase in cholesterol and triglycerides and a reduction of high-density lipoprotein cholesterol). Even the so-called “cardioselective” b-blockers (metoprolol, atenolol, bisoprolol) might cause b-2 blockade at high doses or blood levels; they are only relatively cardioselective.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2014.01.018
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Table 1. Examples of polypills Wald and Law1* Simvastatin 40 mg Metoprolol 50 mg HCTZ 12.5 mg Enalapril 10 mg Aspirin 75 mg Folic acid 0.8 mg
Polycap Plus3
UMPIRE trial4
Simvastatin 20 mg Atenolol 50 mg HCTZ 12.5 mg Ramipril 5 mg Aspirin 100 mg Potassium 30 mEq
Simvastatin 40 mg Atenolol 50 mg (or HCTZ) HCTZ 12.5 mg (or atenolol) Lisinopril 10 mg Aspirin 75 mg
ACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide; UMPIRE, Use of a Multidrug Pill in Reducing Cardiovascular Events. * Individual b-blocker and ACE inhibitor were not specified; likely choices have been selected based on cost and availability as generic drugs.
For metoprolol in particular, there are serious problems relating to copy number variants of cytochrome P450 2D6 (CYP2D6), resulting in huge interindividual differences in metabolism. Only 17% of patients are average or intermediate metabolizers, 75% fast metabolizers, 3.3% ultraslow, and 3% ultrafast metabolizers5; the result is that for a given dose of metoprolol, the range in blood levels is 150-fold (Fig. 1). It is therefore impossible for a single fixed dose to be the right dose for all or even most patientsdindeed metoprolol should probably be avoided because of this problem. Furthermore, metoprolol is short-acting and requires twice-daily dosing; also because of the short action it has the highest potential for rebound hypertension. A better choice to avoid rebound hypertension would be pindolol, which is so tightly bound to receptors that its action lasts nearly a week.6 Because pindolol is a blocker of b-1 receptors but an agonist at b-2 receptors,7 it also has advantages with regard to adverse effects due to blockade of b-2 receptors: asthma, reduced muscle blood flow, and metabolism of glucose and lipids. It might cause
Figure 1. Interindividual variation in metabolism of metoprolol. Because of copy number variants of CYP2D6 there are huge differences between individuals in how they metabolize metoprolol. The range of blood levels achieved is 150-fold, and fewer than 20% of patients are “average metabolizers.” For this reason, it is virtually impossible to dose metoprolol correctly; so metoprolol is not a good choice for b-blockade. CYP2D6, cytochrome P450 2D6. Drawn from data reported by Fux et al.5
vivid dreams and tremor because it is concentrated in the brain. Like nadolol, atenolol is renally excreted, so accumulates in elderly patients and patients with impaired renal function. The resultant bradycardia might aggravate heart failure, cause physical fatigue, and impaired exercise tolerance, and raise systolic blood pressure in elderly patients (because the high stroke volume resulting from bradycardia, when dumped into stiff arteries, widens pulse pressure). The killer, however, for b-blockers in a polypill, is that approximately 7% of the population are asthmatic, and for them b-blockers are contraindicated. Thiazide Diuretics Thiazide diuretics are sulfonamides; they can therefore not be taken by patients with porphyria, and might be dangerous for patients with sulfonamide sensitivity (although the low dose might be tolerable for most patients, because sulfonamide sensitivity is not an allergy, but a hereditary abnormality of sulfonamide metabolism resulting in toxic metabolites). Thiazides also aggravate depletion of potassium, magnesium, and other ions, and depletion of potassium aggravates insulin resistance and diabetes. Thiazides also aggravate gout. Thiazides are therefore not suited for all patients. Aspirin Although low-dose acetylsalicylic acid is usually well tolerated, it might cause gastritis and gastrointestinal hemorrhage, and is contraindicated in patients with nasal polyp/ asthma syndrome. Rarely patients are allergic to aspirin. Statins (Hydroxymethylglutaryl Acyl Coenzyme A Reductase Inhibitors) Statins cause depletion of coenzyme Q10 (CoQ10), resulting in impaired mitochondrial function, with myopathy and an increased risk of diabetes.8 Some patients are predisposed genetically to statin intolerance, either because of polymorphisms affecting statin absorption, distribution, or metabolism, or because of genetic disorders causing mitochondrial dysfunction with a lower threshold for dysfunction resulting from CoQ10 deficiency.9 Simvastatin and lovastatin are particularly problematic, because during absorption, 95% of the drug is metabolized by intestinal CYP3A4 (ie, they are only 5% bioavailable). Simvastatin levels increase 15-fold with grapefruit10 or other inhibitors of intestinal CYP3A4, and rhabdomyolysis has resulted from simvastatin within 4 days of beginning to consume 1 grapefruit daily.11 This means that simvastatin and lovastatin are subject to huge interactions by inhibitors of intestinal CYP3A4, such as grapefruit, erythromycin, clarithromycin, itraconazole, ketoconazole, and other drugs. Although pharmacists might detect problem drug interactions, grocers seldom take a drug history before dispensing grapefruit, so simvastatin is not a safe drug. If a statin were to be used in a polypill it should not be simvastatindrosuvastatin or pravastatin might be betterdbut in any case not all patients can take statins. High-dose statins increase the risk of diabetes,12 so to minimize adverse effects of statins it would be better, in a polypill intended for use on a population basis, to use a low dose of a statin along with ezetimibe
J. David Spence A Polypill is Bad Medicine
(which achieves the same lowering of low-density lipoprotein as high-dose statins, without the adverse effects). Problems With Angiotensin-Converting Enzyme Inhibitors Ramipril and enalapril are both short-acting, so a better angiotensin-converting enzyme (ACE) inhibitor would be perindopril; however, there are problems with ACE inhibitors in general. ACE inhibitors cause a cough in approximately 8% of patients, and rarely cause angioedema. Cough and angioedema are probably due to increased levels of bradykinin; patients with abnormalities of bradykinin metabolism are more susceptible.13 In the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial, amlodipine was better tolerated than lisinopril,14 and was more effective in preventing stroke.15 Long-term persistence with ACE inhibitors is less than that with angiotensin receptor antagonists (ARBs).16 ARBs would be a better choice than ACE inhibitors in a polypill, but there is a still more important problem. The assumption that all patients with hypertension would respond equally well to the same medication is based on the notion that all patients have the same cause of their hypertension, and this is simply not the case. Among patients with resistant hypertension, 20% have primary aldosteronism17,18 (mainly due to bilateral hyperplasia, so this is mainly a medical condition, not surgical).19 For these patients, an aldosterone antagonist is the best therapy, not only to control hypertension, but to reduce the risk of cardiovascular consequences of aldosterone, independent of blood pressure.20 Variants of Liddle syndrome, a renal tubular sodium channel mutation, are the cause of 5%-7% of hypertension, and for that condition amiloride is the specific treatment.21 Both primary aldosteronism and Liddle variants are more common in patients of African origin22; these conditions can be identified, and appropriate individualized therapy chosen, by measuring plasma renin and aldosterone, and interpreting the results appropriately in the light of the medications being taken at the time of blood sampling (Supplemental Table S1).22 At least 3 different kinds of polypill would be needed (see the section, A Better Way of the Supplemental Material), and even then not one pill would be suitable for all patients.
515
without a commensurate improvement in blood pressure.27 When potassium depletion occurs, hydrogen ions are exchanged for potassium ions, so acid urine (avoiding the postprandial alkaline tide) is a better indicator of whole body potassium depletion than serum potassium.26 A better approach than potassium supplementation, which mainly increases urinary potassium, is to prevent urinary potassium losses using the algorithm already described for individualized therapy of resistant hypertension. For patients with low renin and high aldosterone, aldosterone antagonists are best28; for those with low renin and aldosterone, amiloride (a potassium and magnesium-sparing diuretic) is best; for those with secondary hyperaldosteronism, an ARB or aliskiren would be best. Conclusions At least 3 different combination tablets would be needed, and even then not all patients could take them. What would be even better would be a machine that would permit dialing in the individual therapy for each patient, in a single daily tablet or capsule. The notion that a single daily fixed-dose combination is suited to every patient is bad medicine. Disclosures Dr Spence has received grants from the Canadian Institutes for Heath Research, Heart and Stroke Foundation, and the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Lecture honoraria/travel support/consulting fees were provided by Sanofi-Synthelabo, Novartis, Bayer, Merck, and Boehringer-Ingelheim. Research support for investigator-initiated projects was provided by Pfizer Inc (substantial donation in kind of medication to support Heart and Stroke Foundation grant for clinical trial) and Merck (small funds to support a summer research student). Contract research was conducted with all of these pharma companies and Takeda Pharmaceuticals, BristolMyers Squibb, Servier, Wyeth, Miles, Roussel-Uclaf, NMT Medical Inc, Amplatzer, and Gore. Dr Spence is a shareholder and officer of Vascularis Inc. References 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% [errata in 2003;327:586, 2006;60:823]. BMJ 2003;326:1419.
Potassium Supplements There are problems also with potassium supplements, which can cause gastrointestinal irritation. A patient of a clinical pharmacology colleague had erosion of a Slow-K tablet into the wall of the esophagus, at the site where the esophagus was indented by an enlarged left atrium. More importantly, potassium supplements do not restore intracellular potassium unless given with magnesium.23-25 There are better ways to correct or prevent potassium depletion. Whole body potassium depletion is the important issue, not hypokalemia, because serum potassium is very weakly correlated with whole body potassium.26 Sodium restriction is important, because potassium is excreted into the renal tubule in exchange for sodium ions that are reabsorbed. It is also important to limit doses of thiazides; higher doses cause more adverse effects
2. Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009;373:1341-51. 3. Yusuf S, Pais P, Sigamani A, et al. 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. Circ Cardiovasc Qual Outcomes 2012;5:463-71. 4. Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918-29. 5. Fux R, Morike K, Prohmer AM, et al. Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther 2005;78:378-87.
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6. Rangno RE, Langlois S. Comparison of withdrawal phenomena after propranolol, metoprolol, and pindolol. Am Heart J 1982;104:473-8.
18. Clark D 3rd, Ahmed MI, Calhoun DA. Resistant hypertension and aldosterone: an update. Can J Cardiol 2012;28:318-25.
7. Aellig WH, Clark BJ. Is the ISA of pindolol beta 2-adrenoceptor selective? Br J Clin Pharmacol 1987;24(suppl 1):21S-8S.
19. Spence JD. Diagnosis of primary aldosteronism: for medical management, not just surgery. J Hypertens 2009;27:204-5.
8. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8:373-418.
20. de Rita O, Hackam DG, Spence JD. Effects of aldosterone on human atherosclerosis: plasma aldosterone and progression of carotid plaque. Can J Cardiol 2012;28:706-11.
9. Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008;20:648-55.
21. Baker EH, Duggal A, Dong Y, et al. Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension 2002;40: 13-7.
10. Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998;63:397-402. 11. Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004;62:670. 12. Carter AA, Gomes T, Camacho X, et al. Risk of incident diabetes among patients treated with statins: population based study [erratum in 2013;347:f4356]. BMJ 2013;346:f2610. 13. Blais C Jr, Rouleau JL, Brown NJ, et al. Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema. Immunopharmacology 1999;43: 293-302. 14. Messerli FH, Staessen JA. Amlodipine better than lisinopril? How one randomized clinical trial ended fallacies from observational studies. Hypertension 2006;48:359-61. 15. Leenen FH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension 2006;48:374-84. 16. Marentette MA, Gerth WC, Billings DK, Zarnke KB. Antihypertensive persistence and drug class. Can J Cardiol 2002;18:649-56. 17. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51:1403-19.
22. Spence JD. Lessons from Africa: the importance of measuring plasma renin and aldosterone in resistant hypertension. Can J Cardiol 2012;28: 254-7. 23. Dyckner T, Wester PO. Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusions in patients on diuretic treatment. Am Heart J 1979;97:12-8. 24. Dyckner T, Wester PO. Effects of magnesium infusions in diuretic induced hyponatraemia. Lancet 1981;1:585-6. 25. Dyckner T, Wester PO. Intracellular magnesium loss after diuretic administration. Drugs 1984;28(suppl 1):161-6. 26. Brater DC, Morrelli HF. Digoxin toxicity in patients with normokalemic potassium depletion. Clin Pharmacol Ther 1977;22:21-33. 27. Tweeddale MG, Ogilvie RI, Ruedy J. Antihypertensive and biochemical effects of chlorthalidone. Clin Pharmacol Ther 1977;22:519-27. 28. Dyckner T, Wester PO. Effects on muscle electrolytes of potassium and magnesium infusions, spironolactone medication and operation in a case of primary aldosteronism. Acta Med Scand 1979;206:137-40.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.01.018.
Point/Counterpoint
A Single Fixed-Dose Combination for All Patients Is Bad Medicine J. David Spence, MD, FRCPCa,b,c a
Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada b
c
Robarts Research Institute, London, Ontario, Canada
Division of Neurology, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
See article by Feldman and Nattel, pages 517-519 of this issue. ABSTRACT
RESUM E
It has been proposed that cardiovascular risk could be markedly reduced by prescribing a single daily pill to all patients at risk. This concept is bad medicine, because each constituent has problems, and the problems are different for each patient. A key principle of clinical pharmacology is individualization of therapy. Patients are not all the same, so a single polypill cannot work for all of them. For patients with resistant hypertension, at least 3 different versions would be needed for patients with different causes of hypertension, and even then not one pill would be suitable for all patients.
te avance que le risque cardiovasculaire pourrait nettement être Il a e duit en prescrivant une pilule à prise monoquotidienne à tous les pare s à un risque. On ne peut pas dire que ce concept relève de tients expose decine puisque chaque composant pre sente des probla bonne me rents d’un patient à l’autre. Un lèmes, et que les problèmes sont diffe de la pharmacologie clinique est l’individualisation du principe cle tant tous diffe rents, une seule polypilule ne traitement. Les patients e peut fonctionner pour tous. En ce qui concerne les patients souffrant rielle re fractaire, au moins 3 versions diffe rentes d’une hypertension arte cessaires chez ceux dont les causes d’hypertension arte rielle seraient ne jà une seule pilule ne conviendrait pas à tous les patients. diffèrent, et de
Wald and Law first proposed in 20031 that a single polypill containing a combination of fixed doses of a number of drugs for cardiovascular prevention could markedly reduce cardiovascular risk. This concept has engendered much discussion, including proposals that exercise or diet would be more appropriate, and concerns about cost-effectiveness and the difficulties of regulatory approval. These discussions have led to calls for action, and clinical trials2-4 that showed some promise. Unfortunately, the very construct is wrong: a single pill cannot and will not be best for all patients. A fundamental principle of clinical pharmacology is individualization of therapy: the right treatment, in the right dose, in the right regimen, for each individual. This is the basis of personalized medicine, an approach that shows increasing promise with the advent of genomic chips that can scan a large number of polymorphisms determining absorption, distribution, and metabolism of drugs, and response to drugs.
Even without resorting to genomic chips, it is possible to individualize much of cardiovascular therapy on the basis of clinical features and readily available laboratory tests. Table 1 shows the constituents of the polypill described by Wald and Law,1 the Polycap Plus that was used by Yusuf and colleagues in a clinical trial,3 and the polypill used by Thom et al.4 in the UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) trial. As detailed herein, there are problems with each and every one of these constituents, for some patientsdand importantly, the problems are not the same for each individual patient.
Received for publication December 2, 2013. Accepted January 29, 2014. Corresponding author: Dr J. David Spence, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, 1400 Western Rd, London, Ontario N6G 2V2, Canada. Tel.: þ1-519-931-5731; fax: þ1-519-931-5737. E-mail: [email protected] See page 515 for disclosure information.
Problems With b-Blockers All b-receptor antagonists (b-blockers) in clinical use cause adverse events due to blockade of the b-1 receptord bradycardia and impairment of ventricular contraction that can cause or aggravate heart failure. In addition, the nonselective b-blockers (propranolol, nadolol, timolol) cause adverse effects due to blockade of b-2 receptorsdimpaired muscle blood flow, cold extremities, and impairment of metabolism of glucose and lipids (an increase in cholesterol and triglycerides and a reduction of high-density lipoprotein cholesterol). Even the so-called “cardioselective” b-blockers (metoprolol, atenolol, bisoprolol) might cause b-2 blockade at high doses or blood levels; they are only relatively cardioselective.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2014.01.018
514
Canadian Journal of Cardiology Volume 30 2014
Table 1. Examples of polypills Wald and Law1* Simvastatin 40 mg Metoprolol 50 mg HCTZ 12.5 mg Enalapril 10 mg Aspirin 75 mg Folic acid 0.8 mg
Polycap Plus3
UMPIRE trial4
Simvastatin 20 mg Atenolol 50 mg HCTZ 12.5 mg Ramipril 5 mg Aspirin 100 mg Potassium 30 mEq
Simvastatin 40 mg Atenolol 50 mg (or HCTZ) HCTZ 12.5 mg (or atenolol) Lisinopril 10 mg Aspirin 75 mg
ACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide; UMPIRE, Use of a Multidrug Pill in Reducing Cardiovascular Events. * Individual b-blocker and ACE inhibitor were not specified; likely choices have been selected based on cost and availability as generic drugs.
For metoprolol in particular, there are serious problems relating to copy number variants of cytochrome P450 2D6 (CYP2D6), resulting in huge interindividual differences in metabolism. Only 17% of patients are average or intermediate metabolizers, 75% fast metabolizers, 3.3% ultraslow, and 3% ultrafast metabolizers5; the result is that for a given dose of metoprolol, the range in blood levels is 150-fold (Fig. 1). It is therefore impossible for a single fixed dose to be the right dose for all or even most patientsdindeed metoprolol should probably be avoided because of this problem. Furthermore, metoprolol is short-acting and requires twice-daily dosing; also because of the short action it has the highest potential for rebound hypertension. A better choice to avoid rebound hypertension would be pindolol, which is so tightly bound to receptors that its action lasts nearly a week.6 Because pindolol is a blocker of b-1 receptors but an agonist at b-2 receptors,7 it also has advantages with regard to adverse effects due to blockade of b-2 receptors: asthma, reduced muscle blood flow, and metabolism of glucose and lipids. It might cause
Figure 1. Interindividual variation in metabolism of metoprolol. Because of copy number variants of CYP2D6 there are huge differences between individuals in how they metabolize metoprolol. The range of blood levels achieved is 150-fold, and fewer than 20% of patients are “average metabolizers.” For this reason, it is virtually impossible to dose metoprolol correctly; so metoprolol is not a good choice for b-blockade. CYP2D6, cytochrome P450 2D6. Drawn from data reported by Fux et al.5
vivid dreams and tremor because it is concentrated in the brain. Like nadolol, atenolol is renally excreted, so accumulates in elderly patients and patients with impaired renal function. The resultant bradycardia might aggravate heart failure, cause physical fatigue, and impaired exercise tolerance, and raise systolic blood pressure in elderly patients (because the high stroke volume resulting from bradycardia, when dumped into stiff arteries, widens pulse pressure). The killer, however, for b-blockers in a polypill, is that approximately 7% of the population are asthmatic, and for them b-blockers are contraindicated. Thiazide Diuretics Thiazide diuretics are sulfonamides; they can therefore not be taken by patients with porphyria, and might be dangerous for patients with sulfonamide sensitivity (although the low dose might be tolerable for most patients, because sulfonamide sensitivity is not an allergy, but a hereditary abnormality of sulfonamide metabolism resulting in toxic metabolites). Thiazides also aggravate depletion of potassium, magnesium, and other ions, and depletion of potassium aggravates insulin resistance and diabetes. Thiazides also aggravate gout. Thiazides are therefore not suited for all patients. Aspirin Although low-dose acetylsalicylic acid is usually well tolerated, it might cause gastritis and gastrointestinal hemorrhage, and is contraindicated in patients with nasal polyp/ asthma syndrome. Rarely patients are allergic to aspirin. Statins (Hydroxymethylglutaryl Acyl Coenzyme A Reductase Inhibitors) Statins cause depletion of coenzyme Q10 (CoQ10), resulting in impaired mitochondrial function, with myopathy and an increased risk of diabetes.8 Some patients are predisposed genetically to statin intolerance, either because of polymorphisms affecting statin absorption, distribution, or metabolism, or because of genetic disorders causing mitochondrial dysfunction with a lower threshold for dysfunction resulting from CoQ10 deficiency.9 Simvastatin and lovastatin are particularly problematic, because during absorption, 95% of the drug is metabolized by intestinal CYP3A4 (ie, they are only 5% bioavailable). Simvastatin levels increase 15-fold with grapefruit10 or other inhibitors of intestinal CYP3A4, and rhabdomyolysis has resulted from simvastatin within 4 days of beginning to consume 1 grapefruit daily.11 This means that simvastatin and lovastatin are subject to huge interactions by inhibitors of intestinal CYP3A4, such as grapefruit, erythromycin, clarithromycin, itraconazole, ketoconazole, and other drugs. Although pharmacists might detect problem drug interactions, grocers seldom take a drug history before dispensing grapefruit, so simvastatin is not a safe drug. If a statin were to be used in a polypill it should not be simvastatindrosuvastatin or pravastatin might be betterdbut in any case not all patients can take statins. High-dose statins increase the risk of diabetes,12 so to minimize adverse effects of statins it would be better, in a polypill intended for use on a population basis, to use a low dose of a statin along with ezetimibe
J. David Spence A Polypill is Bad Medicine
(which achieves the same lowering of low-density lipoprotein as high-dose statins, without the adverse effects). Problems With Angiotensin-Converting Enzyme Inhibitors Ramipril and enalapril are both short-acting, so a better angiotensin-converting enzyme (ACE) inhibitor would be perindopril; however, there are problems with ACE inhibitors in general. ACE inhibitors cause a cough in approximately 8% of patients, and rarely cause angioedema. Cough and angioedema are probably due to increased levels of bradykinin; patients with abnormalities of bradykinin metabolism are more susceptible.13 In the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial, amlodipine was better tolerated than lisinopril,14 and was more effective in preventing stroke.15 Long-term persistence with ACE inhibitors is less than that with angiotensin receptor antagonists (ARBs).16 ARBs would be a better choice than ACE inhibitors in a polypill, but there is a still more important problem. The assumption that all patients with hypertension would respond equally well to the same medication is based on the notion that all patients have the same cause of their hypertension, and this is simply not the case. Among patients with resistant hypertension, 20% have primary aldosteronism17,18 (mainly due to bilateral hyperplasia, so this is mainly a medical condition, not surgical).19 For these patients, an aldosterone antagonist is the best therapy, not only to control hypertension, but to reduce the risk of cardiovascular consequences of aldosterone, independent of blood pressure.20 Variants of Liddle syndrome, a renal tubular sodium channel mutation, are the cause of 5%-7% of hypertension, and for that condition amiloride is the specific treatment.21 Both primary aldosteronism and Liddle variants are more common in patients of African origin22; these conditions can be identified, and appropriate individualized therapy chosen, by measuring plasma renin and aldosterone, and interpreting the results appropriately in the light of the medications being taken at the time of blood sampling (Supplemental Table S1).22 At least 3 different kinds of polypill would be needed (see the section, A Better Way of the Supplemental Material), and even then not one pill would be suitable for all patients.
515
without a commensurate improvement in blood pressure.27 When potassium depletion occurs, hydrogen ions are exchanged for potassium ions, so acid urine (avoiding the postprandial alkaline tide) is a better indicator of whole body potassium depletion than serum potassium.26 A better approach than potassium supplementation, which mainly increases urinary potassium, is to prevent urinary potassium losses using the algorithm already described for individualized therapy of resistant hypertension. For patients with low renin and high aldosterone, aldosterone antagonists are best28; for those with low renin and aldosterone, amiloride (a potassium and magnesium-sparing diuretic) is best; for those with secondary hyperaldosteronism, an ARB or aliskiren would be best. Conclusions At least 3 different combination tablets would be needed, and even then not all patients could take them. What would be even better would be a machine that would permit dialing in the individual therapy for each patient, in a single daily tablet or capsule. The notion that a single daily fixed-dose combination is suited to every patient is bad medicine. Disclosures Dr Spence has received grants from the Canadian Institutes for Heath Research, Heart and Stroke Foundation, and the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Lecture honoraria/travel support/consulting fees were provided by Sanofi-Synthelabo, Novartis, Bayer, Merck, and Boehringer-Ingelheim. Research support for investigator-initiated projects was provided by Pfizer Inc (substantial donation in kind of medication to support Heart and Stroke Foundation grant for clinical trial) and Merck (small funds to support a summer research student). Contract research was conducted with all of these pharma companies and Takeda Pharmaceuticals, BristolMyers Squibb, Servier, Wyeth, Miles, Roussel-Uclaf, NMT Medical Inc, Amplatzer, and Gore. Dr Spence is a shareholder and officer of Vascularis Inc. References 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% [errata in 2003;327:586, 2006;60:823]. BMJ 2003;326:1419.
Potassium Supplements There are problems also with potassium supplements, which can cause gastrointestinal irritation. A patient of a clinical pharmacology colleague had erosion of a Slow-K tablet into the wall of the esophagus, at the site where the esophagus was indented by an enlarged left atrium. More importantly, potassium supplements do not restore intracellular potassium unless given with magnesium.23-25 There are better ways to correct or prevent potassium depletion. Whole body potassium depletion is the important issue, not hypokalemia, because serum potassium is very weakly correlated with whole body potassium.26 Sodium restriction is important, because potassium is excreted into the renal tubule in exchange for sodium ions that are reabsorbed. It is also important to limit doses of thiazides; higher doses cause more adverse effects
2. Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009;373:1341-51. 3. Yusuf S, Pais P, Sigamani A, et al. 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. Circ Cardiovasc Qual Outcomes 2012;5:463-71. 4. Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918-29. 5. Fux R, Morike K, Prohmer AM, et al. Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther 2005;78:378-87.
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6. Rangno RE, Langlois S. Comparison of withdrawal phenomena after propranolol, metoprolol, and pindolol. Am Heart J 1982;104:473-8.
18. Clark D 3rd, Ahmed MI, Calhoun DA. Resistant hypertension and aldosterone: an update. Can J Cardiol 2012;28:318-25.
7. Aellig WH, Clark BJ. Is the ISA of pindolol beta 2-adrenoceptor selective? Br J Clin Pharmacol 1987;24(suppl 1):21S-8S.
19. Spence JD. Diagnosis of primary aldosteronism: for medical management, not just surgery. J Hypertens 2009;27:204-5.
8. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8:373-418.
20. de Rita O, Hackam DG, Spence JD. Effects of aldosterone on human atherosclerosis: plasma aldosterone and progression of carotid plaque. Can J Cardiol 2012;28:706-11.
9. Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008;20:648-55.
21. Baker EH, Duggal A, Dong Y, et al. Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension 2002;40: 13-7.
10. Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998;63:397-402. 11. Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004;62:670. 12. Carter AA, Gomes T, Camacho X, et al. Risk of incident diabetes among patients treated with statins: population based study [erratum in 2013;347:f4356]. BMJ 2013;346:f2610. 13. Blais C Jr, Rouleau JL, Brown NJ, et al. Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema. Immunopharmacology 1999;43: 293-302. 14. Messerli FH, Staessen JA. Amlodipine better than lisinopril? How one randomized clinical trial ended fallacies from observational studies. Hypertension 2006;48:359-61. 15. Leenen FH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension 2006;48:374-84. 16. Marentette MA, Gerth WC, Billings DK, Zarnke KB. Antihypertensive persistence and drug class. Can J Cardiol 2002;18:649-56. 17. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51:1403-19.
22. Spence JD. Lessons from Africa: the importance of measuring plasma renin and aldosterone in resistant hypertension. Can J Cardiol 2012;28: 254-7. 23. Dyckner T, Wester PO. Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusions in patients on diuretic treatment. Am Heart J 1979;97:12-8. 24. Dyckner T, Wester PO. Effects of magnesium infusions in diuretic induced hyponatraemia. Lancet 1981;1:585-6. 25. Dyckner T, Wester PO. Intracellular magnesium loss after diuretic administration. Drugs 1984;28(suppl 1):161-6. 26. Brater DC, Morrelli HF. Digoxin toxicity in patients with normokalemic potassium depletion. Clin Pharmacol Ther 1977;22:21-33. 27. Tweeddale MG, Ogilvie RI, Ruedy J. Antihypertensive and biochemical effects of chlorthalidone. Clin Pharmacol Ther 1977;22:519-27. 28. Dyckner T, Wester PO. Effects on muscle electrolytes of potassium and magnesium infusions, spironolactone medication and operation in a case of primary aldosteronism. Acta Med Scand 1979;206:137-40.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.01.018.
